untitled h1
13.3 appendix c modified immune-related

For modified irRC, only target and measurable lesions are taken into account. In contrast to the RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and PHDVXUDEOHQHZOHVLRQVGRHVQRWLQFUHDVHE\ The same method of assessment and the same technique should be used to characterize each identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are displayed below. Overall Responses Derived from Changes in Index, Non-Index, and New Lesions  
| Measurable Response                                                                                        | Non-Measurable Response   | Overall Response   |       |
|------------------------------------------------------------------------------------------------------------|---------------------------|--------------------|-------|
| Using Modified irRC                                                                                        |                           |                    |       |
| Index and New, Measurable                                                                                  | Non-Index Lesions         | New, Non-          |       |
| Lesions (Tumor Burden)¹                                                                                    | Measurable Lesions        |                    |       |
| Decrease 100%                                                                                              | Absent                    | Absent             | irCR² |
| irPR²                                                                                                      |                           |                    |       |
| Decrease 100%                                                                                              | Stable                    | Any                |       |
| Decrease 100%                                                                                              | Unequivocal progression   | irPR²              |       |
| Any                                                                                                        |                           |                    |       |
| Decrease ≥ 30%                                                                                             | Absent / Stable           | Any                | irPR² |
| Decrease ≥ 30%                                                                                             | Unequivocal progression   | Any                | irPR² |
| Decrease < 30% to increase <                                                                               | Absent / Stable           | Any                | irSD  |
| 20%                                                                                                        |                           |                    |       |
| Decrease < 30% to increase <                                                                               | Unequivocal progression   | Any                | irSD  |
| 20%                                                                                                        |                           |                    |       |
| Increase ≥ 20%                                                                                             | irPD                      |                    |       |
| Any                                                                                                        | Any                       |                    |       |
| Decreases assessed relative to baseline                                                                    |                           |                    |       |
| ' Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a second, consecutive |                           |                    |       |  
assessment at least 4 weeks apart (normally it should be done 6 weeks apart).  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| It is recommended that management of immune-mediated adverse events (imAEs)  follows the guidelines presented in this table:   | í It is possible that events with an inflammatory or immune mediated        | mechanism could occur in nearly all organs, some of them not noted   | specifically in these guidelines.                                             | í Whether specific immune-mediated events (and/or laboratory indicators of   | such events) are noted in these guidelines or not, patients should be   | thoroughly evaluated to rule out any alternative etiology (e.g., disease   | progression, concomitant medications, and infections) to a possible immune         | mediated event. In the absence of a clear alternative etiology, all such events                       | should be managed as if they were immune related. General   | recommendations follow.   | í Symptomatic and topical therapy should be considered for low-grade (Grade  1 or 2, unless otherwise specified) events.   | í For persistent (>3 to 5 days) low-JUDGH*UDGHRUVHYHUH*UDGH•   | events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent.   | í Some events with high likelihood for morbidity and/or mortality - e.g., myo                                                                                                            | carditis, or other similar events even if they are not currently noted in the   | guidelines - should progress rapidly to high dose IV corticosteroids  (methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if   | clinical suspicion is high and/or there has been clinical confirmation.  Consider, as necessary, discussing with the study physician, and promptly   | pursue specialist consultation.   | í If symptoms recur or worsen during corticosteroid tapering (28 days of   | taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to   |
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| Toxicity Management                                                                                                            | 87                                                                          |                                                                      |                                                                               |                                                                              |                                                                         |                                                                            |         |                                                                                                       |                                                             |                           |                                                                                                                            |   |                                                                           |                                                                                                            |                                                                                 |                                                                                                                                                       |                                                                                                                                                      |                                   |                                                                            |                                                                               |
| Drug administration modifications of study drug/study regimen will be made to                                                  | manage potential immune-related AEs based on severity of treatment-emergent | toxicities graded per NCI CTCAE v4.03.                               | In addition to the criteria for permanent discontinuation of study drug/study | regimen based on CTC grade/severity (table below), permanently discontinue   | study drug/study regimen for the following conditions:                  | x Inability to reduce corticosteroid to a dose RI" mg of prednisone per  day (or equivalent) within 12 weeks after last dose of study drug/study                                                                            | regimen | x Recurrence of a previously experienced Grade 3 treatment-related AE  following resumption of dosing | Grade 1 No dose modification                                | Grade 2 Hold study drug/study regimen dose until Grade 2 resolution to  *UDGH"                           | If toxicity worsens, then treat as Grade 3 or Grade 4.                                                                     | Study drug/study regimen can be resumed once event stabilizes to  *UDGH"DIWHUFRPSOHWLRQRIVWHURLGWDSHU   | Patients with endocrinopathies who may require prolonged or               | continued steroid replacement can be retreated with study  drug/study regimen on the following conditions: | 1. The event stabilizes and is controlled.                                      | 2. The patient is clinically stable as per Investigator or treating                                                                                   | physician's clinical judgement.                                                                                                                      | 3. 'RVHVRISUHGQLVRQHDUHDW" mg/day or equivalent.                                   |                                                                            |                                                                               |  
13.4 APPENDIX D: DOSING MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR IMMUNE-MEDIATED, INFUSIONRELATED, AND NON-IMMUNE–MEDIATED REACTIONS (MEDI4736 MONOTHERAPY OR COMBINATION THERAPY WITH TREMELIMUMAB OR TREMELIMUMAB MONOTHERAPY)1NOVEMBER 2017 VERSIONGeneral ConsiderationsDose Modifications  
í More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) (also refer to the individual sections of the imAEs for specific type of immunosuppressive) should be considered for events not responding to systemic steroids. Progression to use of more potent immunosuppressives should proceed more rapidly in events with high likelihood for morbidity and/or mortality - e.g., myocarditis, or other similar events even if they are not currently noted in the guidelines - when these events are not responding to systemic steroids.í With long-term steroid and other immunosuppressive use, consider need for *Pneumocystis jirovecii* pneumonia (PJP, formerly known as Pneumocystis *carinii* pneumonia) prophylaxis, gastrointestinal protection, and glucose monitoring.í Discontinuation of study drug/study regimen is not mandated for Grade 3/Grade 4 inflammatory reactions attributed to local tumor response (e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). Continuation of study drug/study regimen in this situation should be based upon a benefit-risk analysis for that patient.  
| symptoms, then resume corticosteroid tapering at a slower rate (>28 days of   | taper).                                                                |                                                                    |                                                           |
|-------------------------------------------------------------------------------|------------------------------------------------------------------------|--------------------------------------------------------------------|-----------------------------------------------------------|
| 4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of       |                                                                        |                                                                    |                                                           |
| Toxicity Management                                                           |                                                                        |                                                                    |                                                           |
| General Considerations                                                        | Grade 3 Depending on the individual toxicity, study drug/study regimen | may be permanently discontinued. Please refer to guidelines below. | Grade 4 Permanently discontinue study drug/study regimen. |
| Abbreviated Title: antiPDL1, antiCTLA4 & radiation Version Date: 08/24/2018   | Dose Modifications                                                     |                                                                    |                                                           |  
Grade 3 Depending on the individual toxicity, study drug/study regimen may be permanently discontinued. Please refer to guidelines below.**Grade 4** Permanently discontinue study drug/study regimen.  
Note: FRU*UDGHDV\PSWRPDWLFDP\ODVHRUOLSDVHOHYHOVKROGVWXG\GUXJVWXG\regimen, and if complete work up shows no evidence of pancreatitis, study drug/study regimen may be continued or resumed.Note: Study drug/study regimen should be permanently discontinued in Grade 3 events with high likelihood for morbidity and/or mortality - e.g., myocarditis, or other similar events even if they are not currently noted in the guidelines. Similarly, consider whether study drug/study regimen should be permanently discontinued in Grade 2 events with high likelihood for morbidity and/or mortality - e.g., myocarditis, or other similar events even if they are not currently noted in the guidelines - when they do not rapidly improve to Grade <1 upon treatment with systemic steroids and following full taperNote: There are some exceptions to permanent discontinuation of study drug for Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI National Cancer Institute; PO By mouth.Pediatric ConsiderationsDose Modifications  
| í All recommendations for specialist consultation should occur with a                                                                                                  |    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|
| Toxicity Management                                                                                                                                                    | 88 |
| The criteria for permanent discontinuation of study drug/study regimen based on  CTC grade/severity is the same for pediatric patients as it is for adult patients, as |    |  
| í The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG   | and plasmapheresis that are provided for adult patients should also be used  for pediatric patients.   | í The infliximab 5 mg/kg IV dose recommended for adults is the same as   | UHFRPPHQGHGIRUSHGLDWULFSDWLHQWV•\HDUVROG)RUGRVLQJLQFKLOGUHQ                                                                     | younger than 6 years old, consult with a pediatric specialist.   | í For pediatric dosing of mycophenolate mofetil, consult with a pediatric   | specialist.   | í With long-term steroid and other immunosuppressive use, consider need for  PJP prophylaxis, gastrointestinal protection, and glucose monitoring.   |
|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------|---------------------------------------------------------------------|------------------------------------------------------------------|-----------------------------------------------------------------------------|---------------|------------------------------------------------------------------------------------------------------------------------------------------------------|
| pediatric specialist in the specialty recommended.                             |                                                                                                        |                                                                          |                                                                     |                                                                  |                                                                             |               |                                                                                                                                                      |
| Toxicity Management                                                            |                                                                                                        |                                                                          |                                                                     |                                                                  |                                                                             |               |                                                                                                                                                      |
| Pediatric Considerations                                                       | well as to permanently discontinue study drug/study regimen if unable to reduce                        | FRUWLFRVWHURLG" a dose equivalent to that required for corticosteroid replacement                                                                          | therapy within 12 weeks after last dose of study drug/study regimen |                                                                  |                                                                             |               |                                                                                                                                                      |
| Dose Modifications                                                             |                                                                                                        |                                                                          |                                                                     |                                                                  |                                                                             |               |                                                                                                                                                      |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í Initial work-up may include clinical evaluation, monitoring of   | oxygenation via pulse oximetry (resting and exertion),  laboratory work-up, and high- resolution CT scan.                                                                                       |                                                             |                                                                                                            |                                                      |                                                           |                                                           |                                             |                                                                         |                                                                      |                |    |
|--------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|------------------------------------------------------|-----------------------------------------------------------|-----------------------------------------------------------|---------------------------------------------|-------------------------------------------------------------------------|----------------------------------------------------------------------|----------------|----|
| í Monitor patients for signs and symptoms of pneumonitis or        | ILD (new onset or worsening shortness of breath or cough).  Patients should be evaluated with imaging and pulmonary  function tests, including other diagnostic procedures as  described below. | í Monitor and closely follow up in 2 to 4 days for clinical | symptoms, pulse oximetry (resting and exertion), and  laboratory work-up and then as clinically indicated. | í Consider Pulmonary and Infectious disease consult. | í If no improvement within 3 to 5 days, additional workup | should be considered and prompt treatment with IV         | methylprednisolone 2 to 4 mg/kg/day started | í If still no improvement within 3 to 5 days despite IV                 |                                                                      |                |    |
| í Monitor symptoms daily and consider hospitalization.             | í Promptly start systemic steroids (e.g., prednisone 1 to  2 mg/kg/day PO or IV equivalent).                                                                                                    | í Reimage as clinically indicated.                          |                                                                                                            |                                                      |                                                           |                                                           |                                             |                                                                         |                                                                      |                |    |
| For Grade 2 (mild to moderate new symptoms):                       |                                                                                                                                                                                                 |                                                             |                                                                                                            |                                                      |                                                           |                                                           |                                             |                                                                         |                                                                      |                |    |
| For Grade 1 (radiographic changes only):                           |                                                                                                                                                                                                 |                                                             |                                                                                                            |                                                      |                                                           |                                                           |                                             |                                                                         |                                                                      |                |    |
| Toxicity Management                                                | For Any Grade:                                                                                                                                                                                  |                                                             |                                                                                                            |                                                      |                                                           |                                                           |                                             |                                                                         |                                                                      |                |    |
| Specific Immune-Mediated Reactions                                 | No dose modifications required. However,                                                                                                                                                        | consider holding study drug/study                           | regimen dose as clinically appropriate and  during diagnostic work-up for other                            | etiologies.                                          | Hold study drug/study regimen dose until  *UDGHUHVROXWLRQWR*UDGH"                                                           | x If toxicity worsens, then treat as  Grade 3 or Grade 4. | x ,IWR[LFLW\LPSURYHVWR*UDGH"                                             | then the decision to reinitiate study  drug/study regimen will be based | upon treating physician's clinical  judgment and after completion of | steroid taper. | 91 |
| Dose Modifications                                                 | General Guidance                                                                                                                                                                                |                                                             |                                                                                                            |                                                      |                                                           |                                                           |                                             |                                                                         |                                                                      |                |    |
| Adverse Events Severity Grade of the  Event (NCI CTCAE             | (asymptomatic, clinical                                                                                                                                                                         | or diagnostic                                               | observations only;  intervention not                                                                       | indicated)                                           | (symptomatic; medical  intervention indicated;            | limiting instrumental  ADL)                               |                                             |                                                                         |                                                                      |                |    |
| version 4.03)                                                      | Any Grade                                                                                                                                                                                       | Grade 1                                                     | Grade 2                                                                                                    |                                                      |                                                           |                                                           |                                             |                                                                         |                                                                      |                |    |
| Pneumonitis/Interstitial                                           | Lung Disease (ILD)                                                                                                                                                                              |                                                             |                                                                                                            |                                                      |                                                           |                                                           |                                             |                                                                         |                                                                      |                |    |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia,                                         | life-threatening):                                             | í Promptly initiate empiric IV methylprednisolone 1 to  4 mg/kg/day or equivalent.   | í Obtain Pulmonary and Infectious disease consult; consider, as   | necessary, discussing with study physician.         | í Hospitalize the patient.   | í Supportive care (e.g., oxygen).                    | í If no improvement within 3 to 5 days, additional workup   | should be considered and prompt treatment with additional  immunosuppressive therapy such as TNF inhibitors  (e.g., infliximab at 5 mg/kg every 2 weeks' dose) started.  Caution: rule out sepsis and refer to infliximab label for general   | guidance before using infliximab.   | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOV   | and, in particular, anti-PJP treatment (refer to current NCCN   | guidelines for treatment of cancer-related infections [Category   |
|----------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|--------------------------------------------------------------------------------------|-------------------------------------------------------------------|-----------------------------------------------------|------------------------------|------------------------------------------------------|-------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|------------------------------------------------------------------|---|-----------------------------------------------------------------|-------------------------------------------------------------------|
| important to rule out sepsis and refer to infliximab label for                                           | general guidance before using infliximab.                      |                                                                                      |                                                                   |                                                     |                              |                                                      |                                                             |                                                                                                                                                                                                                                               |                                     |                                                                  |   |                                                                 |                                                                   |
| (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is                                              |                                                                |                                                                                      |                                                                   |                                                     |                              |                                                      |                                                             |                                                                                                                                                                                                                                               |                                     |                                                                  |   |                                                                 |                                                                   |
| methylprednisolone at 2 to 4 mg/kg/day, promptly start  immunosuppressive therapy such as TNF inhibitors | í Once the patient is improving, gradually taper steroids over | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVRU                                                                                      | anti-PJP treatment (refer to current NCCN guidelines for          | treatment of cancer-related infections [Category 2B | recommendation])a            | í Consider pulmonary and infectious disease consult. | í Consider, as necessary, discussing with study physician.  | Permanently discontinue study drug/study                                                                                                                                                                                                      | regimen.                            | 92                                                               |   |                                                                 |                                                                   |
| self-care ADL; oxygen  indicated)                                                                        | (Grade 4: life                                                                | threatening respiratory                                                              | compromise; urgent  intervention indicated                        | [e.g., tracheostomy or  intubation])                |                              |                                                      |                                                             |                                                                                                                                                                                                                                               |                                     |                                                                  |   |                                                                 |                                                                   |
| symptoms; limiting                                                                                       |                                                                |                                                                                      |                                                                   |                                                     |                              |                                                      |                                                             |                                                                                                                                                                                                                                               |                                     |                                                                  |   |                                                                 |                                                                   |
| (Grade 3: severe                                                                                         |                                                                |                                                                                      |                                                                   |                                                     |                              |                                                      |                                                             |                                                                                                                                                                                                                                               |                                     |                                                                  |   |                                                                 |                                                                   |
| Grade 3 or 4                                                                                             |                                                                |                                                                                      |                                                                   |                                                     |                              |                                                      |                                                             |                                                                                                                                                                                                                                               |                                     |                                                                  |   |                                                                 |                                                                   |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| diarrhea/enterocolitis (abdominal pain, cramping, or changes in  bowel habits such as increased frequency over baseline or  blood in stool) or related to bowel perforation (such as sepsis,   | peritoneal signs, and ileus).             | í Patients should be thoroughly evaluated to rule out any   | alternative etiology (e.g., disease progression, other   | medications, or infections), including testing for clostridium  difficile toxin, etc.   | í Steroids should be considered in the absence of clear   | alternative etiology, even for low-grade events, in order to   | prevent potential progression to higher grade event.   | í Use analgesics carefully; they can mask symptoms of   | perforation and peritonitis.   | í Consider symptomatic treatment, including hydration,   | electrolyte replacement, dietary changes (e.g., American  Dietetic Association colitis diet), and loperamide. Use   | probiotics as per treating physician's clinical judgment.   | í Consider symptomatic treatment, including hydration,   | electrolyte replacement, dietary changes (e.g., American   | Dietetic Association colitis diet), and loperamide and/or  budesonide.   | í Promptly start prednisone 1 to 2 mg/kg/day PO or IV   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|-------------------------------------------------------------|----------------------------------------------------------|-----------------------------------------------------------------------------------------|-----------------------------------------------------------|----------------------------------------------------------------|--------------------------------------------------------|---------------------------------------------------------|--------------------------------|----------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|----------------------------------------------------------|------------------------------------------------------------|--------------------------------------------------------------------------|---------------------------------------------------------|
| í Monitor for symptoms that may be related to                                                                                                                                                  | í Monitor closely for worsening symptoms. |                                                             |                                                          |                                                                                         |                                                           |                                                                |                                                        |                                                         |                                |                                                          |                                                                                                                     |                                                             |                                                          |                                                            |                                                                          |                                                         |
| 2B recommendation]).a                                                                                                                                                                          | For Any Grade:                            | For Grade 1:                                                | For Grade 2: Hold study drug/study regimen until         | UHVROXWLRQWR*UDGH"                                                                                         | x If toxicity worsens, then treat as  Grade 3 or Grade 4. | x ,IWR[LFLW\LPSURYHVWR*UDGH"                                                                | then study drug/study regimen can be                   |                                                         |                                |                                                          |                                                                                                                     |                                                             |                                                          |                                                            |                                                                          |                                                         |
| frequency of 4 to 6 over  baseline per day)  (Colitis: abdominal                                                                                                                               | pain; mucus or blood in                   | 93                                                          |                                                          |                                                                                         |                                                           |                                                                |                                                        |                                                         |                                |                                                          |                                                                                                                     |                                                             |                                                          |                                                            |                                                                          |                                                         |
| No dose modifications.                                                                                                                                                                         |                                           |                                                             |                                                          |                                                                                         |                                                           |                                                                |                                                        |                                                         |                                |                                                          |                                                                                                                     |                                                             |                                                          |                                                            |                                                                          |                                                         |
| General Guidance                                                                                                                                                                               | (Colitis: asymptomatic;                   | clinical or diagnostic                                      | observations only)                                       |                                                                                         |                                                           |                                                                |                                                        |                                                         |                                |                                                          |                                                                                                                     |                                                             |                                                          |                                                            |                                                                          |                                                         |
| frequency of <4 over  baseline per day)                                                                                                                                                        |                                           |                                                             |                                                          |                                                                                         |                                                           |                                                                |                                                        |                                                         |                                |                                                          |                                                                                                                     |                                                             |                                                          |                                                            |                                                                          |                                                         |
| (Diarrhea: stool                                                                                                                                                                               | (Diarrhea: stool                          |                                                             |                                                          |                                                                                         |                                                           |                                                                |                                                        |                                                         |                                |                                                          |                                                                                                                     |                                                             |                                                          |                                                            |                                                                          |                                                         |
| Any Grade                                                                                                                                                                                      | Grade 1                                   | Grade 2                                                     |                                                          |                                                                                         |                                                           |                                                                |                                                        |                                                         |                                |                                                          |                                                                                                                     |                                                             |                                                          |                                                            |                                                                          |                                                         |
| Diarrhea/Colitis                                                                                                                                                                               |                                           |                                                             |                                                          |                                                                                         |                                                           |                                                                |                                                        |                                                         |                                |                                                          |                                                                                                                     |                                                             |                                                          |                                                            |                                                                          |                                                         |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í If event is not responsive within 3 to 5 days or worsens despite                 | prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult   | should be obtained for consideration of further workup, such as  imaging and/or colonoscopy, to confirm colitis and rule out   | perforation, and prompt treatment with IV methylprednisolone  2 to 4 mg/kg/day started.   | í If still no improvement within 3 to 5 days despite 2 to 4 mg/kg   | IV methylprednisolone, promptly start immunosuppressives   | such as infliximab at 5 mg/kg once every 2 weeksa. Caution: it is important to rule out bowel perforation and refer to  infliximab label for general guidance before using infliximab.   | í Consider, as necessary, discussing with study physician if no   | UHVROXWLRQWR*UDGH"LQWR days.                           | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG   | anti-PJP treatment (refer to current NCCN guidelines for   | treatment of cancer-related infections [Category 2B   | recommendation]).a   | í Monitor stool frequency and volume and maintain hydration.   | í Urgent GI consult and imaging and/or colonoscopy as   | appropriate.   | í If still no improvement within 3 to 5 days of IV   | methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly   | start further immunosuppressives (e.g., infliximab at 5 mg/kg   | once every 2 weeks). Caution: Ensure GI consult to rule out  bowel perforation and refer to infliximab label for general   |
|------------------------------------------------------------------------------------|------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|---------------------------------------------------------------------|------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|---------------------------|------------------------------------------------------------------|---|------------------------------------------------------------|-------------------------------------------------------|----------------------|----------------------------------------------------------------|---------------------------------------------------------|----------------|------------------------------------------------------|---------------------------------------------------------------|-----------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|
| í Promptly initiate empiric IV methylprednisolone 2 to  4 mg/kg/day or equivalent. |                                                                  |                                                                                                                                |                                                                                           |                                                                     |                                                            |                                                                                                                                                                                          |                                                                   |                           |                                                                  |   |                                                            |                                                       |                      |                                                                |                                                         |                |                                                      |                                                               |                                                                 |                                                                                                                            |
| equivalent.                                                                        | For Grade 3 or 4:                                                | Permanently discontinue study drug/study                                                                                       | regimen for Grade 3 if toxicity does not  LPSURYHWR*UDGH"ZLWKLQ days;                                                                                           | study drug/study regimen can be resumed                             | after completion of steroid taper.                         | Grade 4                                                                                                                                                                                  | Permanently discontinue                                           | study drug/study regimen. |                                                                  |   |                                                            |                                                       |                      |                                                                |                                                         |                |                                                      |                                                               |                                                                 |                                                                                                                            |
| stool) resumed after completion of steroid                                         | 94                                                               |                                                                                                                                |                                                                                           |                                                                     |                                                            |                                                                                                                                                                                          |                                                                   |                           |                                                                  |   |                                                            |                                                       |                      |                                                                |                                                         |                |                                                      |                                                               |                                                                 |                                                                                                                            |
| taper.                                                                             | Grade 3                                                          | (Grade 3 diarrhea: stool  IUHTXHQF\RI•RYHU baseline per day; Grade 4 diarrhea: life                                                                                                                                | threatening                                                                               | consequences) (Grade 3 colitis: severe                              | abdominal pain, change  in bowel habits, medi                                                            | cal intervention indi                                                                                                                                                                                          | cated, peritoneal signs;                                          |                           |                                                                  |   |                                                            |                                                       |                      |                                                                |                                                         |                |                                                      |                                                               |                                                                 |                                                                                                                            |
| Grade 3 or 4                                                                       |                                                                  |                                                                                                                                |                                                                                           |                                                                     |                                                            |                                                                                                                                                                                          |                                                                   |                           |                                                                  |   |                                                            |                                                       |                      |                                                                |                                                         |                |                                                      |                                                               |                                                                 |                                                                                                                            |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURShylactic antibiotics, antifungals, and                                                   | anti-PJP treatment (refer to current NCCN guidelines for                                                                                 | treatment of cancer-related infections [Category 2B   | recommendation]).a                                        | í Monitor and evaluate liver function test: AST, ALT, ALP, and   | TB.                                 | í Evaluate for alternative etiologies (e.g., viral hepatitis, disease   | progression, concomitant medications).   | í Regular and frequent checking of LFTs (e.g., every 1 to 2 days)   | until elevations of these are improving or resolved.   | í ,IQRUHVROXWLRQWR*UDGH"LQWRGD\VFRQVLGHUDV   | necessary, discussing with study physician.   | í If event is persistent (>3 to 5 days) or worsens, promptly start   | prednisone 1 to 2 mg/kg/day PO or IV equivalent.   | í If still no improvement within 3 to 5 days despite 1 to  2 mg/kg/day of prednisone PO or IV equivalent, consider   | additional work up and start prompt treatment with IV   | methylprednisolone 2 to 4 mg/kg/day.   | í If still no improvement within 3 to 5 days despite 2 to  4 mg/kg/day of IV methylprednisolone, promptly start   |
|------------------------------------------------------------------|---------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|-----------------------------------------------------------|------------------------------------------------------------------|-------------------------------------|-------------------------------------------------------------------------|------------------------------------------|---------------------------------------------------------------------|--------------------------------------------------------|---|-----------------------------------------------|----------------------------------------------------------------------|----------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|----------------------------------------|-------------------------------------------------------------------------------------------------------------------|
| í Continue LFT monitoring per protocol.                          |                                                   |                                                                                                                                          |                                                       |                                                           |                                                                  |                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| guidance before using infliximab.                                | For Any Grade:                                    | For Grade 1:                                                                                                                             | For Grade 2:                                          |                                                           |                                                                  |                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| x If it worsens, then treat as Grade 2                           | event.                                            | x Hold study drug/study regimen dose                                                                                                     | XQWLO*UDGHUHVROXWLRQWR*UDGH"                                                       | x If toxicity worsens, then treat as  Grade 3 or Grade 4. | x ,IWR[LFLW\LPSURYHVWR*UDGH"RU baseline, resume study drug/study                                                                  | regimen after completion of steroid | taper.                                                                  |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| x No dose modifications.                                         | 95                                                |                                                                                                                                          |                                                       |                                                           |                                                                  |                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| General Guidance                                                 | (AST or ALT >ULN                                  | aQG"î8/1DQGRU                                                                                                                                          | TB > ULN and                                          | "î8/1                                                           |                                                                  |                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| Grade 4 colitis: life                                                                  | threatening                                       | consequences, urgent  intervention indicated)                                                                                            | ALT >3.0×ULN and                                      | "î8/1DQGRU                                                           | TB >1.5×ULN and                                                  | "î8/1                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| Any Grade                                                        | Grade 2                                           | (AST or                                                                                                                                  |                                                       |                                                           |                                                                  |                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| Grade 1                                                          |                                                   |                                                                                                                                          |                                                       |                                                           |                                                                  |                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| Infliximab should not be                                         | used for management of  immune-related hepatitis. | PLEASE SEE  shaded area  immediately below this section to find guidance for management of "Hepatitis (elevated  LFTS)" in HCC  patients |                                                       |                                                           |                                                                  |                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| (elevated LFTs)                                                  |                                                   |                                                                                                                                          |                                                       |                                                           |                                                                  |                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |
| Hepatitis                                                        |                                                   |                                                                                                                                          |                                                       |                                                           |                                                                  |                                     |                                                                         |                                          |                                                                     |                                                        |   |                                               |                                                                      |                                                    |                                                                                                                      |                                                         |                                        |                                                                                                                   |  
| immunosuppressives (i.e., mycophenolate mofetil).a Discuss                            | with study physician if mycophenolate mofetil is not available.                                                      | Infliximab should NOT be used.                        | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG                                                          | anti-PJP treatment (refer to current NCCN guidelines for   | treatment of cancer-related infections [Category 2B   | recommendation]).a   | í Perform hepatology consult, abdominal workup, and imaging   | as appropriate.                      | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG                                          | anti-PJP treatment (refer to current NCCN guidelines for   | treatment of cancer-related infections [Category 2B                     | recommendation]).a   |
|---------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|------------------------------------------------------------------|----------------------------------------------------------|------------------------------------------------------------|-------------------------------------------------------|----------------------|---------------------------------------------------------------|--------------------------------------|------------------------------------------------------------------|------------------------------------------|------------------------------------------------------------|-------------------------------------------------------------------------|----------------------|
| í Promptly initiate empiric IV methylprednisolone at 1 to  4 mg/kg/day or equivalent. | í If still no improvement within 3 to 5 days despite 1 to  4 mg/kg/day methylprednisolone IV or equivalent, promptly | start treatment with immunosuppressive therapy (i.e., | mycophenolate mofetil). Discuss with study physician if          | mycophenolate is not available. Infliximab should NOT be | used.                                                      |                                                       |                      |                                                               |                                      |                                                                  |                                          |                                                            |                                                                         |                      |
| For Grade 3 or 4:                                                                     | x Hold study drug/study regimen dose                                                                                 | XQWLOUHVROXWLRQWR*UDGH"RU                                                       | baseline                                                         | x Resume study drug/study regimen if                     | HOHYDWLRQVGRZQJUDGHWR*UDGH"RU baseline within 14 days and after                                                            | completion of steroid taper.                          | x Permanently discontinue study  drug/study regimen if the elevations  GRQRWGRZQJUDGHWR*UDGH"RU baseline within 14 days                      | For elevations in transaminases >8 × ULN                      | or elevations in bilirubin >5 × ULN, | discontinue study drug/study regimen.                            | Permanently discontinue study drug/study | regimen for any case meeting Hy's law                      | criteria (AST and/or ALT >3 × ULN +  bilirubin >2 × ULN without initial |                      |
| " × ULN, or elevations in bilirubin                                                                                       | " × ULN:                                                                                                                      |                                                       |                                                                  |                                                          |                                                            |                                                       |                      |                                                               |                                      |                                                                  |                                          |                                                            |                                                                         |                      |
| For elevations in transaminases                                                       | 96                                                                                                                   |                                                       |                                                                  |                                                          |                                                            |                                                       |                      |                                                               |                                      |                                                                  |                                          |                                                            |                                                                         |                      |
| For Grade 3:                                                                          | ALT >5.0×ULN and                                                                                                     | "î8/1DQGRU                                                       | TB >3.0×ULN and                                                  | "î8/1                                                          | (Grade 4: AST or  ALT >20×ULN and/or                       | TB >10×ULN)                                           |                      |                                                               |                                      |                                                                  |                                          |                                                            |                                                                         |                      |
| (Grade 3: AST or                                                                      |                                                                                                                      |                                                       |                                                                  |                                                          |                                                            |                                                       |                      |                                                               |                                      |                                                                  |                                          |                                                            |                                                                         |                      |
| Grade 3 or 4                                                                          |                                                                                                                      |                                                       |                                                                  |                                                          |                                                            |                                                       |                      |                                                               |                                      |                                                                  |                                          |                                                            |                                                                         |                      |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* findings of cholestasis (i.e., elevated alkaline P04) and in the absence of any alternative cause.b**For Grade 4:**
Permanently discontinue study drug/study regimen.  
| For Any Grade:   | í Monitor and evaluate liver function test: AST, ALT, ALP, and   | TB.   | í Evaluate for alternative etiologies (e.g., viral hepatitis, disease   | progression, concomitant medications, worsening of liver   | cirrhosis [e.g., portal vein thrombosis]).   | í For HBV+ patients: evaluate quantitative HBV viral load,   | quantitative HBsAg, or HBeAg   | í For HCV+ patients: evaluate quantitative HCV viral load   | í Consider consulting hepatologist/Infectious disease specialist   | regarding change/implementation in/of antiviral medications  for any patient with an elevated HBV viral load >2000 IU/ml   | í Consider consulting hepatologist/Infectious disease specialist   | regarding change/implementation in/of antiviral HCV   | medications if HCV viral load increased b\•-fold   | í For HCV+ with HBcAB+: Evaluate for both HBV and HCV as   |
|------------------|------------------------------------------------------------------|-------|-------------------------------------------------------------------------|------------------------------------------------------------|----------------------------------------------|--------------------------------------------------------------|--------------------------------|-------------------------------------------------------------|--------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|-------------------------------------------------------|---|------------------------------------------------------------|
| General Guidance |                                                                  |       |                                                                         |                                                            |                                              |                                                              |                                |                                                             |                                                                    |                                                                                                                            |                                                                    |                                                       |   |                                                            |  
  
97  
| í Regular and frequent checking of LFTs (e.g., every 1 to 3 days)   | until elevations of these are improving or resolved.                                   | í Recommend consult hepatologist; consider abdominal   | ultrasound, including Doppler assessment of liver perfusion.   | í Consider, as necessary, discussing with study physician.   | í If event is persistent (>3 to 5 days) or worsens, and investigator   | suspects toxicity to be immune-mediated AE, recommend to   | start prednisone 1 to 2 mg/kg/day PO or IV equivalent.   | í If still no improvement within 3 to 5 days despite 1 to  2 mg/kg/day of prednisone PO or IV equivalent, consider   | additional workup and treatment with IV methylprednisolone 2   | to 4 mg/kg/day.                                           | í If still no improvement within 3 to 5 days despite 2 to  4 mg/kg/day of IV methylprednisolone, consider additional   | abdominal workup (including liver biopsy) and imaging (i.e.,  liver ultrasound), and consider starting immunosuppressives   |
|---------------------------------------------------------------------|----------------------------------------------------------------------------------------|--------------------------------------------------------|----------------------------------------------------------------|--------------------------------------------------------------|------------------------------------------------------------------------|------------------------------------------------------------|----------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|-----------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|
| above                                                               | For Grade 2:                                                                           |                                                        |                                                                |                                                              |                                                                        |                                                            |                                                          |                                                                                                                      |                                                                |                                                           |                                                                                                                        |                                                                                                                             |
| x If ALT/AST elevations represents                                  | significant worsening based on  investigator assessment, then treat as  Grade 2 event. | For all grades, see instructions at bottom             | of shaded area if transaminase rise is not                     | isolated but (at any time) occurs in setting                 | of either increasing bilirubin or signs of                             | DILI/liver decompensation                                  | x Hold study drug/study regimen dose                     | XQWLO*UDGHUHVROXWLRQWR*UDGH"                                                                                                                      | or baseline.                                                   | x If toxicity worsens, then treat as  Grade 3 or Grade 4. | ,IWR[LFLW\LPSURYHVWR*UDGH"RU baseline, resume study drug/study                                                                                                                        | regimen after completion of steroid taper.                                                                                  |
| (Isolated AST or ALT                                                | >5.0×ULN and                                                                           | "î8/1LIQRUPDODW                                                        | baseline)                                                      | (Isolated AST or ALT                                         | >2.0×baseline and                                                      | "î8/1LIHOHYDWHG                                                            | >ULN at baseline)                                        |                                                                                                                      |                                                                |                                                           |                                                                                                                        |                                                                                                                             |
| x No dose modifications.                                            | (Isolated AST or ALT                                                                   | !8/1DQG"î8/1                                                        | whether normal or                                              | elevated at baseline)                                        |                                                                        |                                                            |                                                          |                                                                                                                      |                                                                |                                                           |                                                                                                                        |                                                                                                                             |
| Grade 1                                                             | Grade 2                                                                                |                                                        |                                                                |                                                              |                                                                        |                                                            |                                                          |                                                                                                                      |                                                                |                                                           |                                                                                                                        |                                                                                                                             |
| time) occurs in setting                                             | of either increasing                                                                   | bilirubin or signs of  DILI/liver                      | decompensation                                                 |                                                              |                                                                        |                                                            |                                                          |                                                                                                                      |                                                                |                                                           |                                                                                                                        |                                                                                                                             |  
98 Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| (i.e., mycophenolate mofetil).a Discuss with study physician if   | mycophenolate mofetil is not available. Infliximab should   | NOT be used.   | í Regular and frequent checking of LFTs (e.g., every 1-2 days)   | until elevations of these are improving or resolved.   | í Consult hepatologist (unless investigator is hepatologist);   | obtain abdominal ultrasound, including Doppler assessment of  liver perfusion; and consider liver biopsy.   | í Consider, as necessary, discussing with study physician.   | í If investigator suspects toxicity to be immune-mediated,   | promptly initiate empiric IV methylprednisolone at 1 to  4 mg/kg/day or equivalent.   | í If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day   | methylprednisolone IV or equivalent, obtain liver biopsy (if it  has not been done already) and promptly start treatment with  immunosuppressive therapy (mycophenolate mofetil). Discuss   | with study physician if mycophenolate is not available.   | Infliximab should NOT be used.   | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG   | anti-PCP treatment (refer to current NCCN guidelines for   | treatment of cancer-related infections [Category 2B   | recommendation]).a   | (except would recommend obtaining liver biopsy early)   |
|-------------------------------------------------------------------|-------------------------------------------------------------|----------------|------------------------------------------------------------------|--------------------------------------------------------|-----------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|--------------------------------------------------------------|---------------------------------------------------------------------------------------|-------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------|----------------------------------|------------------------------------------------------------------|---|------------------------------------------------------------|-------------------------------------------------------|----------------------|---------------------------------------------------------|
| For Grade 4:                                                      | Same as above                                               |                |                                                                  |                                                        |                                                                 |                                                                                                             |                                                              |                                                              |                                                                                       |                                                                   |                                                                                                                                                                                             |                                                           |                                  |                                                                  |   |                                                            |                                                       |                      |                                                         |
| For Grade 3: x Hold study drug/study regimen dose                 | XQWLOUHVROXWLRQWR*UDGH"RU                                                             | baseline       | x Resume study drug/study regimen if                             | HOHYDWLRQVGRZQJUDGHWR*UDGH"RU baseline within 14 days and after                                                        | completion of steroid taper.                                    | x Permanently discontinue study  drug/study regimen if the elevations  GRQRWGRZQJUDGHWR*UDGH"RU baseline within 14 days                                                                                                             | Permanently discontinue study drug/study                     | regimen for any case meeting Hy's law                        | criteria, in the absence of any alternative                                           | cause.b                                                           | Permanently discontinue study drug/study                                                                                                                                                    | regimen. (Isolated AST or ALT                             | >20×ULN, whether                 |                                                                  |   |                                                            |                                                       |                      |                                                         |
| (Isolated AST or ALT                                              | >8.0×ULN and                                                | "î8/1LIQRUPDO                | at baseline)                                                     | (Isolated AST or ALT                                   | >12.5×ULN and                                                   | "î8/1LI                                                                                                             | elevated >ULN at                                             | baseline)                                                    |                                                                                       |                                                                   |                                                                                                                                                                                             |                                                           |                                  |                                                                  |   |                                                            |                                                       |                      |                                                         |
| Grade 3                                                           | Grade 4                                                     |                |                                                                  |                                                        |                                                                 |                                                                                                             |                                                              |                                                              |                                                                                       |                                                                   |                                                                                                                                                                                             |                                                           |                                  |                                                                  |   |                                                            |                                                       |                      |                                                         |  
99 Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í Monitor for signs and symptoms that may be related to changes  in renal function (e.g., routine urinalysis, elevated serum BUN   | and creatinine, decreased creatinine clearance, electrolyte  imbalance, decrease in urine output, or proteinuria).   | í Patients should be thoroughly evaluated to rule out any                                 | alternative etiology (e.g., disease progression or infections).                           | í Steroids should be considered in the absence of clear       | alternative etiology even for low-grade events (Grade 2), in   | order to prevent potential progression to higher grade event.   | í Monitor serum creatinine weekly and any accompanying   | symptoms.   | x If creatinine returns to baseline, resume its regular   | monitoring per study protocol.   | x If creatinine worsens, depending on the severity, treat   |
|------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|---------------------------------------------------------------|----------------------------------------------------------------|-----------------------------------------------------------------|----------------------------------------------------------|-------------|-----------------------------------------------------------|----------------------------------|-------------------------------------------------------------|
| If transaminase rise is not isolated but (at any time) occurs in setting of either increasing WRWDOGLUHFWELOLUXELQ•î8/1LIQRUPDODWEDVHOLQHRUîEDVHOLQHLI                                                                                                                                    | >ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR):                                 | - Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise | - Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise | - Grade 3-4: Permanently discontinue study drug/study regimen | Nephritis or renal  dysfunction                                | (elevated serum                                                 | creatinine)                                              |             |                                                           |                                  |                                                             |
| í Consult with nephrologist.                                                                                                       |                                                                                                                      |                                                                                           |                                                                                           |                                                               |                                                                |                                                                 |                                                          |             |                                                           |                                  |                                                             |
| Any Grade General Guidance For Any Grade:                                                                                          | For Grade 1:                                                                                                         | 100                                                                                       |                                                                                           |                                                               |                                                                |                                                                 |                                                          |             |                                                           |                                  |                                                             |
| No dose modifications.                                                                                                             |                                                                                                                      |                                                                                           |                                                                                           |                                                               |                                                                |                                                                 |                                                          |             |                                                           |                                  |                                                             |
| normal or elevated at                                                                                                              | baseline)                                                                                                            | (Serum creatinine > 1                                                                     | to 1.5 × baseline; >                                                                      | ULN to 1.5 × ULN)                                             |                                                                |                                                                 |                                                          |             |                                                           |                                  |                                                             |
| Grade 1                                                                                                                            |                                                                                                                      |                                                                                           |                                                                                           |                                                               |                                                                |                                                                 |                                                          |             |                                                           |                                  |                                                             |  
| í Carefully monitor serum creatinine every 2 to 3 days and as   | clinically warranted.                   | í Consult nephrologist and consider renal biopsy if clinically  indicated.   | í If event is persistent (>3 to 5 days) or worsens, promptly start   | prednisone 1 to 2 mg/kg/day PO or IV equivalent.   | í If event is not responsive within 3 to 5 days or worsens despite   | prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional   | workup should be considered and prompt treatment with IV   | methylprednisolone at 2 to 4 mg/kg/day started.   | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG   | anti-PJP treatment (refer to current NCCN guidelines for   | treatment of cancer-related infections [Category 2B   | recommendation]).a   | í When event returns to baseline, resume study drug/study   | regimen and routine serum creatinine monitoring per study   | protocol.   |
|-----------------------------------------------------------------|-----------------------------------------|------------------------------------------------------------------------------|----------------------------------------------------------------------|----------------------------------------------------|----------------------------------------------------------------------|------------------------------------------------------------------|------------------------------------------------------------|---------------------------------------------------|------------------------------------------------------------------|---|------------------------------------------------------------|-------------------------------------------------------|----------------------|-------------------------------------------------------------|-------------------------------------------------------------|-------------|
| í Consider symptomatic treatment, including hydration,          | electrolyte replacement, and diuretics. | í Consult nephrologist and consider renal biopsy if clinically  indicated.   | í Promptly start prednisone 1 to 2 mg/kg/day PO or IV                |                                                    |                                                                      |                                                                  |                                                            |                                                   |                                                                  |   |                                                            |                                                       |                      |                                                             |                                                             |             |
| í Consider symptomatic treatment, including hydration,          | electrolyte replacement, and diuretics. | í Carefully monitor serum creatinine on daily basis.                         |                                                                      |                                                    |                                                                      |                                                                  |                                                            |                                                   |                                                                  |   |                                                            |                                                       |                      |                                                             |                                                             |             |
| as Grade 2, 3, or 4.                                            | For Grade 3 or 4:                       |                                                                              |                                                                      |                                                    |                                                                      |                                                                  |                                                            |                                                   |                                                                  |   |                                                            |                                                       |                      |                                                             |                                                             |             |
| For Grade 2:                                                    | x ,IWR[LFLW\LPSURYHVWR*UDGH"RU baseline, then resume study  drug/study regimen after completion                                         | of steroid taper.                                                            |                                                                      |                                                    |                                                                      |                                                                  |                                                            |                                                   |                                                                  |   |                                                            |                                                       |                      |                                                             |                                                             |             |
| Hold study drug/study regimen until                             | UHVROXWLRQWR*UDGH"RUEDVHOLQH                                         | x If toxicity worsens, then treat as  Grade 3 or 4.                          | Permanently discontinue study drug/study                             | regimen.                                           | 101                                                                  |                                                                  |                                                            |                                                   |                                                                  |   |                                                            |                                                       |                      |                                                             |                                                             |             |
| (serum creatinine >1.5                                          | to 3.0 × baseline; >1.5                 | to 3.0 × ULN)                                                                | >3.0 × baseline; >3.0 to                                             | 6.0 × ULN;                                         |                                                                      |                                                                  |                                                            |                                                   |                                                                  |   |                                                            |                                                       |                      |                                                             |                                                             |             |
| (Grade 3: serum                                                 | creatinine                              |                                                                              |                                                                      |                                                    |                                                                      |                                                                  |                                                            |                                                   |                                                                  |   |                                                            |                                                       |                      |                                                             |                                                             |             |
| Grade 3 or 4                                                    |                                         |                                                                              |                                                                      |                                                    |                                                                      |                                                                  |                                                            |                                                   |                                                                  |   |                                                            |                                                       |                      |                                                             |                                                             |             |
| Grade 2                                                         |                                         |                                                                              |                                                                      |                                                    |                                                                      |                                                                  |                                                            |                                                   |                                                                  |   |                                                            |                                                       |                      |                                                             |                                                             |             |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í If event is not responsive within 3 to 5 days or worsens despite   | prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional   | workup should be considered and prompt treatment with IV   | methylprednisolone 2 to 4 mg/kg/day started.        | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG   | anti-PJP treatment (refer to current NCCN guidelines for   | treatment of cancer-related infections [Category 2B   | recommendation]).a   | í IF THERE IS ANY BULLOUS FORMATION, THE STUDY   | PHYSICIAN SHOULD BE CONTACTED AND STUDY   | DRUG DISCONTINUED.   | í Consider symptomatic treatment, including oral antipruritics  (e.g., diphenhydramine or hydroxyzine) and topical therapy  (e.g., urea cream).   | í Consider symptomatic treatment, including oral antipruritics  (e.g., diphenhydramine or hydroxyzine) and topical therapy  (e.g., urea cream).   | í Consider moderate-strength topical steroid.   |
|----------------------------------------------------------------------|------------------------------------------------------------------|------------------------------------------------------------|-----------------------------------------------------|------------------------------------------------------------------|---|------------------------------------------------------------|-------------------------------------------------------|----------------------|--------------------------------------------------|-------------------------------------------|----------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|
| í Monitor for signs and symptoms of dermatitis (rash and             | pruritus).                                                       | í Obtain dermatology consult.                              |                                                     |                                                                  |   |                                                            |                                                       |                      |                                                  |                                           |                      |                                                                                                                                                   |                                                                                                                                                   |                                                 |
| equivalent.                                                          | For Any Grade:                                                   | For Grade 1:                                               | For Grade 2: For persistent (>1 to 2 weeks) Grade 2 | events, hold scheduled study drug/study                          | UHJLPHQXQWLOUHVROXWLRQWR*UDGH"RU baseline.   | x If toxicity worsens, then treat as  Grade 3.             | x ,IWR[LFLW\LPSURYHVWR*UDGH"RU                                                       | 102                  |                                                  |                                           |                      |                                                                                                                                                   |                                                                                                                                                   |                                                 |
| No dose modifications.                                               |                                                                  |                                                            |                                                     |                                                                  |   |                                                            |                                                       |                      |                                                  |                                           |                      |                                                                                                                                                   |                                                                                                                                                   |                                                 |
| General Guidance                                                     | (refer to NCI CTCAE                                              | v 4.03 for definition of                                   | severity/grade  depending on type of                | skin rash)                                                       |   |                                                            |                                                       |                      |                                                  |                                           |                      |                                                                                                                                                   |                                                                                                                                                   |                                                 |
| creatinine >6.0 × ULN)                                               |                                                                  |                                                            |                                                     |                                                                  |   |                                                            |                                                       |                      |                                                  |                                           |                      |                                                                                                                                                   |                                                                                                                                                   |                                                 |
| Grade 4: serum                                                       | Any Grade                                                        | Grade 1                                                    | Grade 2                                             |                                                                  |   |                                                            |                                                       |                      |                                                  |                                           |                      |                                                                                                                                                   |                                                                                                                                                   |                                                 |
| (excluding bullous skin  formations)                                 |                                                                  |                                                            |                                                     |                                                                  |   |                                                            |                                                       |                      |                                                  |                                           |                      |                                                                                                                                                   |                                                                                                                                                   |                                                 |
| Rash                                                                 |                                                                  |                                                            |                                                     |                                                                  |   |                                                            |                                                       |                      |                                                  |                                           |                      |                                                                                                                                                   |                                                                                                                                                   |                                                 |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í If no improvement of rash/skin lesions occurs within 3 to  5 days or is worsening despite symptomatic treatment and/or   | use of moderate strength topical steroid, consider, as necessary,  discussing with study physician and promptly start systemic   | steroids such as prednisone 1 to 2 mg/kg/day PO or IV                 | equivalent.                                                    | í Consider skin biopsy if the event is persistent for >1 to 2 weeks   | or recurs.                                                                                                                | í Consider skin biopsy (preferably more than 1) as clinically  feasible.   | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVDQG   | anti-PJP treatment (refer to current NCCN guidelines for   | treatment of cancer-related infections [Category 2B   | recommendation]).a   | í Consider, as necessary, discussing with study physician.   |
|----------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|----------------------------------------------------------------|-----------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|------------------------------------------------------------------|---|------------------------------------------------------------|-------------------------------------------------------|----------------------|--------------------------------------------------------------|
| í Promptly initiate empiric IV methylprednisolone 1 to  4 mg/kg/day or equivalent.                                         | í Consider hospitalization.                                                                                                      | í Monitor extent of rash [Rule of Nines].                             | í Consider consulting an endocrinologist for endocrine events. | í Consider, as necessary, discussing with study physician.            | í Monitor patients for signs and symptoms of endocrinopathies.  Non-specific symptoms include headache, fatigue, behavior |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |
| í Consult dermatology.                                                                                                     |                                                                                                                                  |                                                                       |                                                                |                                                                       |                                                                                                                           |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |
| For Grade 3 or 4:                                                                                                          | For Any Grade:                                                                                                                   |                                                                       |                                                                |                                                                       |                                                                                                                           |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |
| regimen after completion of steroid                                                                                        | taper.                                                                                                                           |                                                                       |                                                                |                                                                       |                                                                                                                           |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |
| baseline, then resume drug/study                                                                                           | improvement of the Grade 3 skin rash to  *UDGH"RUEDVHOLQHZLWKLQ days, then                                                                                                                                  | permanently discontinue study drug/study                              | regimen.                                                       | For Grade 4:                                                          | Permanently discontinue study drug/study                                                                                  | regimen.                                                                   |                                                                  |   |                                                            |                                                       |                      |                                                              |
| Hold study drug/study regimen until                                                                                        | UHVROXWLRQWR*UDGH"RUEDVHOine.                                                                                                                                  | If temporarily holding the study  drug/study regimen does not provide | 103                                                            |                                                                       |                                                                                                                           |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |
| General Guidance                                                                                                           |                                                                                                                                  |                                                                       |                                                                |                                                                       |                                                                                                                           |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |
| For Grade 3:                                                                                                               | (depending on the type                                                                                                           | of endocrinopathy,                                                    | refer to NCI CTCAE                                             | v4.03 for defining the                                                |                                                                                                                           |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |
| Grade 3 or 4                                                                                                               | Any Grade                                                                                                                        | hypothyroidism, Type 1  diabetes mellitus,                            | hypophysitis,                                                  |                                                                       |                                                                                                                           |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |
| (e.g., hyperthyroidism,                                                                                                    |                                                                                                                                  |                                                                       |                                                                |                                                                       |                                                                                                                           |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |
| Endocrinopathy                                                                                                             |                                                                                                                                  |                                                                       |                                                                |                                                                       |                                                                                                                           |                                                                            |                                                                  |   |                                                            |                                                       |                      |                                                              |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í Depending on the suspected endocrinopathy, monitor and                     | evaluate thyroid function tests: TSH, free T3 and free T4 and   | other relevant endocrine and related labs (e.g., blood glucose   | and ketone levels, HgA1c).                                      | í For modest asymptomatic elevations in serum amylase and  lipase, corticosteroid treatment is not indicated as long as there   | are no other signs or symptoms of pancreatic inflammation.     | í If a patient experiences an AE that is thought to be possibly of   | autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis,   | or diabetes insipidus), the investigator should send a blood   | sample for appropriate autoimmune antibody testing.    |                                                               |                                                                                                                  |                                                               |                                                        |                                                        |                                     |
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| unusual bowel habits, polydipsia, polyuria, hypotension, and                 | weakness.                                                       | í Patients should be thoroughly evaluated to rule out any        | alternative etiology (e.g., disease progression including brain | metastases, or infections).                                                                                                     | For Grade 1 (including those with asymptomatic TSH elevation): | í Monitor patient with appropriate endocrine function tests.         | í For suspected hypophysitis/hypopituitarism, consider              | consultation of an endocrinologist to guide assessment of early                                                                | morning ACTH, cortisol, TSH and free T4; also consider | gonadotropins, sex hormones, and prolactin levels, as well as | cosyntropin stimulation test (though it may not be useful in  diagnosing early secondary adrenal insufficiency). | í If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out of | range in 2 subsequent measurements, include free T4 at | subsequent cycles as clinically indicated and consider | consultation of an endocrinologist. |
| CTC grade/severity) changes, changed mental status, vertigo, abdominal pain, | 104                                                             |                                                                  |                                                                 |                                                                                                                                 |                                                                |                                                                      |                                                                     |                                                                |                                                        |                                                               |                                                                                                                  |                                                               |                                                        |                                                        |                                     |
| No dose modifications. Grade 1                                               |                                                                 |                                                                  |                                                                 |                                                                                                                                 |                                                                |                                                                      |                                                                     |                                                                |                                                        |                                                               |                                                                                                                  |                                                               |                                                        |                                                        |                                     |
| amylase/lipase increased                                                     | also included in this                                           | section)                                                         |                                                                 |                                                                                                                                 |                                                                |                                                                      |                                                                     |                                                                |                                                        |                                                               |                                                                                                                  |                                                               |                                                        |                                                        |                                     |
| hypopituitarism, and                                                         | adrenal insufficiency;                                          | exocrine event of                                                |                                                                 |                                                                                                                                 |                                                                |                                                                      |                                                                     |                                                                |                                                        |                                                               |                                                                                                                  |                                                               |                                                        |                                                        |                                     |  
| For Grade 2 (including those with symptomatic endocrinopathy):            | í Consult endocrinologist to guide evaluation of endocrine  function and, as indicated by suspected endocrinopathy and as   | clinically indicated, consider pituitary scan.            | í For all patients with abnormal endocrine work up, except those   | with isolated hypothyroidism or Type 1 DM, and as guided by                       | an endocrinologist, consider short-term corticosteroids (e.g., 1   | to 2 mg/kg/day methylprednisolone or IV equivalent) and   | prompt initiation of treatment with relevant hormone   | replacement (e.g., hydrocortisone, sex hormones).   | í Isolated hypothyroidism may be treated with replacement   | therapy, without study drug/study regimen interruption, and                      | without corticosteroids.   | í Isolated Type 1 diabetes mellitus (DM) may be treated with   | appropriate diabetic therapy, without study drug/study regimen  interruption, and without corticosteroids.   | í Once patients on steroids are improving, gradually taper  immunosuppressive steroids (as appropriate and with guidance   | of endocrinologist) RYHU•GD\VDQGFRQVLGHUSURSK\ODFWLF   | antibiotics, antifungals, and anti-PJP treatment (refer to current   | NCCN guidelines for treatment of cancer-related infections  [Category 2B recommendation]).a   | í For patients with normal endocrine workup (laboratory   | assessment or MRI scans), repeat laboratory assessments/MRI   | as clinically indicated.   | í Consult endocrinologist to guide evaluation of endocrine  function and, as indicated by suspected endocrinopathy and as   | clinically indicated, consider pituitary scan. Hospitalization   | recommended.   |
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| For Grade 3 or 4:                                                         |                                                                                                                             |                                                           |                                                                    |                                                                                   |                                                                    |                                                           |                                                        |                                                     |                                                             |                                                                                  |                            |                                                                |                                                                                                              |                                                                                                                            |   |                                                                      |                                                                                               |                                                           |                                                               |                            |                                                                                                                             |                                                                  |                |
| Study drug/study regimen can be resumed                                   | once event stabilizes and after completion                                                                                  | of steroid taper.                                         | Patients with endocrinopathies who may                             | require prolonged or continued steroid                                            | replacement (e.g., adrenal insufficiency)                          | can be retreated with study drug/study                    | regimen on the following conditions:                   | 1. The event stabilizes and is                      | controlled.                                                 | 2. The patient is clinically stable as per  investigator or treating physician's | clinical judgement.        | 3. 'RVHVRISUHGQLVRQHDUH" mg/day                                                                | or equivalent.                                                                                               |                                                                                                                            |   |                                                                      |                                                                                               |                                                           |                                                               |                            |                                                                                                                             |                                                                  |                |
| For Grade 2 endocrinopathy other than  hypothyroidism and Type 1 diabetes | mellitus, hold study drug/study regimen  dose until patient is clinically stable.                                           | x If toxicity worsens, then treat as  Grade 3 or Grade 4. | than hypothyroidism and Type 1 diabetes                            | mellitus, hold study drug/study regimen  dose until endocrinopathy symptom(s) are | controlled.                                                        |                                                           |                                                        |                                                     |                                                             |                                                                                  |                            |                                                                |                                                                                                              |                                                                                                                            |   |                                                                      |                                                                                               |                                                           |                                                               |                            |                                                                                                                             |                                                                  |                |
| For Grade 3 or 4 endocrinopathy other                                     | 105                                                                                                                         |                                                           |                                                                    |                                                                                   |                                                                    |                                                           |                                                        |                                                     |                                                             |                                                                                  |                            |                                                                |                                                                                                              |                                                                                                                            |   |                                                                      |                                                                                               |                                                           |                                                               |                            |                                                                                                                             |                                                                  |                |
| Grade 3 or 4                                                              |                                                                                                                             |                                                           |                                                                    |                                                                                   |                                                                    |                                                           |                                                        |                                                     |                                                             |                                                                                  |                            |                                                                |                                                                                                              |                                                                                                                            |   |                                                                      |                                                                                               |                                                           |                                                               |                            |                                                                                                                             |                                                                  |                |
| Grade 2                                                                   |                                                                                                                             |                                                           |                                                                    |                                                                                   |                                                                    |                                                           |                                                        |                                                     |                                                             |                                                                                  |                            |                                                                |                                                                                                              |                                                                                                                            |   |                                                                      |                                                                                               |                                                           |                                                               |                            |                                                                                                                             |                                                                  |                |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í For all patients with abnormal endocrine work up, except those   | with isolated hypothyroidism or Type 1 DM, and as guided by   | an endocrinologist, promptly initiate empiric IV   | methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as   | relevant hormone replacement (e.g., hydrocortisone, sex  hormones).   | í For adrenal crisis, severe dehydration, hypotension, or shock,  immediately initiate IV corticosteroids with mineralocorticoid   | activity.                              | í Isolated hypothyroidism may be treated with replacement   | therapy, without study drug/study regimen interruption, and   | without corticosteroids.   | í Isolated Type 1 diabetes mellitus may be treated with                          | appropriate diabetic therapy, without study drug/study regimen  interruption, and without corticosteroids.   | í Once patients on steroids are improving, gradually taper  immunosuppressive steroids (as appropriate and with guidance   | RIHQGRFULQRORJLVWRYHU•GD\VDQGFRQVLGHUSURSK\ODFWLF                | antibiotics, antifungals, and anti-PJP treatment (refer to current  NCCN guidelines for treatment of cancer-related infections  [Category 2B recommendation]).a   | í Patients should be evaluated to rule out any alternative etiology  (e.g., disease progression, infections, metabolic syndromes, or   | medications).   | í Monitor patient for general symptoms (headache, nausea,   | vertigo, behavior change, or weakness).   | í Consider appropriate diagnostic testing (e.g., electromyogram   | and nerve conduction investigations).   |
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| For Any Grade:                                                     |                                                               |                                                    |                                                                 |                                                                       |                                                                                                                                    |                                        |                                                             |                                                               |                            |                                                                                  |                                                                                                              |                                                                                                                            |                |                                                                                                                                                                   |                                                                                                                                        |                 |                                                             |                                           |                                                                   |                                         |
| Study drug/study regimen can be resumed                            | once event stabilizes and after completion                    | of steroid taper.                                  | Patients with endocrinopathies who may                          | require prolonged or continued steroid                                | replacement (e.g., adrenal insufficiency)                                                                                          | can be retreated with study drug/study | regimen on the following conditions:                        | 1. The event stabilizes and is                                | controlled.                | 2. The patient is clinically stable as per  investigator or treating physician's | clinical judgement.                                                                                          | 3. 'RVHVRISUHGQLVRQHDUH" mg/day                                                                                                                            | or equivalent. | 106                                                                                                                                                               |                                                                                                                                        |                 |                                                             |                                           |                                                                   |                                         |
| General Guidance                                                   | (depending on the type                                        | of neurotoxicity, refer                            | to NCI CTCAE v4.03                                              | for defining the CTC                                                  | grade/severity)                                                                                                                    |                                        |                                                             |                                                               |                            |                                                                                  |                                                                                                              |                                                                                                                            |                |                                                                                                                                                                   |                                                                                                                                        |                 |                                                             |                                           |                                                                   |                                         |
| Any Grade                                                          | (to include but not be  limited to limbic                     | encephalitis and                                   | autonomic neuropathy,                                           | excluding Myasthenia  Gravis and Guillain                                                                       | Barre)                                                                                                                             |                                        |                                                             |                                                               |                            |                                                                                  |                                                                                                              |                                                                                                                            |                |                                                                                                                                                                   |                                                                                                                                        |                 |                                                             |                                           |                                                                   |                                         |
| Neurotoxicity                                                      |                                                               |                                                    |                                                                 |                                                                       |                                                                                                                                    |                                        |                                                             |                                                               |                            |                                                                                  |                                                                                                              |                                                                                                                            |                |                                                                                                                                                                   |                                                                                                                                        |                 |                                                             |                                           |                                                                   |                                         |  
| í Consider, as necessary, discussing with the study physician.   | í Obtain neurology consult.   | í Sensory neuropathy/neuropathic pain may be managed by   | appropriate medications (e.g., gabapentin or duloxetine).   | í Promptly start systemic steroids prednisone 1 to 2 mg/kg/day  PO or IV equivalent.   | í If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day   | prednisone PO or IV equivalent, consider additional workup   | and promptly treat with additional immunosuppressive therapy  (e.g., IV IG).   | í Consider, as necessary, discussing with study physician.   | í Obtain neurology consult.        | í Consider hospitalization.              | í Promptly initiate empiric IV methylprednisolone 1 to  2 mg/kg/day or equivalent.   | í If no improvement within 3 to 5 days despite IV   | corticosteroids, consider additional workup and promptly treat   | with additional immunosuppressants (e.g., IV IG).   | í 2QFHVWDEOHJUDGXDOO\WDSHUVWHURLGVRYHU•GD\V              |                                          |          |
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| í Perform symptomatic treatment with neurological consult as     | appropriate.                  | í                                                         | í See "Any Grade" recommendations above.                    | For Grade 3 or 4:                                                                      | For Any Grade:                                                    |                                                              |                                                                                |                                                              |                                    |                                          |                                                                                      |                                                     |                                                                  |                                                     |              |                                          |          |
| For Grade 1:                                                     | For Grade 2:                  | UHJLPHQGRVHXQWLOUHVROXWLRQWR*UDGH"                                                           | For sensory neuropathy/neuropathic pain,                    | consider holding study drug/study                                                      | UHJLPHQGRVHXQWLOUHVROXWLRQWR*UDGH"                                                                   | If toxicity worsens, then treat as  Grade 3 or 4.            | Study drug/study regimen can be resumed                                        | RQFHHYHQWLPSURYHVWR*UDGH"DQG                                                              | after completion of steroid taper. | Hold study drug/study regimen dose until | UHVROXWLRQWR*UDGH"                                                                                      | Permanently discontinue study drug/study            | regimen if Grade 3 imAE does not resolve                         | WR*UDGH"ZLWKLQGD\V                                                     | For Grade 4: | Permanently discontinue study drug/study | regimen. |
| neurotoxicity, hold study drug/study                             |                               |                                                           |                                                             |                                                                                        |                                                                   |                                                              |                                                                                |                                                              |                                    |                                          |                                                                                      |                                                     |                                                                  |                                                     |              |                                          |          |
| For acute motor neuropathies or                                  | 107                           |                                                           |                                                             |                                                                                        |                                                                   |                                                              |                                                                                |                                                              |                                    |                                          |                                                                                      |                                                     |                                                                  |                                                     |              |                                          |          |
| No dose modifications.                                           | General Guidance              |                                                           |                                                             |                                                                                        |                                                                   |                                                              |                                                                                |                                                              |                                    |                                          |                                                                                      |                                                     |                                                                  |                                                     |              |                                          |          |
| For Grade 3: Grade 3 or 4                                        | Any Grade                     |                                                           |                                                             |                                                                                        |                                                                   |                                                              |                                                                                |                                                              |                                    |                                          |                                                                                      |                                                     |                                                                  |                                                     |              |                                          |          |
| Grade 1                                                          | Grade 2                       | Peripheral neuromotor                                     |                                                             |                                                                                        |                                                                   |                                                              |                                                                                |                                                              |                                    |                                          |                                                                                      |                                                     |                                                                  |                                                     |              |                                          |          |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í The prompt diagnosis of immune-mediated peripheral           | neuromotor syndromes is important, since certain patients may   | unpredictably experience acute decompensations that can result  in substantial morbidity or in the worst case, death. Special care   | should be taken for certain sentinel symptoms that may predict   | a more severe outcome, such as prominent dysphagia, rapidly   | progressive weakness, and signs of respiratory insufficiency or   | autonomic instability.   | í Patients should be evaluated to rule out any alternative etiology  (e.g., disease progression, infections, metabolic syndromes or   | medications). It should be noted that the diagnosis of immune   | mediated peripheral neuromotor syndromes can be particularly   | challenging in patients with underlying cancer, due to the   | multiple potential confounding effects of cancer (and its   | treatments) throughout the neuraxis. Given the importance of   | prompt and accurate diagnosis, it is essential to have a low   | threshold to obtain a neurological consult.   | í Neurophysiologic diagnostic testing (e.g., electromyogram and   | nerve conduction investigations, and "repetitive stimulation" if   | myasthenia is suspected) are routinely indicated upon suspicion   | of such conditions and may be best facilitated by means of a   | neurology consultation.   | í It is important to consider that the use of steroids as the primary   | treatment of Guillain-Barre is not typically considered   | effective. Patients requiring treatment should be started with IV   | IG and followed by plasmapheresis if not responsive to IV IG.   | í Care should be taken to monitor patients for sentinel symptoms   |
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| í Consider, as necessary, discussing with the study physician. |                                                                 |                                                                                                                                      |                                                                  |                                                               |                                                                   |                          |                                                                                                                                       |   |                                                                |                                                              |                                                             |                                                                |                                                                |                                               |                                                                   |                                                                    |                                                                   |                                                                |                           |                                                                         |                                                           |                                                                     |                                                                 |                                                                    |
| For Grade 1:                                                   | 108                                                             |                                                                                                                                      |                                                                  |                                                               |                                                                   |                          |                                                                                                                                       |   |                                                                |                                                              |                                                             |                                                                |                                                                |                                               |                                                                   |                                                                    |                                                                   |                                                                |                           |                                                                         |                                                           |                                                                     |                                                                 |                                                                    |
| No dose modifications. Grade 1                                 |                                                                 |                                                                                                                                      |                                                                  |                                                               |                                                                   |                          |                                                                                                                                       |   |                                                                |                                                              |                                                             |                                                                |                                                                |                                               |                                                                   |                                                                    |                                                                   |                                                                |                           |                                                                         |                                                           |                                                                     |                                                                 |                                                                    |
| (such as Guillain-Barre                                        | and myasthenia gravis)                                          |                                                                                                                                      |                                                                  |                                                               |                                                                   |                          |                                                                                                                                       |   |                                                                |                                                              |                                                             |                                                                |                                                                |                                               |                                                                   |                                                                    |                                                                   |                                                                |                           |                                                                         |                                                           |                                                                     |                                                                 |                                                                    |
| syndromes                                                      |                                                                 |                                                                                                                                      |                                                                  |                                                               |                                                                   |                          |                                                                                                                                       |   |                                                                |                                                              |                                                             |                                                                |                                                                |                                               |                                                                   |                                                                    |                                                                   |                                                                |                           |                                                                         |                                                           |                                                                     |                                                                 |                                                                    |  
| í Care should be taken to monitor patients for sentinel symptoms   | of a potential decompensation as described above.   | í Obtain a neurology consult                          | í Sensory neuropathy/neuropathic pain may be managed by   | appropriate medications (e.g., gabapentin or duloxetine).   | MYASTHENIA GRAVIS:   | o Steroids may be successfully used to treat myasthenia   | gravis. It is important to consider that steroid therapy  (especially with high doses) may result in transient   | worsening of myasthenia and should typically be   | administered in a monitored setting under supervision   | of a consulting neurologist.   | o Patients unable to tolerate steroids may be candidates  for treatment with plasmapheresis or IV IG. Such  decisions are best made in consultation with a   | neurologist, taking into account the unique needs of   | each patient.   | o If myasthenia gravis-like neurotoxicity is present,   | consider starting AChE inhibitor therapy in addition   | to steroids. Such therapy, if successful, can also serve   | to reinforce the diagnosis.   | GUILLAIN-BARRE:   | o It is important to consider here that the use of steroids   | as the primary treatment of Guillain-Barre is not   | typically considered effective.   |
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| í Consider, as necessary, discussing with the study physician.     |                                                     |                                                       |                                                           |                                                             |                      |                                                           |                                                                                                                  |                                                   |                                                         |                                |                                                                                                                                                              |                                                        |                 |                                                         |                                                        |                                                            |                               |                   |                                                               |                                                     |                                   |
| of a potential decompensation as described above.                  | í Obtain a neurology consult.                       | For Grade 2: Hold study drug/study regimen dose until | UHVROXWLRQWR*UDGH"                                                           | Permanently discontinue study drug/study                    | UHJLPHQLILWGRHVQRWUHVROYHWR*UDGH"                      | within 30 days or if there are signs of                   | respiratory insufficiency or autonomic  instability.                                                             |                                                   |                                                         |                                |                                                                                                                                                              |                                                        |                 |                                                         |                                                        |                                                            |                               |                   |                                                               |                                                     |                                   |
| Grade 2                                                            |                                                     |                                                       |                                                           |                                                             |                      |                                                           |                                                                                                                  |                                                   |                                                         |                                |                                                                                                                                                              |                                                        |                 |                                                         |                                                        |                                                            |                               |                   |                                                               |                                                     |                                   |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* 109  
| o Patients requiring treatment should be started with IV  IG and followed by plasmapheresis if not responsive   | to IV IG.             | For Grade 3 or 4 (severe or life-threatening events):   | í Consider, as necessary, discussing with study physician.   | í Recommend hospitalization.   | í Monitor symptoms and obtain neurological consult.   | MYASTHENIA GRAVIS:     | o Steroids may be successfully used to treat myasthenia   | gravis. They should typically be administered in a   | monitored setting under supervision of a consulting   | neurologist.   | o Patients unable to tolerate steroids may be candidates  for treatment with plasmapheresis or IV IG.   | o If myasthenia gravis-like neurotoxicity present,   | consider starting AChE inhibitor therapy in addition   | to steroids. Such therapy, if successful, can also serve   | to reinforce the diagnosis.   | GUILLAIN-BARRE:   | o It is important to consider here that the use of steroids   | as the primary treatment of Guillain-Barre is not   | typically considered effective.   | o Patients requiring treatment should be started with IV  IG and followed by plasmapheresis if not responsive   | to IV IG.   | For Any Grade:   |
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| Hold study drug/study regimen dose until                                                                        | reVROXWLRQWR*UDGH"                       | Permanently discontinue study drug/study                | regimen if Grade 3 imAE does not resolve                     | WR*UDGH"ZLWKLQGD\VRULIWKHUHDUH                                | signs of respiratory insufficiency or                 | autonomic instability. | For Grade 4:                                              | Permanently discontinue study drug/study             | regimen.                                              | 110            |                                                                                                         |                                                      |                                                        |                                                            |                               |                   |                                                               |                                                     |                                   |                                                                                                                 |             |                  |
| General Guidance                                                                                                |                       |                                                         |                                                              |                                |                                                       |                        |                                                           |                                                      |                                                       |                |                                                                                                         |                                                      |                                                        |                                                            |                               |                   |                                                               |                                                     |                                   |                                                                                                                 |             |                  |
| For Grade 3: Grade 3 or 4                                                                                       | Any Grade Myocarditis |                                                         |                                                              |                                |                                                       |                        |                                                           |                                                      |                                                       |                |                                                                                                         |                                                      |                                                        |                                                            |                               |                   |                                                               |                                                     |                                   |                                                                                                                 |             |                  |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| - Monitor and closely follow up in 2 to 4 days for clinical                                                | symptoms, BNP, cardiac enzymes, ECG, ECHO, pulse                                                                   | oximetry (resting and exertion), and laboratory work-up as     | clinically indicated.                                         | - Consider using steroids if clinical suspicion is high.        |                                                           |                                                                |                                                             |                                                                                                                             |                                                                                                         |                                                            |                                                         |                                                               |                                                          |                                                       |                            |                                                           |                                                        |                             |                                       |                |
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| í The prompt diagnosis of immune-mediated myocarditis is important, particularly in patients with baseline | cardiopulmonary disease and reduced cardiac function.                                                              | í Consider, as necessary, discussing with the study physician. | í Monitor patients for signs and symptoms of myocarditis (new | onset or worsening chest pain, arrhythmia, shortness of breath, | peripheral edema). As some symptoms can overlap with lung | toxicities, simultaneously evaluate for and rule out pulmonary | toxicity as well as other causes (e.g., pulmonary embolism, | congestive heart failure, malignant pericardial effusion). A  Cardiology consultation should be obtained early, with prompt | assessment of whether and when to complete a cardiac biopsy, including any other diagnostic procedures. | í Initial work-up should include clinical evaluation, BNP, | cardiac enzymes, ECG, echocardiogram (ECHO), monitoring | of oxygenation via pulse oximetry (resting and exertion), and | additional laboratory work-up as indicated. Spiral CT or | cardiac MRI can complement ECHO to assess wall motion | abnormalities when needed. | í Patients should be thoroughly evaluated to rule out any | alternative etiology (e.g., disease progression, other | medications, or infections) | For Grade 1 (no definitive findings): | For Grade 2-4: |
| etiologies. If study drug/study regimen is  held, resume after complete resolution to  Grade 0.            |                                                                                                                    |                                                                |                                                               |                                                                 |                                                           |                                                                |                                                             |                                                                                                                             |                                                                                                         |                                                            |                                                         |                                                               |                                                          |                                                       |                            |                                                           |                                                        |                             |                                       |                |
| No dose modifications required unless                                                                      | clinical suspicion is high, in which case  hold study drug/study regimen dose  during diagnostic work-up for other |                                                                |                                                               |                                                                 |                                                           |                                                                |                                                             |                                                                                                                             |                                                                                                         |                                                            |                                                         |                                                               |                                                          |                                                       |                            |                                                           |                                                        |                             |                                       |                |
| Discontinue drug permanently if biopsy                                                                                                            | proven immune-mediated myocarditis.                                                                                | Grade 2, 3 or 4 - If Grade 2 -- Hold study drug/study          | 111                                                           |                                                                 |                                                           |                                                                |                                                             |                                                                                                                             |                                                                                                         |                                                            |                                                         |                                                               |                                                          |                                                       |                            |                                                           |                                                        |                             |                                       |                |
| laboratory (e.g., BNP)                                                                                     | or cardiac imaging                                                                                                 | abnormalities)                                                 |                                                               |                                                                 |                                                           |                                                                |                                                             |                                                                                                                             |                                                                                                         |                                                            |                                                         |                                                               |                                                          |                                                       |                            |                                                           |                                                        |                             |                                       |                |
| (asymptomatic with                                                                                         |                                                                                                                    |                                                                |                                                               |                                                                 |                                                           |                                                                |                                                             |                                                                                                                             |                                                                                                         |                                                            |                                                         |                                                               |                                                          |                                                       |                            |                                                           |                                                        |                             |                                       |                |
| Grade 1                                                                                                    |                                                                                                                    |                                                                |                                                               |                                                                 |                                                           |                                                                |                                                             |                                                                                                                             |                                                                                                         |                                                            |                                                         |                                                               |                                                          |                                                       |                            |                                                           |                                                        |                             |                                       |                |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í Promptly start IV methylprednisolone 2 to 4 mg/kg/day or                         | equivalent after Cardiology consultation has determined   | whether and when to complete diagnostic procedures including         | a cardiac biopsy.                   | í Supportive care (e.g., oxygen).                                    | í If no improvement within 3 to 5 days despite IV   | methylprednisolone at 2 to 4 mg/kg/day, promptly start  immunosuppressive therapy such as TNF inhibitors  (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is  important to rule out sepsis and refer to infliximab label for   | general guidance before using infliximab.   | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDntifungals, or             | anti-PJP treatment (refer to current NCCN guidelines for   | treatment of cancer-related infections [Category 2B   | recommendation]).a   | í Monitor patients for signs and symptoms of poly/myositis.  Typically, muscle weakness/pain occurs in proximal muscles  including upper arms, thighs, shoulders, hips, neck and back,  but rarely affects the extremities including hands and fingers;   | also difficulty breathing and/or trouble swallowing can occur   | and progress rapidly. Increased general feelings of tiredness   | and fatigue may occur, and there can be new-onset falling,  difficulty getting up from a fall, and trouble climbing stairs,   | standing up from a seated position, and/or reaching up.   | í If poly/myositis is suspected, a Neurology consultation should  be obtained early, with prompt guidance on diagnostic   |
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| í Monitor symptoms daily, hospitalize.                                             | Any Grade General Guidance For Any Grade:                 |                                                                      |                                     |                                                                      |                                                     |                                                                                                                                                                                                                                         |                                             |                                                                  |             |                                                            |                                                       |                      |                                                                                                                                                                                                                                                           |                                                                 |                                                                 |                                                                                                                               |                                                           |                                                                                                                           |
| Grade 0. If toxicity rapidly improves to  Grade 0, then the decision to reinitiate | study drug/study regimen will be based                    | upon treating physician's clinical  judgment and after completion of | steroid taper. If toxicity does not | rapidly improve, permanently.  discontinue study drug/study regimen. | If Grade 3-4, permanently discontinue               | study drug/study regimen.                                                                                                                                                                                                               |                                             |                                                                  |             |                                                            |                                                       |                      |                                                                                                                                                                                                                                                           |                                                                 |                                                                 |                                                                                                                               |                                                           |                                                                                                                           |
| regimen dose until resolution to                                                   | 112                                                       |                                                                      |                                     |                                                                      |                                                     |                                                                                                                                                                                                                                         |                                             |                                                                  |             |                                                            |                                                       |                      |                                                                                                                                                                                                                                                           |                                                                 |                                                                 |                                                                                                                               |                                                           |                                                                                                                           |
| (Grade 2: Symptoms                                                                 | with mild to moderate                                     | activity or exertion)                                                | (Grade 3: Severe with               | symptoms at rest or                                                  | with minimal activity                               | or exertion;                                                                                                                                                                                                                            | intervention indicated)                     | (Grade 4: Life                                                                  | threatening | consequences; urgent                                       | intervention indicated                                | (e.g., continuous IV | therapy or mechanical  hemodynamic support))                                                                                                                                                                                                              | Myositis/Polymyositis  ("Poly/myositis")                        |                                                                 |                                                                                                                               |                                                           |                                                                                                                           |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í Consider, as necessary, discussing with the study physician.      | í Initial work-up should include clinical evaluation, creatine  kinase, aldolase, LDH, BUN/creatinine, erythrocyte   | sedimentation rate or C-reactive protein level, urine myoglobin,                                                   | and additional laboratory work-up as indicated, including a        | number of possible rheumatological/antibody tests (i.e.,       | consider whether a rheumatologist consultation is indicated and   | could guide need for rheumatoid factor, antinuclear antibody,   | anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or   | signal-recognition particle antibodies). Confirmatory testing   | may include electromyography, nerve conduction studies, MRI   | of the muscles, and/or a muscle biopsy. Consider Barium   | swallow for evaluation of dysphagia or dysphonia.   |
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| procedures. Myocarditis may co-occur with poly/myositis;            | refer to guidance under Myocarditis. Given breathing                                                                 | complications, refer to guidance under Pneumonitis/ILD.  Given possibility of an existent (but previously unknown) | autoimmune disorder, consider Rheumatology consultation.           | í Consider, as necessary, discussing with the study physician. |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |
| í Monitor and closely follow up in 2 to 4 days for clinical         | symptoms and initiate evaluation as clinically indicated.                                                            | í Consider Neurology consult.                                                                                      |                                                                    |                                                                |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |
| Patients should be thoroughly evaluated to rule out any alternative | etiology (e.g., disease progression, other medications, or infections).                                              | í Consider, as necessary, discussing with the study physician.                                                     |                                                                    |                                                                |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |
| í Monitor symptoms daily and consider hospitalization.              | í Obtain Neurology consult, and initiate evaluation.                                                                 |                                                                                                                    |                                                                    |                                                                |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |
| For Grade 1:                                                        | For Grade 2: Hold study drug/study regimen dose until                                                                | UHVROXWLRQWR*UDGH"                                                                                                                    | - Permanently discontinue study  drug/study regimen if it does not | UHVROYHWR*UDGH"ZLWKLQGD\VRU                                                                |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |
| weakness; pain limiting  instrumental activities                    |                                                                                                                      |                                                                                                                    |                                                                    |                                                                |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |
| - No dose modifications.                                            | 113                                                                                                                  |                                                                                                                    |                                                                    |                                                                |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |
| (moderate pain                                                      | associated with                                                                                                      |                                                                                                                    |                                                                    |                                                                |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |
| (mild pain)                                                         |                                                                                                                      |                                                                                                                    |                                                                    |                                                                |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |
| Grade 1                                                             | Grade 2                                                                                                              |                                                                                                                    |                                                                    |                                                                |                                                                   |                                                                 |                                                                  |                                                                 |                                                               |                                                           |                                                     |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í If clinical course is rapidly progressive (particularly if  difficulty breathing and/or trouble swallowing), promptly start   | IV methylprednisolone 2 to 4 mg/kg/day systemic steroids   | along with receiving input from Neurology consultant      | í If clinical course is not rapidly progressive, start systemic   | steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV   | equivalent); if no improvement within 3 to 5 days, continue   | additional work up and start treatment with IV   | methylprednisolone 2 to 4 mg/kg/day   | í If after start of IV methylprednisolone at 2 to 4 mg/kg/day   | there is no improvement within 3 to 5 days, consider start of  immunosuppressive therapy such as TNF inhibitors  (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is  important to rule out sepsis and refer to infliximab label for   | general guidance before using infliximab.   | í Once the patient is improving, gradually taper steroids over   | •GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVRU   | anti-PJP treatment (refer to current NCCN guidelines for   | treatment of cancer-related infections [Category 2B   | recommendation]).a   | í Consider, as necessary, discussing with the study physician.   | í Promptly start IV methylprednisolone 2 to 4 mg/kg/day   | systemic steroids along with receiving input from Neurology   | consultant.   | í If after start of IV methylprednisolone at 2 to 4 mg/kg/day   | there is no improvement within 3 to 5 days, consider start of  immunosuppressive therapy such as TNF inhibitors   |
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| For Grade 3 or 4 (severe or life-threatening events):                                                                           | í Monitor symptoms closely; recommend hospitalization.     | í Obtain Neurology consult, and complete full evaluation. |                                                                   |                                                        |                                                               |                                                  |                                       |                                                                 |                                                                                                                                                                                                                                                |                                             |                                                                  |   |                                                            |                                                       |                      |                                                                  |                                                           |                                                               |               |                                                                 |                                                                                                                   |
| Hold study drug/study regimen dose until                                                                                        | UHVROXWLRQWR*UDGH"                                                            | Permanently discontinue study drug/study                  | regimen if Grade 3 imAE does not resolve                          | WR*UDGH"ZLWKLQGD\VRULIWKHUHDUH                                                        | signs of respiratory insufficiency.                           | For Grade 4:                                     | - Permanently discontinue study       |                                                                 |                                                                                                                                                                                                                                                |                                             |                                                                  |   |                                                            |                                                       |                      |                                                                  |                                                           |                                                               |               |                                                                 |                                                                                                                   |
| of daily living [ADLs]) if there are signs of respiratory  insufficiency.                                                       | For Grade 3:                                               | (pain associated with                                     | severe weakness;                                                  | limiting self-care  ADLs)                              |                                                               |                                                  |                                       |                                                                 |                                                                                                                                                                                                                                                |                                             |                                                                  |   |                                                            |                                                       |                      |                                                                  |                                                           |                                                               |               |                                                                 |                                                                                                                   |
| Grade 3 or 4                                                                                                                    |                                                            |                                                           |                                                                   |                                                        |                                                               |                                                  |                                       |                                                                 |                                                                                                                                                                                                                                                |                                             |                                                                  |   |                                                            |                                                       |                      |                                                                  |                                                           |                                                               |               |                                                                 |                                                                                                                   |  
114 Abbreviated Title: *antiPDL1, antiCTLA4 & radiation* í Consider whether patient may require IV IG, plasmapheresis.í Once the patient is improving, gradually taper steroids over GD\VDQGFRQVLGHUSURSK\ODFWLFDQWLELRWLFVDQWLIXQJDOVRUanti-PJP treatment (refer to current NCCN guidelines for treatment of cancer-related infections [Category 2B recommendation]).a
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is important to rule out sepsis and refer to infliximab label for general guidance before using infliximab.  
aASCO Educational Book 2015 "Managing Immune Checkpoint Blocking Antibody Side Effects" by Michael Postow MD.bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury - Premarketing Clinical Evaluation.AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI Magnetic resonance imaging; NCI National Cancer Institute; NCCN National Comprehensive Cancer Network; PJP *Pneumocystis jirovecii* pneumonia (formerly known as *Pneumocystis carinii* pneumonia); PO By mouth; T3 Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal.  
drug/study regimen.  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*  
| í Manage per institutional standard at the discretion of investigator.                                                       | í Monitor patients for signs and symptoms of infusion-related                                                                    | reactions (e.g., fever and/or shaking chills, flushing and/or itching,   | alterations in heart rate and blood pressure, dyspnea or chest  discomfort, or skin rashes) and anaphylaxis (e.g., generalized   | urticaria, angioedema, wheezing, hypotension, or tachycardia).   | í 6WHURLGVVKRXOGQRWEHXVHGIRUURXWLQHSUHPHGLFDWLRQRI*UDGH" infusion reactions.                                                                         |                                                                                                                        |
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| í Acetaminophen and/or antihistamines may be administered per  institutional standard at the discretion of the investigator. | í Consider premedication per institutional standard prior to                                                                     | subsequent doses.                                                        | í Manage severe infusion-related reactions per institutional                                                                     | standards (e.g., IM epinephrine, followed by IV diphenhydramine  | and ranitidine, and IV glucocorticoid).                                 | CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. |
| Dose Modifications Toxicity Management                                                                                       | For Grade 1 or 2:                                                                                                                | For Grade 3 or 4:                                                        |                                                                                                                                  |                                                                  |                                                                         |                                                                                                                        |
| For Any Grade:                                                                                                               |                                                                                                                                  |                                                                          |                                                                                                                                  |                                                                  |                                                                         |                                                                                                                        |
| Infusion-Related Reactions                                                                                                   | The infusion rate of study drug/study regimen may be decreased  by 50% or temporarily interrupted until resolution of the event. | For Grade 2:                                                             | The infusion rate of study drug/study regimen may be decreased                                                                   | 50% or temporarily interrupted until resolution of the event.    | Subsequent infusions may be given at 50% of the initial  infusion rate. | Permanently discontinue study drug/study regimen.                                                                      |
| General Guidance                                                                                                             | For Grade 3 or 4:                                                                                                                |                                                                          |                                                                                                                                  |                                                                  |                                                                         |                                                                                                                        |
| For Grade 1:                                                                                                                 |                                                                                                                                  |                                                                          |                                                                                                                                  |                                                                  |                                                                         |                                                                                                                        |
| Severity Grade of the  Event (NCI CTCAE                                                                                      | version 4.03)                                                                                                                    | Grade 1 or 2                                                             | Grade 3 or 4                                                                                                                     |                                                                  |                                                                         |                                                                                                                        |
| Any Grade                                                                                                                    |                                                                                                                                  |                                                                          |                                                                                                                                  |                                                                  |                                                                         |                                                                                                                        |  
117  
| Note: As applicable, for early phase studies, the following sentence may be added: "Any event greater than or equal to Grade 2, please discuss with Study Physician." AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.   |                                                                                                                                                                                           |                                                   |                                                                    |                                                                 |          |
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| Treat accordingly, as per institutional standard.                                                                                                                                                                                                                              | No dose modifications. Treat accordingly, as per institutional standard.                                                                                                                  | Treat accordingly, as per institutional standard. | Treat accordingly, as per institutional standard.                  | Treat accordingly, as per institutional standard.               |          |
| Toxicity Management                                                                                                                                                                                                                                                            |                                                                                                                                                                                           |                                                   |                                                                    |                                                                 |          |
| Non–Immune-Mediated Reactions                                                                                                                                                                                                                                                  | Note: Dose modifications are not required for AEs not deemed to  be related to study treatment (i.e., events due to underlying  disease) or for laboratory abnormalities not deemed to be | clinically significant.                           | clinical signs/symptoms, the Investigator's clinical judgment, and | consultation with the Sponsor.).                                |          |
| Discontinue study drug/study regimen (Note: For Grade 4 labs,  decision to discontinue should be based on accompanying                                                                                                                                                         |                                                                                                                                                                                           |                                                   |                                                                    |                                                                 |          |
| +ROGVWXG\GUXJVWXG\UHJLPHQXQWLOUHVROXWLRQWR"*UDGHRU baseline.                                                                                                                                                                                                                                                                                | +ROGVWXG\GUXJVWXG\UHJLPHQXQWLOUHVROXWLRQWR"*UDGHRU baseline.                                                                                                                                                                                           | )RU$(VWKDWGRZQJUDGHWR"*UDGHZLWKLQGD\VRUUHVROYHWR                                                   | "*UDGHRUEDVHOLQHZLWKLQGD\VUHVXPHVWXG\GUXJVWXG\                                                                    | regimen administration. Otherwise, discontinue study drug/study | regimen. |
| Dose Modifications Severity Grade of the Event  (NCI CTCAE version 4.03)                                                                                                                                                                                                       | Any Grade                                                                                                                                                                                 | Grade 1                                           | Grade 2                                                            | Grade 3                                                         | Grade 4  |  
Abbreviated Title: *antiPDL1, antiCTLA4 & radiation*