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appendix appendix 1 management algorithms

These general guidelines constitute guidance to the Investigator and may be supplemented at the discretion of the treating physician. The guidance applies to all immuno-oncology agents and regimens.  
A general principle is that differential diagnoses should be diligently evaluated according to standard medical practice. Non-inflammatory etiologies should be considered and appropriately treated.  
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral equivalent of the recommended IV doses may be considered for ambulatory patients with low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.  
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or therapeutic procedure, is recommended. The frequency and severity of the related adverse events covered by these algorithms will depend on the immuno-oncology agent or regimen being used. Patients will not be able to resume treatment following events that require Cemiplimab-rwlc to be discontinued for more than 84 days (12 weeks) from last scheduled dose. Reference the Dose Adjustments/Modifications/Delays section for additional details.  
| MCC 20114                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                         |
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| Events                                                                                                                                                                                                                                                                                                                                                                                | CTCA E v5  Grade                                                                                                                              | Management /Cemiplimab  Dosing                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Action/Supportive Care Guidelines                       |
| Colitis events - Bowel  obstruction - Colitis - Colitis  microscopic - Enterocolitis  hemorrhagic - GI perforation - Necrotizing  colitis - Diarrhea:  All patients who  experience  diarrhea should  be advised to  drink liberal  quantities of clear  fluids. If sufficient  oral fluid intake is  not feasible, fluid  and electrolytes  should be  substituted via IV  infusion. | ≤Grad                                                                                                                                         | No change in                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | - For diarrhea, treat symptomatically (loperamide, oral |
| e 1                                                                                                                                                                                                                                                                                                                                                                                   | dose                                                                                                                                          | hydration, electrolyte substitution and ADA colitis diet).  Endoscopy is recommended if symptoms persist.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                         |
| - Grade 1 diarrhea that persist for >1 week should be treated  with the addition of oral diphenoxylate hydrochloride and  atropine sulfate four times daily and budesonide 9 mg daily.                                                                                                                                                                                                |                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                         |
| Grade                                                                                                                                                                                                                                                                                                                                                                                 | Hold until                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                         |
| 2                                                                                                                                                                                                                                                                                                                                                                                     | <Grade 1.  Resume at  same dose.                                                                                                              | - GI consultation and endoscopy is recommended to confirm  or rule out colitis for grade 2 diarrhea that persists >1 week  or grade 1-2 diarrhea with rectal bleeding (additional  guidelines for the treatment of persistent colitis are provided  below). - Grade 2 diarrhea should be treated with the addition of oral  diphenoxylate hydrochloride and atropine sulfate four times  daily and budesonide 9 mg daily. - Grade 2 diarrhea with diffuse ulceration and bleeding seen  on endoscopy may require oral steroids with prolonged  taper and represent an increased risk for the development  of bowel perforation. Consider prophylactic antibiotics for  opportunistic infections. - When symptoms improve to Grade 1 or less, steroid taper  should be started and continued over no less than 4 weeks. - In patients with Grade 2 enterocolitis, cemiplimab should be  withheld and antidiarrheal treatment should be started. If  symptoms are persistent for more than one week, systemic  corticosteroids should be initiated (eg, 0.5 mg/kg/day of  prednisone or equivalent). When symptoms improve to  Grade 1 or less, corticosteroid taper should be started and  continued over at least 1 month. |                                                         |
| Grade                                                                                                                                                                                                                                                                                                                                                                                 | Hold                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                         |
| 3-4                                                                                                                                                                                                                                                                                                                                                                                   | cemiplimab Discontinue  if unable to  reduce  corticosteroid  dose to ≤ 10  mg per day  prednisone  equivalent  within 12  weeks of  toxicity | - In patients with Grade 3 enterocolitis, cemiplimab will be  permanently discontinued and treatment with systemic  corticosteroids should be initiated at a dose of 1–2  mg/kg/day of prednisone or equivalent. When symptoms  improve to Grade 1 or less, corticosteroid taper should be  started and continued over at least 1 month. Consider  prophylactic antibiotics for opportunistic infections. For Grade 3–4 diarrhea (or Grade 2 diarrhea that persists  after initial steroid treatment), - Rule out bowel perforation. Imaging with plain films or  computed tomography (CT) can be useful. - Consider consultation with gastroenterologist and  confirmation biopsy with endoscopy. - Treat with intravenous (IV) steroids (methylprednisolone 125  mg) followed by high-dose oral steroids (prednisone 1–2  mg/kg once per day or dexamethasone 4 mg every 4 hours).  When symptoms improve to Grade 1 or less, steroid taper  should be started and continued over no less than 4 weeks.  Taper over 6–8 weeks in patients with diffuse and severe  ulceration and/or bleeding.49                                                                                                                         |                                                         |  
| MCC 20114                                                           | - If IV steroids followed by high dose oral steroids does not  reduce initial symptoms within 48–72 hours, consider  treatment with infliximab at 5 mg/kg once every 2 weeks.  Discontinue infliximab upon symptom relief and initiate a  prolonged steroid taper over 45–60 days. If symptoms  worsen during steroid reduction, initiate a retapering of  steroids starting at a higher dose of 80 or 100 mg followed  by a more prolonged taper and administer infliximab.  CAUTION: infliximab is contraindicated in patients with  bowel perforation or sepsis. - If symptoms persist despite the above treatment a surgical  consult should be obtained.   |                                                                                                                                                                                                                                                                       |                                                              |
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| Endocrine  events - Hyperthyroidism - Hypopituitarism               | Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | No change in                                                                                                                                                                                                                                                          | - Monitor thyroid function or other hormonal level tests and |
| 1-2                                                                 | dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | serum chemistries more frequently until returned to baseline  values.                                                                                                                                                                                                 |                                                              |
| Endocrine  events - Hypothyroidism - Thyroid disorder - Thyroiditis | Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Hold until on                                                                                                                                                                                                                                                         |                                                              |
| 3-4                                                                 | stable  replacement  dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | - Consider endocrine consultation.  - Rule out infection and sepsis with appropriate cultures and  imaging.  - Replacement of appropriate hormones as required.                                                                                                       |                                                              |
| Endocrine  events - Adrenal  insufficiency - Hypophysitis - Panhypopituitarism                                                                     | - Thyroid hormone and/or steroid replacement therapy to  manage adrenal insufficiency.  - If Grade 1-2 hypophysitis is considered, pituitary gland  imaging should be considered (magnetic resonance imaging  [MRIs] with gadolinium and selective cuts of the pituitary can  show enlargement or heterogeneity and confirm the  diagnosis).  - Grade 3-4 hypophysitis with clinically significant adrenal  insufficiency and hypotension, dehydration, and electrolyte  abnormalities (such as hyponatremia and hyperkalemia)  constitutes adrenal crisis. Hospitalization and IV  methylprednisolone should be initiated.                                     |                                                                                                                                                                                                                                                                       |                                                              |
| Eye event: Uveitis  (iritis, iridocyclitis)                         | Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Hold until on                                                                                                                                                                                                                                                         |                                                              |
| 1-4                                                                 | stable  replacement  dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                       |                                                              |
| Grade                                                               | Discontinue                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                       |                                                              |
| 1                                                                   | cemiplimab if  symptoms  persist  despite  treatment  with topical  immunosupp ressive  therapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | - Evaluation by an ophthalmologist is strongly recommended. - Treat with topical steroids such as 1% prednisolone acetate  suspension and iridocyclitics.                                                                                                             |                                                              |
| Grade                                                               | Discontinue                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                       |                                                              |
| 2                                                                   | cemiplimab if  symptoms  persist  despite  treatment  with topical  immunosupp ressive                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | - Evaluation by an ophthalmologist is strongly recommended. - Treat with topical steroids such as 1% prednisolone acetate  suspension and iridocyclitics. - Discuss with and obtain approval from site PI prior to  resumption once there is resolution to grade ≤150 |                                                              |  
| MCC 20114                                                                                                 | therapy and  do not  improve to  Grade 1  within the  retreatment  period OR  requires  systemic  treatment.                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                           |
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| Grade                                                                                                     | Discontinue                                                                                                                  | - Treat with systemic corticosteroids such as prednisone at a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                           |
| 3-4                                                                                                       | cemiplimab.                                                                                                                  | dose of 1-2 mg/kg per day. When symptoms improve to  ≤Grade 1, steroid taper should be started and continued  over no less than 4 weeks.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                           |
| - Discuss with and obtain approval from site PI prior to  resumption once there is resolution to grade ≤1 |                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                           |
| Hepatic events - Hepatitis - Hepatitis,  Autoimmune                                                       | Grade                                                                                                                        | Withhold                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                           |
| 1-2                                                                                                       | cemiplimab if  there is a  treatmentemergent  concurrent  elevation of  ALT and  bilirubin that  corresponds  to an upward  shift of 2 or  more grades  in both  parameters.                                                                                                                              | - Monitor liver function tests more frequently until returned to  baseline values. - Consider appropriate consultation and liver biopsy to  establish etiology of hepatic injury, if necessary. - Treat with high-dose IV glucocorticosteroids for 24–48  hours. When symptoms improve to grade 1 or less, a steroid  taper with dexamethasone 4 mg every 4 hours or  prednisone at 1–2 mg/kg should be started and continued  over no less than 4 weeks. - If serum transaminase levels do not decrease 48 hours after  initiation of systemic steroids, oral mycophenolate mofetil  500 mg every 12 hours may be given. Infliximab is not  recommended due to its potential for hepatotoxicity. - Several courses of steroid tapering may be necessary as  symptoms may worsen when the steroid dose is decreased. |                                                                                           |
| Pneumonitis  events - Pneumonitis - Interstitial lung  disease - Acute interstitial  pneumonitis          | Grade                                                                                                                        | Withhold                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                           |
| 3-4                                                                                                       | (and  consider  Discontinuati on of)  cemiplimab when AST or  ALT  >5.0 times  ULN and/or  total bilirubin  >3.0 times  ULN. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                           |
| Grade                                                                                                     | Consider                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                           |
| 1                                                                                                         | hold of  therapy.  Cemiplimab may be  continued  with close  monitoring.                                                     | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Radiologic findings should be followed on serial  imaging studies at least every 3 weeks. |
| -                                                                                                         | Monitor for symptoms every 2–3 days.                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                           |
| -                                                                                                         | Consider pulmonary consultation and/or bronchoscopy  if clinically indicated.51                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                           |  
| MCC 20114                                                        | Grade                                                     | Hold                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | To rule out other causes such as infection:   |
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| 2                                                                | Cemiplimab                                                | - Consider pulmonary consultation with bronchoscopy and  biopsy/bronchoalveolar lavage (BAL). - Consider pulmonary function test. - Follow radiologic findings on serial imaging studies every 1- 3 days. If the patient is determined to have study drug associated  pneumonitis:  - Monitor symptoms daily; consider hospitalization. - Treat with systemic corticosteroids at a dose of 1-2  mg/kg/day prednisone or equivalent. When symptoms  improve to Grade 1 or less, steroid taper should be started  and continued over no less than 4 weeks. - Treatment with cemiplimab may be resumed if the event  improves to ≤ Grade 1 within 12 weeks and corticosteroids  have been reduced to the equivalent of methylprednisolone  10 mg by mouth daily or less. Repeat chest imaging monthly  as clinically indicated.  For Grade 2 pneumonitis that improves to ≤Grade 1 within 12  weeks, the following rules should apply:  - First episode of pneumonitis: May increase dosing interval  by one week in subsequent cycles. - Second episode of pneumonitis: Discontinue cemiplimab if  upon rechallenge the patient develops a second episode of  ≥ Grade 2 pneumonitis. |                                               |
| Grade                                                            | Discontinue                                               | - Consider pulmonary function tests with pulmonary consult.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                               |
| 3-4                                                              | cemiplimab                                                | - Bronchoscopy with biopsy and/or BAL is recommended. - Treat with IV steroids (2–4 mg/kg per day prednisone or  equivalent). When symptoms improve to grade 1 or less, a  high-dose oral steroid (1–2 mg/kg prednisone once per day  or 4 mg dexamethasone every 4 hours) taper should be  started and continued over no less than 4 weeks. - Add prophylactic antibiotics for opportunistic infections. - If IV steroids followed by high-dose oral steroids does not  reduce initial symptoms within 48–72 hours, treat with  infliximab at 5 mg/kg once every 2 weeks. Discontinue  infliximab upon symptom relief and initiate a prolonged  steroid taper over 45–60 days. If symptoms worsen during  steroid reduction, initiate a retapering of steroids starting at a  higher dose of 80 or 100 mg followed by a more prolonged  taper and administer infliximab.                                                                                                                                                                                                                                                                                                          |                                               |
| Renal events - Nephritis - Nephritis  autoimmune - Renal failure | Grade                                                     | Consider                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                               |
| 1                                                                | withholding  Cemiplimab  if event does  not improve  with | - Provide symptomatic treatment. - Monitor creatinine weekly; when it returns to baseline,  resume routine creatinine monitoring per protocol.52                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                               |  
| MCC 20114                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                           |                                                      |
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| - Renal failure,                                                                                                                                                                                                                                                                                                                                                                                            | symptomatic                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                           |                                                      |
| Acute                                                                                                                                                                                                                                                                                                                                                                                                       | treatment.                                                                                                                                                                                                                                                                           | - Systemic corticosteroids at a dose of 1–2 mg/kg/day of  prednisone or equivalent may be indicated. When symptoms  improve to Grade 1 or less, corticosteroid taper should be  started and continued over at least 1 month. - Consider prophylactic antibiotics for opportunistic infections. - Consider renal biopsy. - If elevations persist >7 days or worsen, treatment as Grade  4. |                                                      |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                       | Discontinue                                                                                                                                                                                                                                                                          | - Renal consultation with consideration of ultrasound and/or                                                                                                                                                                                                                                                                                                                              |                                                      |
| 3-4                                                                                                                                                                                                                                                                                                                                                                                                         | cemiplimab                                                                                                                                                                                                                                                                           | biopsy as appropriate.                                                                                                                                                                                                                                                                                                                                                                    |                                                      |
| - Monitor creatinine daily. - Treat with systemic corticosteroids at a dose of 1–2 mg/kg  prednisone or equivalent once per day. - When symptoms improve to grade 1 or less, steroid taper  should be started and continued over no less than 4 weeks. - Discontinue cemiplimab if unable to reduce corticosteroid  dose for irAEs to ≤10 mg. - Cemiplimab treatment may be restarted if symptoms  resolve. |                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                           |                                                      |
| Skin events - Dermatitis  exfoliative - Erythema  multiforme - StevensJohnson  syndrome - Toxic epidermal  necrolysis If considered to  be immune  related,  ≥ Grade 3 or result in dose  modification or  discontinuation: - Pruritus - Rash - Rash,  generalized - Rash  maculopapular - Vitiligo                                                                                                                                                                                                                                                                                                                                                                                                             | Grade                                                                                                                                                                                                                                                                                | Consider                                                                                                                                                                                                                                                                                                                                                                                  |                                                      |
| 2                                                                                                                                                                                                                                                                                                                                                                                                           | withholding  Cemiplimab.                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                           |                                                      |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                       | No change                                                                                                                                                                                                                                                                            | -                                                                                                                                                                                                                                                                                                                                                                                         | Symptomatic treatment should be given such as        |
| 1-2                                                                                                                                                                                                                                                                                                                                                                                                         | topical glucocorticosteroids (eg, betamethasone 0.1% cream  or hydrocortisone 1%) or urea-containing creams in  combination with oral antipruritics (eg, diphenhydramine HCl  or hydroxyzine HCl). - Treatment with oral steroids is at investigator discretion  for Grade 2 events. |                                                                                                                                                                                                                                                                                                                                                                                           |                                                      |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                       | Hold                                                                                                                                                                                                                                                                                 | -                                                                                                                                                                                                                                                                                                                                                                                         | Consider dermatology consultation and biopsy for     |
| 3                                                                                                                                                                                                                                                                                                                                                                                                           | cemiplimab                                                                                                                                                                                                                                                                           | confirmation of diagnosis. - Treatment with oral steroids is recommended, starting  with 1 mg/kg prednisone or equivalent once per day or  dexamethasone 4 mg four times orally daily. When  symptoms improve to Grade 1 or less, steroid taper should  be started and continued over no less than 4 weeks.                                                                               |                                                      |
| Grade                                                                                                                                                                                                                                                                                                                                                                                                       | Permanently                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                           |                                                      |
| 4                                                                                                                                                                                                                                                                                                                                                                                                           | discontinue  cemiplimab                                                                                                                                                                                                                                                              | -                                                                                                                                                                                                                                                                                                                                                                                         | Dermatology consultation and consideration of biopsy |
| and clinical dermatology photograph. - Initiate steroids at 1–2 mg/kg prednisones or  equivalent. When symptoms improve to grade 1 or less,  steroid taper should be started and continued over no less  than 4 weeks.                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                           |                                                      |
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appendix 2 composite response criteria

These criteria are designed primarily for patients whose target lesions will be evaluated by clinical measurements (ie caliper or ruler measurements). This appendix also provides composite response criteria for disease that is measurable by both clinical response criteria and radiographic images. These patients will be followed by clinical measurements and will also undergo radiologic imaging at baseline, and this will also be performed serially at each response assessment unless the investigator deems that baseline radiologic imaging was uninformative. Radiologic imaging will be essential in the evaluation of tumors that have subdermal components that cannot be adequately assessed by clinical measurements.  
A new cutaneous lesion consistent with CSCC will be considered as PD if the lesion is ≥10 mm in both maximal perpendicular diameters, and can be clearly documented as not being previously present, unless it is confirmed on biopsy not to be consistent with CSCC. If a new cutaneous lesion is not biopsied or if the histology is inconclusive, it should be considered CSCC and deemed PD.  
| Clinical Response                                                         | Radiographic      | Composite          |
|---------------------------------------------------------------------------|-------------------|--------------------|
| (caliper/ ruler)                                                          | Response (CT/MRI) | (Overall) Response |
| CR                                                                        | CR or NAa         | CR                 |
| NAa                                                                       | CR                | CR                 |
| CR                                                                        | PR or SD          | PR                 |
| PR                                                                        | CR, PR, SD or NAa | PR                 |
| NA                                                                        | PR                | PR                 |
| SD                                                                        | CR or PR          | PR                 |
| SD                                                                        | SD or NAa         | SD                 |
| NAa                                                                       | SD                | SD                 |
| PD                                                                        | Any               | PD                 |
| Any                                                                       | PD                | PD                 |
| a NA indicates "Not applicable" (eg, because the assessment was not done) |                   |                    |
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composite response criteria

These criteria are for patients who have locally advanced or metastatic CSCC that is measurable by BOTH clinical response criteria by clinical measurement and radiologic imaging.  
In addition, if all previously inoperable target lesions are rendered operable with clear margins obtained at the time of surgery, this will be considered a PR.