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9.0 study calendar

| 9.1                                     | Arm A: Investigator's Choice of Standard of Care PRE-STUDY (w/in 28 days  prior to  randomization,  unless  otherwise  noted) Cycle Length = 21 days (+/- 3 days)   | At Off Tx                        | Off Tx FU Prior to   | Off Tx FU After   |                      |     |     |     |     |
|-----------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------|----------------------|-------------------|----------------------|-----|-----|-----|-----|
| Prog                                    | Prog 7                                                                                                                                                              |                                  |                      |                   |                      |     |     |     |     |
| REQUIRED  STUDIES                       | Cycle 1                                                                                                                                                             | Cycle 2                          | Cycle 3              | Cycle 4           | Subsequent  Cycles 5 |     |     |     |     |
| PHYSICAL History & Physical  Exam       | X                                                                                                                                                                   | X                                | X                    | X                 | X                    | X   | X   | X 6 |     |
| Weight &  Performance                   | X                                                                                                                                                                   | X                                | X                    | X                 | X                    | X   | X   | X 6 |     |
| Status Vital Signs (BP, HR, Temp)       | X                                                                                                                                                                   |                                  |                      |                   |                      |     |     |     |     |
| Toxicity Notation                       | X                                                                                                                                                                   | X                                | X                    | X                 | X                    | X   | X 9 | X 9 |     |
| Smoking Status  Assessment              | X                                                                                                                                                                   | X                                |                      |                   |                      |     |     |     |     |
| LABORATORY                              | If labs obtained w/in 14 days  prior to tx, tests need not be  repeated on C1D1, unless  otherwise noted.                                                           | Up to 48 hours prior to Day 1 tx |                      |                   |                      |     |     |     |     |
| CBC/Diff/Platelets/  Hgb                | X                                                                                                                                                                   | X 3                              | X                    | X                 | X                    | X   | X   | X 9 | X 9 |
| Serum Bilirubin                         | X                                                                                                                                                                   | X 3                              | X                    | X                 | X                    | X   | X   | X 9 | X 9 |
| ALT or AST                              | X                                                                                                                                                                   | X 3                              | X                    | X                 | X                    | X   | X   | X 9 | X 9 |
| Serum  Creatinine/Calc                  | X                                                                                                                                                                   | X 3                              | X                    | X                 | X                    | X   | X   | X 9 | X 9 |
| CrCl                                    | X                                                                                                                                                                   |                                  |                      |                   |                      |     |     |     |     |
| (w/in 28 days  prior to  randomization) |                                                                                                                                                                     |                                  |                      |                   |                      |     |     |     |     |
| INR and PTT 17                          | X 18                                                                                                                                                                |                                  |                      |                   |                      |     |     |     |     |
| TSH w/ Reflex to  Free T4               | X 18                                                                                                                                                                | X 18                             | (every 3rd           | X 9               | X 9                  |     |     |     |     |
| cycle)                                  |                                                                                                                                                                     |                                  |                      |                   |                      |     |     |     |     |
| Urine Protein  Check                    | X                                                                                                                                                                   | X 13                             | X 13                 | X 13              | X 13                 | X 9 | X 9 |     |     |  
| Version Date 8/4/2022                                                        |                                     |                                   |                    |                 |                      |
|------------------------------------------------------------------------------|-------------------------------------|-----------------------------------|--------------------|-----------------|----------------------|
| PRE-STUDY (w/in 28 days  prior to  randomization,  unless  otherwise  noted) | Cycle Length = 21 days (+/- 3 days) | At Off Tx                         | Off Tx FU Prior to | Off Tx FU After |                      |
| Prog                                                                         | Prog 7                              |                                   |                    |                 |                      |
| REQUIRED  STUDIES                                                            | Cycle 1                             | Cycle 2                           | Cycle 3            | Cycle 4         | Subsequent  Cycles 5 |
| X                                                                            |                                     |                                   |                    |                 |                      |
| HIV viral load test                                                          | (within 6                           |                                   |                    |                 |                      |
| 19                                                                           | months)                             | X 4 (w/in 7  days prior  to C1D1) |                    |                 |                      |
| Serum Pregnancy  Test X-RAYS & SCANS CT or MRI for  Disease                  | X                                   | X 1                               | X 1                | X 6             |                      |
| Assessment  Brain CT/MRI 2                                                   | X                                   | X 2                               | X 2                |                 |                      |
| SPECIMEN SUBMISSION Whole Blood -                                            | X 14                                |                                   |                    |                 |                      |
| (pre-tx)                                                                     | X 14                                |                                   |                    |                 |                      |
| ctDNA Buffy Coat  /Plasma for  Banking 8                                     | X8                                  |                                   |                    |                 |                      |
| (pre-tx)                                                                     | X 8                                 | X 8                               | X 8                | X 8             |                      |
| Arm A Treatment Choices  (21 day cycle) Choice 1 Dexamethasone               | X                                   | X                                 | X                  | X               | X                    |
| 10                                                                           | (Days 0-2)                          | (Days 0-2)                        | (Days 0-2)         | (Days 0-2)      | (Days 0-2)           |
| Docetaxel                                                                    | X                                   | X                                 | X                  | X               | X                    |
| (Day 1)                                                                      | (Day 1)                             | (Day 1)                           | (Day 1)            | (Day 1)         |                      |
| Choice 2                                                                     |                                     |                                   |                    |                 |                      |  
| PRE-STUDY (w/in 28 days  prior to  randomization,  unless  otherwise  noted)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Cycle Length = 21 days (+/- 3 days)   | At Off Tx   | Off Tx FU Prior to   | Off Tx FU After   |                      |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|-------------|----------------------|-------------------|----------------------|
| Prog                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Prog 7                                |             |                      |                   |                      |
| REQUIRED  STUDIES                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Cycle 1                               | Cycle 2     | Cycle 3              | Cycle 4           | Subsequent  Cycles 5 |
| X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                       |             |                      |                   |                      |
| Gemcitabine 11                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | (Days 1  and 8)                       | X           |                      |                   |                      |
| (Days 1  and 8)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | X                                     |             |                      |                   |                      |
| (Days 1  and 8)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | X                                     |             |                      |                   |                      |
| (Days 1  and 8)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | X                                     |             |                      |                   |                      |
| (Days 1  and 8)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                       |             |                      |                   |                      |
| Choice 3 - Pemetrexed is not FDA-approved for squamous cell NSCLC and should not be used to treat patients with squamous cell NSCLC. X  (until 4  wks after  last dose) X  Folic Acid 16 (7 days  prior to tx) X  (7 days  prior to tx) X  (7 days  prior to tx) X  (7 days  prior to tx) X  (7 days  prior to tx) X  Vitamin B12 12 (7 days  prior to tx) X  (7 days  prior to tx) X  (7 days  prior to tx) Dexamethasone  X  X  X  X  X  10 (Days 0-2) (Days 0-2) (Days 0-2) (Days 0-2) (Days 0-2) Pemetrexed 15 X X X X X (Day 1) (Day 1) (Day 1) (Day 1) (Day 1) Choice 4 Ramucirumab X  X  X  X  X  (Day 1) (Day 1) (Day 1) (Day 1) (Day 1) Dexamethasone  X  X  X  X  X  10 (Days 0-2) (Days 0-2) (Days 0-2) (Days 0-2) (Days 0-2) Docetaxel X X X X X (Day 1) (Day 1) (Day 1) (Day 1) (Day 1) NOTE: Forms are found on the CTSU website (www.ctsu.org). Forms submission guidelines are found in Section 14.0. NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for |                                       |             |                      |                   |                      |  
Docetaxel X  
(Day 1)  
X  
(Day 1)  
X  
(Day 1)  
X  
(Day 1)  
X  
(Day 1)  
NOTE: Forms are found on the CTSU website (www.ctsu.org). Forms submission guidelines are found in Section 14.0.  
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in https://www.swog.org/sites/default/files/docs/2019-07/BestPracticesupdate.pdf  
Footnotes for Calendar Arm A: Investigator's Choice of Standard of Care 1 CT or MRI (the same method used at pre-study to meet the eligibility criteria in Section 5.3 of **S1800A**) must be repeated every 6 weeks (± 7 day window),
for the first year regardless of treatment delays, then every 12 weeks until disease progression and discontinuation of protocol treatment. The 6 weeks should start from Cycle 1 Day 1. See Sections 5.3 and 7.1 for additional details.  
2 Brain CT/MRI is required per Sections 5.3 and 7.1. If patient has brain metastases at baseline, scans must use the same modality as baseline and be repeated every 12 weeks (+/- 7 days) while on treatment. If patient has brain metastases at baseline, continue brain CT or MRI scans (same modality as baseline) after off protocol treatment prior to progression, as clinically indicated. For alignment with the protocol and good clinical practice, recommended frequency of brain scans after off protocol treatment (and prior to progression) is at least every 12 weeks, unless more frequent scans are clinically appropriate.  
3 If the pre-study tests are obtained within 14 days prior to treatment, tests need not be repeated on Cycle 1 Day 1.  
4 Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to Cycle 1 Day 1. 5 During continued treatment, items marked under physical and laboratory should be performed prior to every subsequent cycle unless otherwise noted.  
Disease assessments and image submission are to take place every 6 weeks (± 7 days) regardless of treatment delays. Treatment and evaluation will continue until any one of the criteria in Section 7.3 **S1800A** is met.  
6 After off protocol treatment prior to progression, patients should be followed by repeating indicated studies every 12 weeks or more often as clinically indicated until progression. Disease assessments should continue per Section 7.1.  
7 After off protocol treatment after progression, follow-up will occur (with lab tests and scans performed at the discretion of the treating physician) every 6 months for 2 years then at end of year 3 from date of randomization.  
8 With patient's consent, additional research blood for banking will be collected at pre-study (prior to treatment initiation), on weeks 4, 7, and 10, and at first progression (defined in Section 10 of **S1800A**) after study treatment (see Section 15.0 of **S1800A**). First progression blood should be collected by the time of the next visit after documenting progression and prior to starting any non-protocol therapy.  
9 Assessments should continue if clinically indicated and until resolution of all acute adverse events.  
10 Dexamethasone should be given twice daily the day before, the day of, and the day after therapy, per institutional guidelines.  
11 Gemcitabine must be given on Days 1 and 8 of every cycle per Section 7.2 12 Vitamin B12 should be given one week prior to pemetrexed every 3rd cycle. 13 Urine protein should be performed throughout treatment as clinically indicated.  
14 ctDNA must be collected per Section 15.3. First progression blood should be collected by the time of the next visit after documenting progression and prior to starting any non-protocol therapy. Note: Kits must be ordered and will take up to 3 days to arrive. 15 Pemetrexed is not FDA-approved for squamous cell NSCLC and should not be used to treat patients with squamous cell NSCLC.  
16 Folic Acid should be given daily beginning 7 days prior to first dose of pemetrexed until 4 weeks after last dose of pemetrexed. 17 INR and PTT should be performed if clinically indicated, per Section 5.3i.  
18 **For all patients**: As clinically indicated, collect TSH pre-study and every 3rd cycle while on treatment to monitor for late endocrine toxicity from prior immune checkpoint inhibitor therapy. **For patients receiving ramucirumab**:, Collect TSH pre-study, if clinically indicated. While on treatment, monitor thyroid function every 3rd cycle. For all patients: If TSH is abnormal, reflex to Free T4 and other work up per investigator discretion. See Section 8.4 for ramucirumab dose modifications. 19 See Section 5.1 for details.  
| 9.2                                     | Arm B: Ramucirumab plus Pembrolizumab (MK-3475) PRE-STUDY (w/in 28 days  prior to  randomization,  unless  otherwise noted) Cycle Length = 21 days (+/- 3 days)   | At Off Tx                        | Off Tx FU Prior to  Prog   | Off Tx  FU After  Prog 7   |                      |     |     |     |     |
|-----------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------|----------------------------|----------------------------|----------------------|-----|-----|-----|-----|
| REQUIRED  STUDIES                       | Cycle 1                                                                                                                                                           | Cycle 2                          | Cycle 3                    | Cycle 4                    | Subsequent  Cycles 5 |     |     |     |     |
| PHYSICAL History & Physical  Exam       | X                                                                                                                                                                 | X                                | X                          | X                          | X                    | X   | X   | X 6 |     |
| Weight &  Performance Status            | X                                                                                                                                                                 | X                                | X                          | X                          | X                    | X   | X   | X 6 |     |
| Vital Signs (BP, HR, Temp)              | X                                                                                                                                                                 | X                                | X                          | X                          | X                    | X   |     |     |     |
| Toxicity Notation                       | X                                                                                                                                                                 | X                                | X                          | X                          | X                    | X   | X 9 | X 9 |     |
| Smoking Status  Assessment              | X                                                                                                                                                                 | X                                |                            |                            |                      |     |     |     |     |
| LABORATORY                              | If labs obtained w/in 14 days  prior to tx, tests need not be                                                                                                     | Up to 48 hours prior to Day 1 tx |                            |                            |                      |     |     |     |     |
| repeated on C1D1.                       |                                                                                                                                                                   |                                  |                            |                            |                      |     |     |     |     |
| CBC/Diff/Platelets/  Hgb                | X                                                                                                                                                                 | X 3                              | X                          | X                          | X                    | X   | X   | X 9 | X 9 |
| Serum Bilirubin                         | X                                                                                                                                                                 | X 3                              | X                          | X                          | X                    | X   | X   | X 9 | X 9 |
| ALT or AST                              | X                                                                                                                                                                 | X 3                              | X                          | X                          | X                    | X   | X   | X 9 | X 9 |
| Serum  Creatinine/Calc CrCl             | X                                                                                                                                                                 | X 3                              | X                          | X                          | X                    | X   | X   | X 9 | X 9 |
| X                                       |                                                                                                                                                                   |                                  |                            |                            |                      |     |     |     |     |
| (w/in 28 days  prior to  randomization) |                                                                                                                                                                   |                                  |                            |                            |                      |     |     |     |     |
| INR and PTT 12                          | X 13                                                                                                                                                              |                                  |                            |                            |                      |     |     |     |     |
| TSH w/ Reflex to  Free T4               | X 13                                                                                                                                                              | X 13                             | (every 3rd                 | X 9                        | X 9                  |     |     |     |     |
| cycle)                                  |                                                                                                                                                                   |                                  |                            |                            |                      |     |     |     |     |
| Urine Protein Check                     | X                                                                                                                                                                 | X 10                             | X 10                       | X 10                       | X 10                 | X 9 | X 9 |     |     |  
| Version Date 8/4/2022                                                        |                                     |                                   |                          |                          |                      |
|------------------------------------------------------------------------------|-------------------------------------|-----------------------------------|--------------------------|--------------------------|----------------------|
| PRE-STUDY (w/in 28 days  prior to  randomization,  unless  otherwise noted)  | Cycle Length = 21 days (+/- 3 days) | At Off Tx                         | Off Tx FU Prior to  Prog | Off Tx  FU After  Prog 7 |                      |
| REQUIRED  STUDIES                                                            | Cycle 1                             | Cycle 2                           | Cycle 3                  | Cycle 4                  | Subsequent  Cycles 5 |
| X                                                                            |                                     |                                   |                          |                          |                      |
| HIV viral load test 14                                                       | (within 6  months)                  | X 4 (w/in 7  days prior  to C1D1) |                          |                          |                      |
| Serum Pregnancy  Test X-RAYS & SCANS CT or MRI for  Disease Assessment       | X                                   | X 1                               | X 1                      | X 6                      |                      |
| Brain CT/MRI 2                                                               | X                                   | X 2                               | X 2                      |                          |                      |
| SPECIMEN SUBMISSION Whole Blood - ctDNA                                      | X 11                                |                                   |                          |                          |                      |
| (pre-tx)                                                                     | X 11                                |                                   |                          |                          |                      |
| X8                                                                           |                                     |                                   |                          |                          |                      |
| (pre-tx)                                                                     | X 8                                 | X 8                               | X 8                      | X 8                      |                      |
| Buffy Coat /Plasma  for Banking 8 Arm B Treatment (21 day cycle) Ramucirumab | X                                   | X                                 | X                        | X                        | X  X                 |
| Pembrolizumab (MK3475)                                                                              | X                                   | X                                 | X                        | X                        | (up to 35  cycles)   |  
NOTE: Forms are found on the CTSU website (www.ctsu.org). Forms submission guidelines are found in Section 14.0.  
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in https://www.swog.org/sites/default/files/docs/2019-07/BestPracticesupdate.pdf  
Footnotes for Calendar Arm B: Ramucirumab plus Pembrolizumab **(MK-3475)** 1 CT or MRI (the same method used at pre-study to meet the eligibility criteria in Section 5.3 of **S1800A**) must be repeated every 6 weeks (± 7 day window),
for the first year regardless of treatment delays, then every 12 weeks until disease progression and discontinuation of protocol treatment. The 6 weeks should start from Cycle 1 Day 1. See Sections 5.3 and 7.1 for additional details.  
2 Brain CT/MRI is required per Sections 5.3 and 7.1. If patient has brain metastases at baseline, scans must use the same modality as baseline and be repeated every 12 weeks (+/- 7 days) while on treatment. If patient has brain metastases at baseline, continue brain CT or MRI scans (same modality as baseline) after off protocol treatment prior to progression, as clinically indicated. For alignment with the protocol and good clinical practice, recommended frequency of brain scans after off protocol treatment (and prior to progression) is at least every 12 weeks, unless more frequent scans are clinically appropriate. 3 If the pre-study tests are obtained within 14 days prior to treatment, tests need not be repeated on Cycle 1 Day 1.
4 Women of child bearing potential must have a negative serum pregnancy test within 7 days prior to Cycle 1 Day 1.  
5 During continued treatment, items marked under physical and laboratory should be performed prior to every subsequent cycle unless otherwise noted.  
Disease assessments and image submission are to take place every 6 weeks (± 7 days) regardless of treatment delays. Treatment and evaluation will continue until any one of the criteria in Section 7.3 **S1800A** is met.  
6 After off protocol treatment prior to progression, patients should be followed by repeating indicated studies every 12 weeks or more often as clinically indicated until progression. Disease assessments should continue per Section 7.1.  
7 After off protocol treatment after progression, follow-up will occur (with lab tests and scans performed at the discretion of the treating physician) every 6 months for 2 years then at end of year 3 from date of randomization.  
8 With patient's consent, additional research blood for banking will be collected at pre-study (prior to treatment initiation), on weeks 4, 7, and 10, and at first progression (defined in Section 10 of **S1800A**) after study treatment (see Section 15.0 of **S1800A**). First progression blood should be collected by the time of the next visit after documenting progression and prior to starting any non-protocol therapy. 9 Assessments should continue if clinically indicated and until resolution of all acute adverse events.  
10 Urine protein should be performed throughout treatment as clinically indicated.
11 ctDNA must be collected per Section 15.3. First progression blood should be collected by the time of the next visit after documenting progression and prior to starting any non-protocol therapy. Note: Kits must be ordered and will take up to 3 days to arrive. 12 INR and PTT should be performed if clinically indicated, per Section 5.3i.  
13 TSH and if abnormal, reflex to Free T4 and other work up per investigator, should be performed as clinically indicated at pre-study. While on treatment, monitor thyroid function every 3rd cycle. See Section 8.4 for ramucirumab dose modifications and Section 8.5 for pembrolizumab dose modifications.  
14 See Section 5.1 for details.
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10.0 criteria for evaluation and

10.1 Measurability of Lesions a. **Measurable disease**: Measurable disease is defined differently for lymph nodes compared with other disease and will be addressed in a separate section below.  
1. Lesions that can be accurately measured in at least one dimension
(longest diameter to be recorded) as ≥ 2.0 cm by chest x-ray, by ≥ 1.0 cm with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All tumor measurements must be recorded in decimal fractions of centimeters (or millimeters). The defined measurability of lesions on CT scan is based on the assumption that CT slice thickness is 0.5 cm or less. It is strongly recommended that CT slice of 0.5 cm be used. If CT scans have slice thickness greater than 0.5 cm, the minimum size for a measurable lesion should be twice the slice thickness.  
2. Malignant lymph nodes are to be considered pathologically enlarged and measurable if it measures ≥ 1.5 cm in **SHORT AXIS** (greatest diameter perpendicular to the long axis of the lymph node) when assessed by scan (CT scan slice recommended being no greater than 0.5 cm).  
b. Non-measurable **disease**: All other lesions (or sites of disease), including small lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 1.5 cm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable as are previously radiated lesions that have not progressed.  
c. Notes on measurability 1. For CT and MRIs, the same type of scanner should be used, and the image acquisition protocol should be followed as closely as possible to prior scans. It is no longer necessary to distinguish between spiral and conventional CT.  
2. Body scans should be performed with breath-hold scanning techniques, if possible.  
3. PET-CT: At present, the low dose or attenuation correction CT portion of a PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT, then the CT portion of the PET-CT can be used for RECIST
measurements and can be used interchangeably with stand-alone CT.  
The slice thickness of 0.5 cm or less is highly recommended. If CT scans have slice thickness > 0.5 cm, the minimum size for a measurable lesion should be twice the slice thickness.  
4. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement.  
5. Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition simple cysts.
6. If a target lesion becomes very small some radiologists indicate that it is too small to measure. If the lesion is actually still present, a default measurement of 0.5 cm should be applied. If the radiologist believes the lesion has gone, a default measurement of 0.0 cm should be recorded.  
10.2 Objective Status at Each Disease Evaluation Objective Status is to be recorded at each evaluation. All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of all involved organs, should be identified as *target* lesions at baseline. All other lesions (or sites of disease)
including any measurable lesions over and above the 5 target lesions should be identified as *non-target* lesions. Measurements must be provided for target measurable lesions, while presence or absence must be noted for non-target measurable and non-measurable disease. For studies that use disease progression as an endpoint, all potential sites of metastases should be evaluated at each time point rather than following only sites of disease identified at baseline. It is acceptable to image only the areas of the body most likely to be involved with metastatic disease for the tumor type (chest, abdomen, pelvis, and/or bone scan are typical), with the addition of any areas with suspected involvement based upon clinical symptoms. For study-specific imaging requirements, see the Study Calendar in Section 9.0.  
a. **Complete Response (CR)**: Complete disappearance of all target and non-target lesions (with the exception of lymph nodes mentioned below). No new lesions. No disease related symptoms. Any lymph nodes (whether target or non-target) must have reduction in short axis to < 1.0 cm. All disease must be assessed using the same technique as baseline.  
b. **Partial Response (PR)**: Applies only to patients with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of appropriate diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. All target measurable lesions must be assessed using the same techniques as baseline.  
c. **Stable**: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as baseline.  
d. **Progression**: One or more of the following must occur: 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline, as well as an absolute increase of at least 0.5 cm. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Appearance of any new lesion/site. Death due to disease without prior documentation of progression and without symptomatic deterioration (see 10.2e).
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notes on progression and new

1. For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of progression should be the earlier date when progression was suspected.  
2. FDG-PET imaging can complement regular scans in identifying new lesions according to the following algorithm.  
o Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of progression based on a new lesion.  
o No FDG-PET at baseline and a positive FDG-PET at follow-up corresponding to a potential new site of disease must have a confirmation by anatomical assessment (e.g. CT, MRI, x-ray) as new site of disease to be considered progressive disease. In such a case, the date of progressive disease will be the date of the initial abnormal FDG-PET.  
3. A previous abnormal target lymph node that became normal and subsequently enlarged in size meeting the criteria for a pathologic and measurable lymph node (a short axis of ≥ 1.5 cm) should be added to the sum of diameters to determine if criteria for progression are met based on target lesions.  
2. A previously abnormal non-target lymph node that became normal and subsequently recurred must meet the criteria for progression based on non-target lesions to be considered progression.  
3. A normal lymph node at baseline (<1.0 cm) that subsequently becomes pathologic is considered a new lesion and should be considered progression.  
4. If a single pathologic lymph node is driving the progression event, continuation of treatment/follow-up and confirmation by a subsequent exam should be contemplated. If it becomes clear that the new lymph node has not resolved, or has increased in size, the date of progression would be the date the new lymph node was first documented.  
e. **Symptomatic deterioration**: Global deterioration of health status requiring discontinuation of treatment without objective evidence of progression. Efforts should be made to obtain objective evidence of progression after discontinuation.  
f. **Assessment inadequate, objective status unknown**: Progression or symptomatic deterioration has not been documented, and one or more target measurable lesions have not been assessed or inconsistent assessment methods were used.
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objective status notes

1. Non-measurable and non-target measurable disease do not affect Objective Status in determination of CR (must be absent--a patient who otherwise has a CR, but who has non-measurable or non-target measurable disease present or not assessed, will be classified as having a PR). However, non-measurable and non-target lesions are included in determination of progression (if new sites of disease develop or if unequivocal progression occurs in the opinion of the treating physician).  
2. An objective status of PR or stable cannot follow one of CR. Stable can follow PR only in the rare case that tumor increases too little to qualify as progression, but enough that a previously documented 30% decrease no longer holds.  
3. In cases for which initial flare reaction is possible (hypercalcemia, increased bone pain, erythema of skin lesions), objective status is not progression unless either symptoms persist beyond 4 weeks or there is additional evidence of progression.  
4. Lesions that appear to increase in size due to presence of necrotic tissue will not be considered to have progressed.  
Page 61 Version Date 8/4/2022  
5. For bone disease documented on bone scan only, increased uptake does not constitute unequivocal progression. However, increase in the soft tissue component of a lesion as measured by CT or MRI would constitute progression.  
6. Appearance of new pleural effusions does not constitute unequivocal progression unless cytologically proven of neoplastic origin, since some effusions are a toxicity related to therapy or other medical conditions.  
Increase in the size of an existing effusion does not constitute unequivocal progression, since the fluid status of the patient could alter the size of the effusion.  
7. If CR determination depends on a lesion for which the status is unclear by the required tests, it is recommended the residual lesion be investigated with biopsy or fine needle aspirate.  
8. Lymph nodes are considered one organ. Only two lymph nodes should be selected as target lesions. Other involved lymph nodes should be assessed and followed as non-target lesions.
9. "Paired" organs, i.e. lungs, kidneys and ovaries, are considered one organ.  
10. Pleural-based lung lesions are considered part of the lung in determining target lesions (a maximum of two lung lesions should be selected),
whereas pleural effusions/thickening can be reported as a separate site.
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10.3 best response

This is calculated from the sequence of objective statuses.  
a. CR: Two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration.  
b. PR: Two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration, but not qualifying as CR.  
c. Unconfirmed CR: One objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR.  
d. Unconfirmed PR: One objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.  
e. Stable/no response: At least one objective status of stable/no response documented at least 6 weeks after registration and before progression or symptomatic deterioration, but not qualifying as anything else above.  
f. Increasing disease: Objective status of progression within 12 weeks of registration, not qualifying as anything else above.  
g. Symptomatic deterioration: Objective status of symptomatic deterioration within 12 weeks of registration, not qualifying as anything else above.  
h. Inadequate assessment, response unknown: Progression or symptomatic deterioration greater than 12 weeks after registration and no other response category applies.  
10.4 Performance Status
Patients will be graded according to the Zubrod Performance Status Scale.  
10.5 Time to Death
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point description

0 Fully active, able to carry on all pre-disease performance without restriction.  
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.  
2 Ambulatory and capable of self-care but unable to carry out any work activities; up and about more than 50% of waking hours.  
3 Capable of limited self-care, confined to bed or chair more than  
50% of waking hours.  
4 Completely disabled; cannot carry on any self-care; totally  
confined to bed or chair.  
From date of sub-study registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.  
10.6 Investigator-Assessed Progression-Free Survival From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration (as defined above), or death due to any cause. Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans)
whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) will be used as the date of progression.  
10.7 Progression-Free Survival by Central Review
From date of sub-study registration to date of first documentation of progression assessed by central review or symptomatic deterioration (as defined above), or death due to any cause. Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) will be used as the date of progression.
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10.8 duration of response (dor)

From date of first documentation of response (CR or PR) to date of first documentation of progression assessed by local review or symptomatic deterioration (as defined above), or death due to any cause among patients who achieve a response (CR or PR). Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) will be used as the date of progression.
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11.0 statistical considerations 11.1 study

Overall survival has been chosen as the key primary endpoint because neither response nor PFS have been demonstrated to be a robust and reliable endpoint in the immunotherapy relapsed setting. The study design includes randomization against a standard-of-care (SoC) arm as there is limited historical data on response, PFS, and OS in this setting to be able to specify benchmarks. While responses are not necessarily expected, the design includes an evaluation of response rate as a key secondary objective.  
The standard of care is chemotherapy (monotherapy) for these patients. However, there is limited data on clinical outcomes for patients receiving chemotherapy after immunotherapy. To approximate the control arm event rates, we use published data on chemotherapy in the second-line setting.
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11.2 primary objective

The primary objective is to evaluate if there is sufficient evidence to pursue an independent Phase III study by comparing overall survival (OS) between patients previously treated with platinum-based chemotherapy and immunotherapy for Stage IV or recurrent non-small cell lung cancer randomized to ramucirumab and pembrolizumab (MK-3475) versus standard of care (SoC).  
11.3 Sample Size, Accrual Duration, and Estimated Analysis Times
The accrual goal is 65 eligible patients per arm. Assuming 10% of patients will be determined to be not eligible, the total accrual goal is 144 patients (72 patients per arm).  
The estimated accrual rate is 6-7 patients/month. The estimated duration of accrual is 2124 months. It is assumed that the SoC arm will be a mixture of patients receiving docetaxel monotherapy or docetaxel combined with ramucirumab. The expected median OS for patients receiving docetaxel and ramucirumab is 10.5 months, based on the REVEL trial, and 8 months for single agent chemotherapy. We estimate that around 50% of patients will receive docetaxel/ramucirumab. Given this, we estimate that the median OS for all patients will be around 9 months on the control arm. Given these assumptions, the estimated timing of the final analysis is 30-32 months after activation (10-12 months after completion of accrual).
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11.4 design sample size justification

OS will be compared using the maximum of the standard and weighted log-rank test with weights equal to 1-S(t), where S(t) is the pooled survival estimate at time t (G(rho=0, gamma=1). See for example, Freidlin 1999 (Biometrics). This analysis will be done using the svylogrank function in the survey package in R (https://cran.rproject.org/web/packages/survey/survey.pdf). Testing will be done at the 1-sided 0.10 level. Because the proportional hazards assumption may not hold, sample size calculations were not done using the standard approaches. Simulations were performed to evaluate the properties of the design. The final analysis would take place when 90 OS events are observed. The power to detect differences in OS, if the study reaches full accrual (N=130),
using the combination test for various amounts of time delay in separation of curves is in Table 1.  
| Table 1. Power for Primary analysis of OS (90 events) Hazard Ratio after Separation Time Delay in Separation (months) 0 3 4 5 1.5 62% 53% 53% 47% 2.0 94% 90% 84% 80% 2.5 99% 97% 96% 91% 3.0 100% 100% 99% 97%   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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11.5 interim analysis plan

The study will include two interim analyses evaluating early stopping for futility.  
The first interim analysis evaluating early stopping for futility alone, will take place when at least 24 weeks have elapsed since the 18th eligible patient randomized to Arm B. The analysis will likely take place approximately 12-14 months after study activation (~7-8 months after the 18th eligible patient on Arm B has been enrolled to allow for required data to be submitted and reviewed). It is estimated that by this time a total of 40 eligible patients will have been randomized to ramucirumab and pembrolizumab, 30 eligible patients will be evaluable for disease control at 12 weeks, and a total of 80 eligible patients will have been enrolled onto the study. If the study reaches 80 total eligible patients prior to this time point, accrual to the study will be place on temporary hold until the decision of this analysis is determined.  
The objective of the interim futility analysis is to evaluate the response rate among patients with at least 24 weeks of follow-up and the disease control rate at 12 weeks (after randomization) among patients randomized to ramucirumab and pembrolizumab (MK3475) to determine if there is sufficient evidence to continue accrual to the study.  
For the evaluation of response, a patient will be coded as a responder if they have a CR or PR, confirmed or unconfirmed, per the definition in Section 10. Patients not known to have a response will be coded as non-responder.  
For the evaluation of disease control at 12 weeks, a patient will be coded as having disease control at 12 weeks if they have a CR, PR, or stable disease at 12 weeks (+/- 2 week window), per the definition in Section 10. Patients not known to have disease control at 12 weeks who have at least 12 weeks of follow-up, will be coded as not having disease control at 12 weeks. The study will continue accrual (Section 11.3) if 1) 3 or more responses or, 2) DCR12 of 50% or greater and at least 1 response. If neither of these criteria are met, then the study will be closed to further accrual. The probability of continuing based on the response rates and DCR12 are presented in the following table.  
| Additional Probability of Disease Control at 12 weeks   |       |      |       |      |       |      |
|---------------------------------------------------------|-------|------|-------|------|-------|------|
| Probability of  Response                                | +0.25 | +0.3 | +0.35 | +0.4 | +0.45 | +0.5 |
| 0.025                                                   | 0.9   | 1.3  | 3.6   | 8.1  | 11.8  | 20.2 |
| 0.05                                                    | 6     | 6.9  | 9.9   | 16.3 | 23.4  | 36.7 |
| 0.1                                                     | 27.1  | 28.5 | 31.4  | 41.6 | 50.9  | 64.2 |
| 0.15                                                    | 52.9  | 54.9 | 59.3  | 64.7 | 72.2  | 79.8 |
| 0.2                                                     | 73.4  | 74.3 | 76.6  | 82   | 87.7  | 92.5 |
| 0.25                                                    | 87.8  | 88.5 | 89.4  | 92.7 | 94.1  | 95.7 |
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table 2. probability of continuing

For example, if the true response probability were 20% and the additional likelihood of DCR12 is 40%, or a 60% chance of DCR12, then the probability of continuing the study based on these criteria is 82%.  
It is estimated that this interim analysis will take place approximately 12-14 months after study activation.  
The second interim analysis evaluating futility will take place when at least 45 (50%) of the expected deaths have occurred, with the provision that this analysis will occur when at least two-thirds of these deaths were at least 3 months after randomization. This analysis will evaluate early stopping for futility testing the alternative hypothesis of a hazard ratio equal to 0.69 using a modified log-rank test for testing non-null hazard ratios at the 1-sided 0.075 level. The alternative was chosen given that we estimate the average hazard ratio to be 0.69 (46% improvement) at the interim analysis if there is a 3-month delay in treatment effect and the hazard ratio after 3 months is 0.5.  
This approach results in a 7.5% chance of falsely concluding futility under the alternative and a 45% chance of not concluding futility under the null. It is estimated that the earliest this analysis would take place is around 19 months (under the null). The total estimated accrual duration is 21 months. Therefore, with the 3-month stipulation, we estimate this analysis will occur around the time of completion of accrual to the study (with approximately 55 events observed).
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a. analysis plans

If the study continues to full accrual, the final analysis will take place upon the observation of 90 OS events, or a maximum of 15 months after completion of accrual. At this time, it is estimated that 110 PFS events will have been reported.  
OS will be evaluated at the one-sided 10% level, as the interim futility analysis does not affect the type I error for OS testing.  
OS and PFS will be compared between the arms using the maximum of the standard log-rank test score statistic and a weighted log-rank test score statistic with weights equal to w(t) =1-S(t), the G(rho,gamma) weights with rho = 0 and gamma = 1 (Fleming and Harrington, 1996). The threshold for this score statistic was determined based on simulation under the null to achieve a type I error rate of 10%.  
The primary analysis of OS is estimated to take place 10-12 months after completion of accrual (or at a maximum of 15 months after completion of accrual as noted above).  
Page 66 Version Date 8/4/2022 Survival distributions will be estimated using the method of Kaplan-Meier (OS, IAPFS, DoR). Median and landmark time-point estimates will be based on the KMestimates. The average hazard ratio will be estimated using a Cox Proportional hazards model. An assessment of the proportional hazards assumption will be performed, and an assessment of the time-dependent HR will be done. Secondary objectives include a comparison of response rates (RR), toxicity, and IA-PFS between the arms. Binary proportions will be summarized with associated confidence intervals. IA-PFS will be summarized as above and using the same test statistic. RR and toxicities will be compared using a chi-squared test at the 1-sided 0.05 level. With 130 patients, this study has 92% power to detect a 20% improvement in RR between the arms (and 80% power to detect a 16% difference).  
An approximate 10% difference in proportions between the arms would be statistically significant at the 10% level. With 65 patients per arm, any toxicity with at least 5% prevalence is likely to be observed (96% chance). Binary proportions can be estimated to within 12% with 95% confidence. If OS is not found to be significantly different between the two arms, but the RR is, then the investigational drug combination may be considered a candidate for definitive evaluation in a Phase III study if there is evidence to support a difference in other efficacy outcomes such as duration of response and/or IA-PFS. In this event, the study team and NCI will discuss the data in detail. If the decision is to pursue a follow-on Phase III within the Lung-MAP infrastructure, a follow-on Phase III study would be developed per SWOG/NCI procedures for new sub-studies. Subgroup analyses will be performed comparing OS, PFS, response between the arms within the stratification factors (PD-L1 and histology) and by TMB status. It is estimated that 70% of patients will be PD-L1 positive and 25% of patients will have squamous histology. TMB will be evaluated both as a continuous factor at categorized as high and low/negative (>10 and <=10). There will be limited power to detect differences between the arms in the smaller of the subsets, but the analysis within the larger subgroups for these factors may have sufficient power to evaluate if there is a differential association within the entire study population versus the subgroup.  
To address the analysis of ctDNA (objective 1.3c), a proposal to use these specimens will be submitted as an amendment to CTEP for approval prior to commencing NGS assays. This proposal will include a scientific justification, clear statement of objectives, and a statistical analysis plan and justification.  
| Table 3: Summary of Design and Planned Analyses                                                                | Final                           |            |             |
|----------------------------------------------------------------------------------------------------------------|---------------------------------|------------|-------------|
| Interim Analysis #1                                                                                            | Interim                         | Analysis   |             |
| Analysis # 2                                                                                                   | (OS)                            |            |             |
| Analysis  Description                                                                                          | Futility evaluation             | Futility   |             |
| evaluation                                                                                                     | Primary  objective              |            |             |
| Analysis                                                                                                       | Single arm evaluation           | Compare OS | Compare  OS |
| Full                                                                                                           |                                 |            |             |
| population  accrued, at                                                                                        |                                 |            |             |
| observation of  45 OS events  when at least  30 of these  deaths were  at least 3  months after  randomization |                                 |            |             |
| 18 eligible patients on                                                                                        |                                 |            |             |
| ramucirumab/pembrolizumab with at least 24 weeks of  follow-up Estimated 30 evaluable for  DCR12               | All eligible  patients  accrued |            |             |
| Analysis  population                                                                                           | Up to 130                       | Up to 130  |             |
| eligible                                                                                                       | eligible  patients  (65/arm)    |            |             |
| Total                                                                                                          | Up to 80 eligible patients      |            |             |
| Accrued                                                                                                        | (40/arm)                        | Test       |             |
| alternative,  P<0.075                                                                                          | P< 0.10                         |            |             |
| Continue:                                                                                                      |                                 |            |             |
| 3+ responses or (DCR12  50% and Response 1+) Stop: 0 responses or (DCR12 <  50% and 1-2 Responses)             |                                 |            |             |
| Decision  Rule                                                                                                 | 30-32  months                   |            |             |
| (maximum  15 months  after  completion  of accrual)                                                            |                                 |            |             |
| Estimated  Time of  Analysis (months  after study  activation)                                                 | 12-14 months                    | 19 months  |             |  
11.6 Accrual Justification  
Accrual estimates are based on our observed experience with Lung-MAP. Eligibility to Lung-MAP has changed over the course of the study with a major modification from initially only allowing 2nd line squamous patients to allowing all previously-treated stage IV or recurrent patients. Given this, the accrual estimates included here are based on observed accrual to Lung-MAP between January 1, 2016 and December 31, 2017. While squamous histology only accounts for 25% of NSCLC, we conservatively estimated that the expansion of eligibility to all histologic types of NSCLC, will double our accrual numbers. Between January 1, 2016 and December 31, 2017, a total of 953 registered to be screened, 737 received a sub-study assignment, and 335 registered to a sub-study of LUNGMAP. However, in this time approximately 50% of patients not able to register to a sub-study was due to the lack of a study for non-match patients who had received immunotherapy previously, therefore we expect an additional 20-50% of sub-study registrations. Given these numbers, we estimate 400-500 patients registering to a substudy.  
We further estimate based on Lung-MAP experience, that approximately 60% of sub-study registrations will be to a non-match sub-study and 40% of the total registrations (2/3rds of non-match) will be previously-exposed to immunotherapy (IO). Given that this sub-study population is restricted to patients who received IO either concurrently or following platinum-based chemotherapy (estimated to be approximately 70% of patients) and must not have progressed within 12 weeks of IO (estimated to be approximately 60-65% of patients), the estimated proportion patients registering to **S1800A** of all sub-study registrations is 17%, or 68-85 patients per year (6-7/month).
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11.7 data and safety monitoring

The SWOG Data and Safety Monitoring Committee will oversee the conduct of the study.  
The Committee consists of four members from outside of SWOG, 3 SWOG members, 3 non-voting representatives from the National Cancer Institute (NCI), and the Group Statistician (non-voting). The members of this Committee will receive confidential reports every 6 months from the SWOG Statistics and Data Management Center, and will meet at the Group's bi-annual meetings as necessary. The Committee will be responsible for decisions regarding possible termination and/or early reporting of the study.
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12.0 discipline review 12.1 radiology

Central collection is required but review of scans will not be triggered if the study will not be submitted to the FDA for FDA approval of the investigational therapy. Central review of scans will be triggered only if deemed necessary for FDA evaluation. A detailed description of the central radiology PFS review, including image acquisition parameters and image submission instructions, can be found in **LUNGMAP** Section 18.2f.  
a. To ensure the highest standards and consistency between different centers, all scans for disease assessment (baseline, interim and end of treatment scans) must be submitted to the National Cancer Institute's National Clinical Trials Network
(NCTN) Imaging and RT Quality Assurance Service Core (IROC) in Ohio for centralized review (see **S1800A** Section 15.0).  
b. Centralized review will be performed by 3 radiology experts. The scans will be submitted to IROC. IROC will transmit the scans to the reviewers who will transmit the results to the SWOG Statistics and Data Management Center.  
c. Details of submission of scans to IROC for centralized review and on the central review process are listed in **S1800A** Section 15.0 and **LUNGMAP** Section 15.6.
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13.0 registration guidelines

See Section 13.0 of **LUNGMAP** for registration guidelines.  
In order to open Lung-MAP studies at the site, a separate Study Specific Worksheet (SSW) is required to be submitted to the CIRB for the **LUNGMAP** screening protocol and each sub-study.  
13.1 Registration Timing
Patients must plan to begin treatment within 10 calendar days after sub-study registration.  
Note: Some of the standard of care treatments have premedications required prior to start of treatment. See Section 7.2.  
13.2 Investigator/Site Registration
For investigator/site registration, please refer to Section 13.2 of the **LUNGMAP** screening protocol. In addition, a Delegation Task Log is required for this sub-study. Delegation Tasks Log (DTL): Each site must complete a protocol-specific DTL using the DTL application in the Delegation Log section on the CTSU members' website. The Clinical Investigator (CI) is required to review and electronically sign the DTL prior to the site receiving an approved site registration status and enrolling patients to the study. To maintain an approved site registration status the CI must re-sign the DTL at least annually and when a new version of the DTL is released; and activate new task assignments requiring CI sign-off. Any individual at the enrolling site on a participating roster may initiate the site DTL. Once the DTL is submitted for CI approval, only the designated DTL Administrators or the CI may update the DTL. Instructions on completing the DTL are available in the Help Topics button in the DTL application and include a Master Task List, which describes DTL task assignments, CI signature, and CTEP registration requirements.
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14.0 data submission schedule

14.1 Data Submission Requirements Data must be submitted according to the protocol requirements for ALL patients registered, whether or not assigned treatment is administered, including patients deemed to be ineligible. Patients for whom documentation is inadequate to determine eligibility will generally be deemed ineligible.
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14.2 master forms

Master forms can be found on the protocol page on the CTSU website (www.ctsu.org) and (with the exception of the sample consent form and the Registration Worksheet) must be submitted on-line via the Web; see Section below for details.  
14.3 Data Submission Procedures
a. Data collection for this study will be done exclusively through the Medidata Rave®
clinical data management system. Medidata Rave is a clinical data management system being used for data collection for this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role assignments.  
Requirements to access Rave via iMedidata:
- A valid CTEP-IAM account; and
- Assigned a Rave role on the relevant LPO or PO roster at the enrolling site of:
Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements:
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus (AP) registration type; o Rave Investigator role must be registered as a Non-Physician Investigator (NPIVR) or Investigator (IVR); and o Rave Read Only role must hold an Associates (A) registration type.
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and documentation required. Individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the Delegation of Tasks Log (DTL). Upon initial site registration approval for the study in Regulatory Support System (RSS), all persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site staff must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Site staff will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning is required and has not yet been taken, the link to the eLearning will appear under the study name in iMedidata instead of the Rave EDC
link; once the successful completion of the eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC link will display under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website in the Data Management section under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU
members' website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.comi'm having a .  
b. You may also access Rave® via the SWOG CRA Workbench via the SWOG
website (http://swog.org).  
$${\mathsf{n n c h}},$$  
For difficulties with the CRA Workbench, please email technicalquestion@crab.org.  
c. Institutions participating through the Cancer Trials Support Unit (CTSU) please refer to the CTSU Participation Table.  
d. The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered queries and form delinquencies, monitor data quality and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members' website under Data Management. The Rave Home section displays a table providing summary counts of Total Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are available to access details and reports of unanswered queries, delinquent forms, and timeliness reports. Review the DQP modules on a regular basis to manage specified queries and delinquent forms.  
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU website. Staff that have Rave study access can access the Rave study data using a direct link on the DQP.  
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, DQP Queries, and DQP Delinquent Forms modules. Note: Some Rave protocols may not have delinquent form details or reports specified on the DQP. A protocol must have the Calendar functionality implemented in Rave by the Lead Protocol Organization (LPO) for delinquent form details and reports to be available on the DQP. Site staff should contact the LPO
Data Manager for their protocol regarding questions about Rave Calendaring functionality.
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a. within 15 days of

S1800A Onstudy Form If needed, also submit:
Radiation Therapy Form Brain Metastases Form S1800A Eligibility Criteria Form Smoking Status Assessment Form Baseline Tumor Assessment Form (RECIST 1.1)
Radiology reports from all scans performed to assess disease at baseline* If needed, RT summary and/or planning document* If needed, radiology report from brain CT/MRI*
*(NOTE: Upload reports via the Source Documentation: Baseline form in Rave)
For patients screened under legacy **S1400**: PD-L1 testing (Dako 22C3 PharmDX
assay) report.  
(NOTE: Upload report via the Source Documentation: Baseline form in Rave)
Submit to IROC via TRIAD for Central Radiology Review: Images from scans performed to assess disease at baseline as specified in Section 15.5.  
b. IF PATIENT CONSENTS, SUBMIT SPECIMENS:
Specimens as specified in Section 15.0 of **S1800A.**
c. WITHIN 15 DAYS AFTER EACH CYCLE (CYCLE = 21 DAYS) OF TREATMENT,
SUBMIT:
S1800A Treatment Form S1800A Adverse Event Form* S1800A Laboratory Values Form For Cycle 1 only: submit the **S1800A** Pre-Treatment Laboratory Values Form.  
*For the last cycle of treatment, include all adverse events occurring within 30 days  
  
after the last treatment.
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d. within 15 days after

Follow-Up Tumor Assessment Form (RECIST 1.1) documenting results of  
  
assessment Radiology reports from all scans performed to assess disease at follow-up (NOTE:
Upload reports via the Source Documentation: Follow-up form in Rave)
Submit to IROC via TRIAD for Central Radiology Review: Images from scans performed to assess disease as specified in **S1800A** Section 15.5.  
Off Protocol Treatment Notice documenting reasons for off protocol treatment Smoking Status Assessment Form Forms specified in Section 14.4.c.
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f. once off protocol treatment

Advanced NSCLC Follow-Up Form If needed, also submit:
Radiation Therapy Form Brain Metastases Form Late Adverse Events (if prior to treatment for progression or relapse or a second primary, and prior to non-protocol treatment, the patient experiences any severe
[Grade ≥ 3] adverse event that is possibly, probably, or definitely related to protocol treatment, or a Serious Adverse Event [SAE] of any grade/attribution, that has not been previously reported). Note: Patients who enroll on a new sub-study following progression must continue follow-up on this sub-study, in addition to follow-up on the new sub-study. See Section 14.4i.
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g. within 15 days of

Site(s) of Progression or Relapse Form Follow-Up Tumor Assessment Form (RECIST 1.1)
Radiology reports from all scans performed to assess disease at follow-up (NOTE:
Upload reports via the Source Documentation: Follow-up form in Rave)
Submit to IROC via TRIAD for Central Radiology Review: Images from scans performed to assess disease as specified in Section 15.5.
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h. within 28 days of

Submit the Notice of Death documenting death information and **S1800A** End of Study form. In addition, if the patient was still on protocol treatment, submit materials specified in Section 14.4e or if patient was no longer on treatment, submit a final Advanced NSCLC Follow-Up Form.
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i. data submission for patients

Submit the Request for New Sub-Study Assignment Form under the patient's screening protocol (LUNGMAP or **S1400**) in Rave®. Continue follow-up on S1800A per Section 9.0. See Section 14 of the screening protocol for additional data submission requirements following request for new sub-study assignment.
s1800a end of study form
15.0 special instructions

15.1 SWOG Specimen Tracking System (STS)
See **LUNGMAP** Section 15.1 for SWOG Specimen Tracking System (STS) instructions.  
15.2 Correlative Studies and Banking (Optional for Patients)
Specimens for correlative studies and banking (submitted to the SWOG Biospecimen Bank
- Solid Tissue, Myeloma and Lymphoma Division, Lab \#201) are considered optional for the patient:
a. With patient's consent, specimens must be collected and submitted as follows:
1. Buffy Coat and Plasma:
Specimens must be collected at the following times:
- Pre-study (after consenting and prior to treatment initiation on substudy)
Note: If a patient provided buffy coat and plasma for **LUNGMAP** (see Section 15.0 of **LUNGMAP**) and the blood collection was within 42 days prior to the sub-study randomization, then no additional prestudy blood specimen is required.  
- Weeks 4, 7, 10 - Patients that go off protocol treatment are not required to continue to submit specimens.  
- First Progression after study treatment - First progression blood should be collected by the time of the next visit after documenting progression and prior to starting any non-protocol therapy.  
Collect approximately 8-10 mL of blood in EDTA tubes. Blood should be processed within one hour after venipuncture. If immediate processing within this time frame is not possible, then refrigerate (4°C) blood in EDTA
tubes. The approximate time from collection to processing should be recorded as part of the patient's source documentation. EDTA tubes must be centrifuged at 800 x g for 10 minutes at 4°C for the collection of plasma.  
[Note: Sites that do not have a refrigerated centrifuge should spin at room temperature and ensure specimens are placed on ice (regular, not dry)
immediately after being drawn and process rapidly.] Using a pipette, transfer the plasma to a 15-mL centrifuge tube. Remove the buffy coat layer (thin white or gray layer of cells between the plasma and red blood cells) and split between two appropriately labeled 2-mL cryovials.  
Spin the plasma in the 15-mL centrifuge tube at 800 x g for an additional 10 minutes. Avoiding any pelleted material, pipette the plasma into labeled cryovials at 0.5 ml aliquots. Plasma must be clear before freezing; no cells or debris should be present. Plasma and buffy coat vials must be placed upright in a -80˚C freezer immediately after processing to ensure long-term viability. Frozen plasma and buffy coat specimens must be shipped to the SWOG
Biospecimen Bank on dry ice. Frozen specimens may be shipped in batches - refer to Section 15b.  
Samples for multiple patients may be shipped in batches to the SWOG
Biospecimen Bank - Solid Tissue, Myeloma and Lymphoma Division, Lab \#201, every 3 months, with a maximum of 5 patients recommended, if not more frequently. For additional information about labeling and shipping instructions for frozen plasma and buffy coat specimens, refer to the SWOG Specimen Submission webpage (https://www.swog.org/clinical-trials/biospecimenresources/biospecimen-processing-and-submission-procedures).  
1. Liquid specimens must be labeled with the following:
- SWOG patient number
- Patient initials
- Collection date (date the specimen was collected from the patient) - Specimen type (e.g. blood, serum, etc.)
c. Specimen collection kits are not being provided for this submission; sites must use institutional supplies.
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15.3 lungmap ctdna assay -

Blood specimens will be collected in order to isolate and investigate circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB) - a form of fragmented DNA released into patient peripheral circulation specifically from the tumors. Analysis of ctDNA can reveal the presence of tumor-specific mutations and other abnormalities that can serve as biomarkers. The information collected will be limited to tumor-specific abnormalities known or suspected to play roles in tumor evolution. Patient germ-line genetic information will not be collected.
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a. kit ordering

Immediately after identifying a patient for trial and prior to treatment initiation, sites must contact Foundation Medicine Inc. - Blood Samples, Lab \#232, to order kits as follows:
- Email request to FMI Client Services at lung.map@FoundationMedicine.com
- Site must identify itself as a participant in the **S1800A** SWOG Lung-MAP substudy and request the "Lung-MAP ctDNA Clinical Trial Kit."
- Reference the FMI Study ID: FoundationOneLiquidDx-AMC-PRO-20-1496
- Provide the following information:
o Treating physician's name o Treating physician's email address o Contact name o Contact email address o Contact phone o Address to which kits should be sent o Number of kits needed (one per patient per timepoint)
Kits will arrive within 3 days after ordering (excluding weekends and holidays).  
Kits will read "Foundation Medicine Clinical Trials Kit," and include two Roche CellFree DNA blood collection tubes, collection instructions, FedEx return bags, and pre-printed FedEx airway bills. Blood collection tubes must be used before their expiration date.  
Collect blood:
- After sub-study registration and prior to treatment initiation o Recommended to collect on Cycle 1 Day 1 (prior to treatment)
during other labs to lessen patient visits Note: This is a separate requirement for a ctDNA whole blood specimen for all patients registered to **S1800A**, regardless of whether or not there was a ctDNA blood collection for LUNGMAP.  
- At progression - First progression blood should be collected by the time of the next visit after documenting progression and prior to starting any non-protocol therapy c. Specimen Collection and Shipment Instructions Specimen must be logged via the SWOG Specimen Tracking System.  
Step 1: Check special tubes provided in kits to confirm liquid is clear and without cloudiness or crystals.  
Step 2: Label tubes with date of collection, patient identifiers as requested on the included labels (patient date of birth can be added as an extra identifier),
and sub-study number.  
Step 3: Collect two tubes of whole blood (8.5 mL per tube)
o Prevent backflow: tubes contain chemical additives and it is important to avoid backflow into patient o Collect specimen by venipuncture o Fill tubes completely (8.5 mL per tube)
Step 4: Remove the tube from adapter and immediately mix by gentle inversion 8  
  
to 10 times. Inadequate or delayed mixing may result in inaccurate test results. One inversion is a complete turn of the wrist, 180̊ and back, per the figure below.  
Step 5: Place specimen into the specimen collection kit.  
o Confirm each tube is labeled with the supplied labels indicating the date of collection and two unique patient identifiers (label included in kit).  
Step 6: Select "Ship this Shipment and Generate Packing List" in the SWOG
Specimen Tracking System to generate the Packing List. A copy of the SWOG Specimen Tracking Packing List must be included in the shipment.  
Confirm that the tubes are labeled as specified on the Packing List.  
Step 7: Preferably on the same day of collection, ship via FedEx overnight delivery at ambient temperature. Do not freeze or refrigerate blood samples. Keep at 43-99̊F (6-37̊C).  
FMI accepts Saturday deliveries. If shipping on a Friday, please overnight shipment, and mark for Saturday delivery.
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d. specimen usage

Cell-free, circulating DNA will be isolated from the plasma component of the whole blood. Using a hybrid-capture, next-generation sequencing technology (developed by Foundation Medicine), alterations in clinically significant cancer genes (oncogenes and tumor suppressor genes) will be identified and quantitated relative to wild-type sequences. Tumor-specific alterations will include point mutations, small insertions and deletions, chromosomal rearrangements and copy number/amplification events in (**LUNGMAP** ctDNA Assay) including an assessment of tumor mutation burden (TMB) will be conducted using ctDNA. A full proposal will be developed, reviewed, and approved by SWOG and CTEP once funding has been obtained.  
The ctDNA results are for research purposes and will not be shared with the investigator or patient.
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15.4 specimen flow diagram

Please refer to Section 15 of **LUNGMAP** for the specimen flow diagram for the screening protocol.  
15.5 Radiology Review (Required)
CT, PET/CT, and/or MRI images must be locally read and interpreted by the local site radiology service. Imaging exams must then be submitted to the Imaging and Radiation Oncology Core (IROC) at Ohio via TRIAD Imaging Submission procedures for central data collection and quality control (QC) check as well as retrospective central review.  
a. CT, PET/CT, and/or MRI images must be submitted to IROC Ohio for central review at the following timepoints:  
- Baseline
- Every 6 weeks for the first year, then every 12 weeks until progression and discontinuation of treatment.
All study participants must have a CT (or MR or PET/CT) exam prior to sub-study entry. Participants must then undergo additional imaging every 6 weeks for the first year, then every 12 weeks until progression of disease and discontinuation of treatment. The same imaging modality used for the pre-treatment exam must be used for the post-treatment exams (see Section 10.1c). Each exam should be performed per **LUNGMAP** Section 18.2f. IROC will perform a QC of the imaging exams.  
Clinical management and treatment decisions will be made by the treating physician based on local site assessments and other clinically appropriate considerations. Central review of scans will not be triggered if the study will not be submitted to the FDA for FDA approval of the investigational therapy. Central review of scans will be triggered only if deemed necessary for FDA evaluation. A detailed description of the central radiology PFS review, including image acquisition parameters and image submission instructions, can be found in **LUNGMAP**
Section 18.2f. Transfer of Images and Data (TRIAD) is the American College of Radiology's
(ACR) image exchange application. TRIAD provides sites participating in clinical trials a secure method to transmit images. TRIAD anonymizes and validates the images as they are transferred.
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1. triad access requirements

TRIAD will be the sole means of image transfer to the IROC Ohio. TRIAD
should be installed prior to study participant enrollment to ensure prompt secure, electronic submission of imaging.  
- A valid CTEP-IAM account (see **LUNGMAP** Section 13.2).  
- Registration type of: Associate (A), Associate Plus (AP), NonPhysician Investigator (NPIVR), or Investigator (IVR). Refer to the CTEP Registration Procedures section for instructions on how to request a CTEP-IAM account and complete registration in RCR.  
- TRIAD Site User role on the NCTN or ETCTN roster.
All individuals on the Imaging and Radiation Oncology Core provider roster have access to TRIAD and may submit images for credentialing purposes, or for enrollments to which the provider is linked in OPEN.
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2. triad installations

To submit images, the individual holding the TRIAD Site User role will need to install the TRIAD application on their workstation. TRIAD
installation documentation is available at: https://triadinstall.acr.org/triadclient/. This process can be done in parallel to obtaining your CTEP-IAM account and RCR registration.  
For questions, contact TRIAD Technical Support staff via email TRIADSupport@acr.org or 1-703-390-9858.
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16.0 ethical and regulatory considerations

The following must be observed to comply with Food and Drug Administration regulations for the conduct and monitoring of clinical investigations; they also represent sound research practice.
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informed consent

The principles of informed consent are described by Federal Regulatory Guidelines (Federal Register Vol. 82, No. 12, January 19, 2017) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They must be followed to comply with FDA regulations for the conduct and monitoring of clinical investigations.
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institutional review

This study must be approved by an appropriate institutional review committee as defined by Federal Regulatory Guidelines (Federal Register Vol. 82, No. 12, January 19, 2017) and the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  
An investigator is required to maintain adequate records of the disposition of investigational drugs according to procedures and requirements governing the use of investigational new drugs as described in the Code of Federal Regulations 21 CFR 312 and the CTEP Investigator's Handbook.
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publication and industry contact

The agents supplied by CTEP, DCTD, NCI used in this protocol are provided to the NCI under Collaborative Agreements (CRADA, CTA, CSA) between the Pharmaceutical Companies
(hereinafter referred to as "Collaborators") and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines in addition to the provisions in the
"Intellectual Property Option to Collaborator"
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms of award apply to the use of the Agents in this study:
1. Agents may not be used for any purpose outside the scope of this protocol, nor can Agents be transferred or licensed to any party not participating in the clinical study. Collaborators data for Agents are confidential and proprietary to Collaborators and shall be maintained as such by the investigators. The protocol documents for studies utilizing Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient's family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov.  
2. For a clinical protocol where there is an investigational Agent used in combination with
(an)other investigational Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"):
a. NCI will provide all Collaborators with written notice regarding the existence and nature of any agreements governing their collaboration with NCI, the design of the proposed combination protocol, and the existence of any obligations which would tend to restrict NCI's participation in the proposed combination protocol.  
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own investigational Agent.  
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the MultiParty Data solely for development, regulatory approval, and commercialization of its own Agent.  
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available exclusively to Collaborators, the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order as described in the IP
Option to Collaborator
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.  
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them.  
5. Any data provided to the Collaborators for Phase III studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.  
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group office for Cooperative Group studies or by the principal investigator for nonCooperative Group studies for immediate delivery to Collaborators for advisory review and comment prior to submission for publication. Collaborators will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to the Collaborator's intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborators for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/media presentation should be sent to:
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e-mail ncicteppubs@mail.nih.gov

The Regulatory Affairs Branch will then distribute them to the Collaborators. No publication, manuscript or other form of public disclosure shall contain any of the Collaborator's confidential/proprietary information.
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monitoring

This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 31.
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trial master file

This is an FDA registration study; therefore, all participating sites should be FDA "inspection ready".  
This entails maintaining a Trial Master File that includes essential documents that may be subject to FDA oversight. A list of essential documents is available on the SWOG website under QA/Audits, https://swog.org/Visitors/QA/Index.asp.
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confidentiality

Please note that the information contained in this protocol is considered confidential and should not be used or shared beyond the purposes of completing protocol requirements until or unless additional permission is obtained.  
16.1 Serious Adverse Event Reporting Requirements
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a. definition and purpose

Definition: Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. (FDA,
21 CFR 312.32). See Table 16.1 for definition of a Serious Adverse Event (SAE) and reporting requirements.  
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. (Directions for routine reporting are provided in Section 14.0.) Additionally, certain adverse events must be reported in an expedited manner to allow for more timely monitoring of patient safety and care. The following guidelines prescribe expedited adverse event reporting for this protocol.
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b. reporting method

This study requires that expedited adverse events be reported to SWOG
Operations Office using the Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS). CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  
NOTE: For this study, all adverse events requiring expedited reporting must initially be reported on the Adverse Event Form in the appropriate Treatment Cycle folder in Medidata Rave. The CTEP-AERS report must then be initiated directly from the Adverse Event Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-AERS website.  
c. When to report an event in an expedited manner Some adverse events require 24-hour notification (refer to Table 16.1) via CTEPAERS.  
In the rare event when internet connectivity is disrupted, a 24-hour notification is made to SWOG by telephone at 210-614-8808 or by email at adr@swog.org. An electronic report MUST be submitted immediately upon re-establishment of internet connection.  
When the adverse event requires expedited reporting, submit the report via CTEPAERS within the number of calendar days of learning of the event specified in Table 16.1.  
d. Other recipients of adverse event reports The SWOG Operations Office will forward reports and documentation to the appropriate regulatory agencies and drug companies as required.  
Adverse events determined to be reportable to the Institutional Review Board responsible for oversight of the patient must be reported according to local policy and procedures.
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e. expedited reporting for investigational

Expedited reporting is required if the patient has received at least one dose of the investigational agent(s) as part of the trial. Reporting requirements are provided in Table 16.1. The investigational agent(s) used in Arm B of this study are ramucirumab and pembrolizumab (MK-3475). If there is any question about the reportability of an adverse event or if internet connectivity is disrupted, please telephone or email the SAE Program Manager at the Operations Office, 210/6148808 or adr@swog.org, before preparing the report. NOTE: For this study, all adverse events requiring expedited reporting must initially be reported on the Adverse Event Form in the appropriated Treatment Cycle folder in Medidata Rave. Once the adverse event is entered into RAVE, the Rules Engine will confirm whether or not the adverse event requires expedited reporting. The CTEP-AERS report must then be initiated directly from the Adverse Event Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-AERS website. Sites are encouraged to confirm the Expedited Reporting Evaluation Recommendation with the reporting criteria outlined in Table 16.1 **(or**
section 16.1f).
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table 16.1 late phase 2

An adverse event is considered serious if it results in ANY of the following outcomes:  
  
  
1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥
24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
ALL **SERIOUS** adverse events that meet the above criteria **MUST** be immediately reported to the NCI via CTEP-AERS within the timeframes detailed in the table below.  
| Hospitalization                                                                                                                           | Grade 1          | Timeframes       | Grade 3 Timeframes   | Grade 4 & 5   |
|-------------------------------------------------------------------------------------------------------------------------------------------|------------------|------------------|----------------------|---------------|
| Grade 2                                                                                                                                   |                  |                  |                      |               |
| Timeframes                                                                                                                                | Timeframes       |                  |                      |               |
| Resulting in  Hospitalization                                                                                                             | 10 Calendar Days | 24-Hour 5        |                      |               |
| ≥ 24 hrs                                                                                                                                  | Calendar  Days   |                  |                      |               |
| Not resulting in Hospitalization                                                                                                          | Not required     | 10 Calendar Days |                      |               |
| ≥ 24 hrs NOTE: Protocol specific exceptions to expedited reporting of serious adverse events (if applicable) are  found in Section 16.1f. |                  |                  |                      |               |  
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events (if applicable) are  
  
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
  
- All Grade 4, and Grade 5 AEs Expedited 10 calendar day reports for:
- Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization
- Grade 3 adverse events May 5, 2011 f. Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent under a non-CTEP-IND:
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1. group-specific instructions.

Supporting Documentation Submission - Within 5 **calendar days** submit the documentation supporting the CTEP-AERS report to the SWOG
Operations Office by fax 210-614-0006. Specific instructions will be sent by email to the reporting site by the SAE Program Manager.
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g. expedited reporting for commercial

Commercial reporting requirements are provided in Table 16.2. The commercial agent(s) used in Arm A of this study are docetaxel, gemcitabine, pemetrexed, or ramucirumab plus docetaxel. If there is any question about the reportability of an adverse event or if internet connectivity is disrupted please telephone or email the SAE Program Manager at the Operations Office, 210/614-8808 or adr@swog.org, before preparing the report. NOTE: For this study, all adverse events requiring expedited reporting must initially be reported on the Adverse Event Form in the appropriated Treatment Cycle folder in Medidata Rave. Once the adverse event is entered into RAVE, the Rules Engine will confirm whether or not the adverse event requires expedited reporting. The CTEP-AERS report must then be initiated directly from the Adverse Event Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-AERS website. Sites are encouraged to confirm the Expedited Reporting Evaluation Recommendation with the reporting criteria outlined in Table 16.2.  
Table 16.2. Expedited reporting requirements for adverse events experienced by patients on study Arm A who have received the commercial drug(s) listed in 16.1g above within 30 days of the last administration of the commercial agent(s).  
| Attribution                                                                                                                   | Grade 4   | Grade 5a   |           |
|-------------------------------------------------------------------------------------------------------------------------------|-----------|------------|-----------|
| Unexpected                                                                                                                    | Expected  | Unexpected | Expected  |
| Unrelated or  Unlikely                                                                                                        | CTEP-AERS | CTEP-AERS  |           |
| Possible,  Probable,                                                                                                          | CTEP-AERS | CTEP-AERS  | CTEP-AERS |
| Definite                                                                                                                      |           |            |           |
| CTEP-AERS: Indicates an expedited report is to be submitted via CTEP-AERS within 10 calendar days  of learning of the eventb. |           |            |           |  
CTEP-AERS: Indicates an expedited report is to be submitted via CTEP-AERS within 10 calendar days of learning of the eventb.  
a This includes all deaths within 30 days of the last dose of treatment with a commercial agent(s),
regardless of attribution. Any death that occurs more than 30 days after the last dose of treatment with a commercial agent(s) and is attributed (possibly, probably, or definitely) to the agent(s) and is not due to cancer recurrence must be reported according to the instructions above.  
b Submission of the on-line CTEP-AERS report plus any necessary amendments generally completes the reporting requirements. You may, however, be asked to submit supporting clinical data to the Operations Office in order to complete the evaluation of the event. If requested, the specified data should be sent within 5 calendar days by fax to 210-614-0006.
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h. reporting secondary malignancy including

radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm.  
SWOG requires all secondary malignancies that occur following treatment with an agent under a Non-NCI IND to be reported via CTEP-AERS. Three options are available to describe the event.  
- Leukemia secondary to oncology chemotherapy (e.g., Acute Myelocytic Leukemia [AML])
- Myelodysplastic syndrome (MDS) - Treatment-related secondary malignancy Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.  
Second Malignancy: A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). *Second malignancies require ONLY routine reporting.* For more information see:
https://ctep.cancer.gov/protocolDevelopment/electronic_applicati ons/docs/aeguidelines.pdf Supporting documentation should be submitted to CTEP in accordance with instructions provided by the CTEP-AERS system. Supporting documentation must also be submitted to SWOG Operations Office by fax to 210/614-0006 NOTE: If a patient has been enrolled in more than one NCI-sponsored study, the report must be submitted for the most recent trial.
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i. reporting pregnancy pregnancy loss

1. **Pregnancy** Study participants who become pregnant while on study; that pregnancy should be reported in an expedited manner via CTEP-AERS
as Grade 3 "Pregnancy, puerperium and perinatal conditions - Other (pregnancy)" under the **Pregnancy, puerperium and perinatal** conditions SOC.  
Additionally, the pregnancy outcome for patients on study should be reported via CTEP-AERS at the time the outcome becomes known, accompanied by the same Pregnancy Report Form used for the initial report.  
2. **Pregnancy Loss** Pregnancy loss is defined in CTCAE as "Death in utero." Pregnancy loss should be reported expeditiously as Grade 4
"Pregnancy loss" under the Pregnancy, puerperium and perinatal conditions SOC. A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, puerperium and perinatal conditions SOC, as currently CTEPAERS recognizes this event as a patient death.  
3. **Death Neonatal** Death neonatal is defined in CTCAE as "Newborn death occurring during the first 28 days after birth A neonatal death should be reported expeditiously as **Grade 4 "Death neonatal"** under the General disorders and administration SOC. Neonatal death should NOT be reported as a Grade 5 event under the General disorders and administration SOC as currently CTEP-AERS
recognizes this event as a patient death.  
NOTE: When submitting CTEP-AERS reports for "Pregnancy, "Pregnancy loss",
or "Neonatal loss", the Pregnancy Information Form should also be completed and faxed with any additional medical information to 210/614-0006. The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) should be documented in the "Description of Event" section of the CTEP-AERS report.  
The Pregnancy Information Form is available at:
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm
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17.0 bibliography

1 **Nivolumab** versus Docetaxel in Advanced Nonsquamous Non-Small-Cell **Lung Cancer**. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E,
Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE,
Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med.;373(17):1627-39. doi: 10.1056/NEJMoa1507643, 2015.  
2 **Nivolumab** versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell **Lung Cancer**, Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR.  
Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 373(2):123-35. doi: 10.1056/NEJMoa1504627, 2015.  
3 **Pembrolizumab** versus Chemotherapy for PD-L1-Positive Non-Small-Cell **Lung Cancer**, Reck M,
Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive nonsmall-cell lung vancer. N Engl J Med. 375(19):1823-1833, 2016.  
4 **Pembrolizumab** versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Herbst RS, Baas P, Kim DW, Felip E,
Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE010): a randomised controlled trial. Lancet. 387(10027):1540-50. doi: 10.1016/S01406736(15)01281-7, 2016.  
5 **Atezolizumab** versus docetaxel in patients with previously treated non-small-cell **lung cancer**
(OAK): a phase 3, open-label, multicentre randomised controlled trial. Rittmeyer A, Barlesi F,
Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 389(10066):255265. doi: 10.1016/S0140-6736(16)32517-X, 2017 6 **Nivolumab** plus ipilimumab as first-line treatment for advanced non-small-cell lung **cancer**
(CheckMate 012): results of an open-label, phase 1, multicohort study. Hellmann MD, Rizvi NA,
Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, Ready NE, Gerber DE, Chow LQ, Juergens RA, Shepherd FA, Laurie SA, Geese WJ, Agrawal S, Young TC, Li X, Antonia SJ. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. (1):31-41. doi: 10.1016/S14702045(16)30624-6, 2017.  
7 Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:711–23.  
8 **Nivolumab** plus ipilimumab as first-line treatment for advanced non-small-cell **lung cancer**
(CheckMate 012): results of an open-label, phase 1, multicohort study.  
Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, Ready NE, Gerber DE, Chow LQ, Juergens RA, Shepherd FA, Laurie SA, Geese WJ, Agrawal S, Young TC, Li X,
Antonia SJ. Lancet Oncol. 2017 Jan;18(1):31-41. doi: 10.1016/S1470-2045(16)30624-6.  
9 Ziogas AC, Gavalas NG, Tsiatas M, Tsitsilonis O, Politi E, Terpos E, Rodolakis A, Vlahos G,
Thomakos N, Haidopoulos D, Antsaklis A, Dimopoulos MA, Bamias A. EGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2. Int J Cancer. 2012 Feb 15;130(4):857-64. doi: 10.1002/ijc.26094. Epub V Ziogas et al., Int. J.  
Cancer 130, 857–864.  
10 Suzuki H, Onishi H, Wada J, Yamasaki A, Tanaka H, Nakano K, Morisaki T, Katano M. VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur J Immunol. (1):197-203. doi: 10.1002/eji.200939887, 2010.  
11 Terme M, Tartour E, Taieb J. VEGFA/VEGFR2-targeted therapies prevent the VEGFA-induced proliferation of regulatory T cells in cancer. Oncoimmunol.Oncoimmunology. 2(8): e25156. Epub, 2013.  
12 Roland CL, et al. Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer.  
13 Gabrilovich D, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system.  
Nat Rev Immunol. (3):162-74. doi: 10.1038/nri2506, 2009.  
14 Rivera et al. Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends Immunol.  
Epub 36(4):240-9. Rivera LB1, Bergers G2. Trends in Immunology, April 2015, Vol. 36, No. 4, 2015.  
15 Jennifer S, Ko, Zea AH, Rini, BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH. Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients. Clin Cancer Res. 15: 2148-2157, 2009.  
16 Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, Yagita H, Nakajima Y.  
Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2
(VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. 172(3):500-6. doi:
10.1111/cei.12069, 2013.  
17 Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O'Bryant C, Chow LQ,
Serkova NJ, Meropol NJ, Lewis NL, Chiorean EG, Fox F, Youssoufian H, Rowinsky EK, Eckhardt SG. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor2. J Clin Oncol. 28(5):780-7. doi: 10.1200/JCO.2009.23.7537, 2010.  
18 Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Published: PlumX Metrics, Volume 384, No. 9944, p665–673, 23 August 2014, doi:
http://dx.doi.org/10.1016/S0140-6736(14)60845-X, 2014.  
19 Reck M, Paz-Ares LG, Bidoli P, Cappuzzo F, Dakhil SR, Moro-Sibilot D. Exploratory subgroup analysis of patients (Pts) refractory to first-line (1L) chemotherapy from REVEL, a randomized phase III study of docetaxel (DOC) with ramucirumab (RAM) or placebo (PBO) for second-line (2L)
treatment of stage IV non-small-cell lung cancer (NSCLC). doi: 10.1200/JCO. 34.15_suppl.9079 Journal of Clinical Oncology 34, no. 15_suppl (May 2016) 9079-9079, 2016.  
20 Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott D, Cho DC, Vaishampayan U, George S, Olencki T, Tarazi J, Rosbrook B, Fernandez K, Keefe, S Choueiri TK. ESMO Congress, Genitourinary tumours, non-prostate. Annals of Oncology 27 (6): 266-295. 10.1093/annonc/mdw373, 2016.  
21 Herbst RS, Baas P, Kim D, Felip E, Pérez-Gracia JL, Han J, Molina J, KimJ, Dubos Arvis C, Ahn MA, Majem M, Fidler MJ, De Castro Jr. G, Garrido M, Shentu1 Y, Lubiniecki G, Garon EB. Interim safety and clinical activity in patients with advanced NSCLC from a multi-cohort phase 1 study of ramucirumab plus pembrolizumab. ESMO 2016 Congress, NSCLC, metastatic. Annals of Oncology 7 (6): 1-36. 10.1093/annonc/mdw435.34, 2016.  
22 Herbst RS, Chau I, Petrylak DP, et al. Activity of ramucirumab with pembrolizumab by PD-L1 expression in advanced solid tumors: phase 1a/b study in later lines of therapy. ASCO, 2018.  
23 Rizvi NA, Antonia SJ, Shepherd FA, et al. Nivolumab (Anti-PD-1; BMS-936558, ONO-4538)
maintenance as monotherapy or in combination with bevacizumab (BEV) for non-small lung cancer
(NSCLC) previously treated with chemotherapy. Radiation Oncol, 90 (suppl 5) 2014, p. S32
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18.0 appendix

18.1 New York Heart Association Classification  
| 18.4   | Live Vaccines Examples   |
|--------|--------------------------|  
| 18.5   | PD-L1 22C3 IHC Assay   |
|--------|------------------------|  
18.2 Instructions for the SWOG Biospecimen Bank 18.3 Child-Pugh Scoring  
| Need for                                          | Physical Ability                                                                                        |             |                     |                   |
|---------------------------------------------------|---------------------------------------------------------------------------------------------------------|-------------|---------------------|-------------------|
| Class                                             | Cardiac Symptoms                                                                                        | Limitations | Additional Rest*    | To Work**         |
| I                                                 | None                                                                                                    | None        | None                | Full Time         |
| II                                                | Only moderate                                                                                           | Slight      | Usually only slight | Usually full time |
| or occasional                                     |                                                                                                         |             |                     |                   |
| III                                               | Defined, with less                                                                                      | Marked      | Usually moderate    | Usually part time |
| than ordinary activity                            |                                                                                                         |             |                     |                   |
| IV                                                | May be present                                                                                          | Extreme     | Marked              | Unable to work    |
| even at rest, & any activity increases discomfort |                                                                                                         |             |                     |                   |
| *                                                 | To control or relieve symptoms, as determined by the patient, rather than as advised by  the physician. |             |                     |                   |
| **                                                | At accustomed occupation or usual tasks.                                                                |             |                     |                   |  
18.1 New York Heart Association Classification  
18.2 Instructions for the SWOG Biospecimen Bank
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frozen plasma and buffy coat

The SWOG Biospecimen Bank will receive frozen plasma and buffy coat at up to 5 timepoints per patient. Upon receipt, the Bank will accession, barcode, and bank specimens in a -80°C freezer.
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formalin-fixed paraffin-embedded (ffpe) tissue

The SWOG Biospecimen Bank will receive FFPE specimens as either blocks or slides/sections at up to 1 timepoint per patient. Upon receipt, the Bank will accession, barcode, and bank specimens at ambient temperature. At the end of the study, the Bank will receive notification from the SWOG Statistics and Data Management Center to distribute specimens for testing, if applicable.
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18.3 child-pugh scoring

The score is used to assess the prognosis of chronic liver disease and employs five clinical measures of liver disease. Each measure is scored 1–3, with 3 indicating most severe derangement.  
| Measure                                    | 1 point         | 2 points                 | 3 points           |
|--------------------------------------------|-----------------|--------------------------|--------------------|
| Total bilirubin, mmol/L  (mg/dL)           | <34 (<2)        | 34–50 (2–3)              | >50 (>3)           |
| Serum albumin, g/dL                        | >3.5            | 2.8–3.5                  | <2.8               |
| Prothrombin time,  prolongation in seconds | <4.0 (<1.7)     | 4.0–6.0 (<1.7-2.2)       | > 6.0 (>2.2)       |
| (or INR) Ascites                           | None            | Mild (or suppressed with | Moderate to severe |
| medication)                                | (or refractory) |                          |                    |
| Hepatic encephalopathy                     | None            | Grade I–II               | Grade III–IV       |
| Class A                                    | Class B         | Class C                  |                    |
| Total points                               | 5-6             | 7-9                      | 10-15              |
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18.4 live vaccines examples

Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed.  
The FMI Dako PD-L1 (22C3) IHC assay was done as part of the Lung-MAP Screening Study to randomize patients for **S1800A**. PD-L1 IHC 22C3 pharmDx is indicated as an aid in identifying NSCLC patients for treatment. The results are based on PD-L1 protein expression determined by Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. A specimen was considered to have PD-L1 expression if TPS ≥ 1% and high PD-L1 expression if TPS ≥ 50%. The clinical value for testing PDL1 expression is well documented.(1)
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reference

1 Covert, M., Sheehan, C., Crouch, T., and Ramikissoon, S. Dako PD-L1 IHC 22C3 pharmDx Immunohistochemistry (IHC) Assay Verification Report. Foundation Medicine, Inc.PD-L1 MBS-037, 2017.