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PRIVILEGED COMMUNICATION FOR INVESTIGATIONAL USE ONLY T
S1800A: (Non-Match Immunotherapy Combination Sub-Study)
SWOG **CANCER RESEARCH NETWORK**
TITLE
LUNGMAP, A MASTER PROTOCOL TO EVALUATE BIOMARKER-DRIVEN THERAPIES AND
IMMUNOTHERAPIES IN PREVIOUSLY TREATED NON-SMALL CELL LUNG CANCER (LUNG-MAP
SCREENING STUDY)
S1800A, A PHASE II RANDOMIZED STUDY OF RAMUCIRUMAB PLUS PEMBROLIZUMAB (MK-3475)
VERSUS STANDARD OF CARE FOR PATIENTS PREVIOUSLY TREATED WITH IMMUNOTHERAPY
FOR STAGE IV OR RECURRENT NON-SMALL CELL LUNG CANCER (LUNG-MAP NON-MATCHED
SUB-STUDY)
NCT \#03971474 This is an **FDA Registration Trial. Additional site requirements include:**
- **maintenance of a Trial Master File (https://www.swog.org/sites/default/files/docs/2017-**
10/Guidance%20on%20FDA%20Inspection.pdf)
- completion of a protocol **specific Delegation of Task Log (DTL) (see Section 13.2)**
- additional monitoring (see LUNGMAP Appendix 18.2)
LUNGMAP and its sub-studies are being conducted under SWOG IND **143217 and CIRB. The**
LUNGMAP **study is considered a single study under one IND, consisting of the screening protocol**
and multiple sub-studies. Each sub-study protocol operates independently and has its own version date. However, for regulatory purposes, all LUNGMAP **sub-study protocols should be**
processed as a single study for Continuing Review.  
STUDY CHAIRS: **AGENTS:**  
Karen L. Reckamp, M.D. (Medical Oncology) NCI Supplied Investigational Agents:  
NCTN Group: SWOG Ramucirumab (NSC 749128)  
Cedars-Sinai Medical Center Pembrolizumab (MK-3475) (NSC 776864) 8700 Beverly Blvd, SCCT 1S27  
Los Angeles, California 90048 Commercially Available Agents: Phone: 310/423-5362 Docetaxel (NSC 628503)  
FAX: 310/423-7182 Gemcitabine hydrochloride (NSC 613327)  
E-mail: karen.reckamp@cshs.org Pemetrexed (NSC 698307)  
Konstantin H. Dragnev, M.D. (Medical Oncology) **BIOSTATISTICIANS:**  
NCTN Group: Alliance Mary Redman, Ph.D.  
Dartmouth Cancer Center Katherine Minichiello, M.S.  
One Medical Center Drive SWOG Statistics and Data Management Center  
Lebanon, NH 03756 1100 Fairview Ave N, M3-C102 Phone: 603/650-6345 P.O. Box 19024 FAX: 603/650-7791 Seattle, WA 98109-1024  
E-mail: konstantin.h.dragnev@hitchcock.org Phone: 206/667-4623  
FAX: 206/667-4408  
E-mail: mredman@fredhutch.org  
E-mail: kmini@fredhutch.org  
U.S.-Only Participants:  
| ALLIANCE/Alliance for Clinical Trials in Oncology                                              |
|------------------------------------------------------------------------------------------------|
| ECOG-ACRIN/ECOG-ACRIN Cancer Research Group NRG/NRG Oncology SWOG/SWOG Cancer Research Network |  
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| TABLE OF CONTENTS                                                                                                                                           |                                                                                                                                                                                |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| TITLE                                                                                                                                                       | ..                                                                                                                                                                             |
| TABLE OF CONTENTS                                                                                                                                           |                                                                                                                                                                                |
| CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION                                                                                           |                                                                                                                                                                                |
| SCHEMA                                                                                                                                                      |                                                                                                                                                                                |
| 1.0                                                                                                                                                         | OBJECTIVES .                                                                                                                                                                   |
| 1.1                                                                                                                                                         | Primary Objective                                                                                                                                                              |
| 1.2                                                                                                                                                         | Secondary Objectives ........................................................................................................................................................8 |
| Translational Medicine Objectives ........................................................................................................................8 |                                                                                                                                                                                |
| 1.3                                                                                                                                                         |                                                                                                                                                                                |
| 2.0                                                                                                                                                         | B BACKGROUND                                                                                                                                                                   |
| 2.1                                                                                                                                                         | LUNG-MAP .                                                                                                                                                                     |
| 2.2                                                                                                                                                         | General Background .                                                                                                                                                           |
| 2.3                                                                                                                                                         | S STUDY DESIGN                                                                                                                                                                 |
| 2.4                                                                                                                                                         | Ramucirumab and Pembrolizumab (MK-3475)                                                                                                                                        |
| 2.5                                                                                                                                                         | PD-L1 Test                                                                                                                                                                     |
| 2.6                                                                                                                                                         | Circulating tumor DNA (ctDNA)                                                                                                                                                  |
| 2.7                                                                                                                                                         | Inclusion of Women and Minorities and Planned Enrollment Report                                                                                                                |
| 3.0                                                                                                                                                         | DRUG INFORMATION .                                                                                                                                                             |
| Docetaxel (Taxotere®) (NSC-628503)                                                                                                                          |                                                                                                                                                                                |
| 3.1                                                                                                                                                         | Gemcitabine hydrochloride (Gemzar®) (NSC-613327) .                                                                                                                             |
| 3.2                                                                                                                                                         | P Political Politics (NSC 698037)                                                                                                                                              |
| 3.3                                                                                                                                                         | Ramucirumab (Cyramza™, IMC-1121B, LY3009806) (NSC 749128, IND 143217) ....................... 17                                                                               |
| 3.4                                                                                                                                                         |                                                                                                                                                                                |
| 3.5                                                                                                                                                         | Pembrolizumab (MK-3475) (NSC-776864) (IND 143217)                                                                                                                              |
| 3.6                                                                                                                                                         | DRUG ORDERING & ACCOUNTABILITY FOR INVESTIGATIONAL AGENTS ..............................27                                                                                     |
| STAGING CRITERIA                                                                                                                                            |                                                                                                                                                                                |
| 4.0                                                                                                                                                         |                                                                                                                                                                                |
| 5.0                                                                                                                                                         | ELIGIBILITY CRITERIA .                                                                                                                                                         |
| 5.1                                                                                                                                                         | Disease Related Criteria .                                                                                                                                                     |
| 5.2                                                                                                                                                         | Prior/Concurrent Therapy Criteria                                                                                                                                              |
| 5.3                                                                                                                                                         | Clinical/Laboratory Criteria                                                                                                                                                   |
| 5.4                                                                                                                                                         | Specimen Submission Criteria .                                                                                                                                                 |
| 5.5                                                                                                                                                         | Regulatory Criteria                                                                                                                                                            |
| 6.0                                                                                                                                                         | STRATIFICATION FACTORS                                                                                                                                                         |
| 7.0                                                                                                                                                         | TREATMENT PLAN .                                                                                                                                                               |
| 7.1                                                                                                                                                         | Disease Assessment                                                                                                                                                             |
| 7.2                                                                                                                                                         | Pre-Medication and Supportive Care                                                                                                                                             |
| 7.3                                                                                                                                                         | T Treatments .                                                                                                                                                                 |
| 7.4                                                                                                                                                         | Criteria for Removal from Protocol Treatment ..........................................................................................41                                      |
| 7.5                                                                                                                                                         | D Discontinuation of Treatment ...........................................................................................................................41                   |
| 7.6                                                                                                                                                         | Follow-Up Period                                                                                                                                                               |
| TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS ..........................................................41                                              |                                                                                                                                                                                |
| 8.0                                                                                                                                                         |                                                                                                                                                                                |
| 8.1                                                                                                                                                         | NCI Common Terminology Criteria for Adverse Events .........................................................................41                                                 |
| 8.2                                                                                                                                                         | G General Considerations ..............................................................................................................................................41      |
| 8.3                                                                                                                                                         | Dose Modifications for Chemotherapy                                                                                                                                            |
| 8.4                                                                                                                                                         | Dose Modifications for Ramucirumab ............................................................................................................46                              |
| 8.5                                                                                                                                                         |                                                                                                                                                                                |
| 8.6                                                                                                                                                         | Dose Modification Contacts .                                                                                                                                                   |
| 8.7                                                                                                                                                         | Adverse Event Reporting                                                                                                                                                        |
| 9.0                                                                                                                                                         | STUDY CALENDAR                                                                                                                                                                 |
| 9.1                                                                                                                                                         | Arm A: Investigator's Choice of Standard of Care .                                                                                                                             |
| Arm B: Ramucirumab plus Pembrolizumab (MK-3475)                                                                                                             |                                                                                                                                                                                |
| 9.2                                                                                                                                                         |                                                                                                                                                                                |
| 10.0                                                                                                                                                        | Best Response                                                                                                                                                                  |
| 10.3                                                                                                                                                        |                                                                                                                                                                                |
| 10.4                                                                                                                                                        | Performance Status .                                                                                                                                                           |
| 10.5                                                                                                                                                        | Time to Death                                                                                                                                                                  |
| 10.6                                                                                                                                                        | Investigator-Assessed Progression-Free Survival ......................................................................................62                                       |
| 10.7                                                                                                                                                        | Progression-Free Survival by Central Review ......................................................................................................62                           |  
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| Version Date 8/4/2022   |                                                                                                                                                                      |
|-------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 10.8                    | Duration of Response (DoR)                                                                                                                                           |
| 1.0                     | STATISTICAL CONSIDERATIONS .                                                                                                                                         |
| 11.1                    | Study Design and Endpoint Justification                                                                                                                              |
| 11.2                    | Primary Objective                                                                                                                                                    |
| 1.3                     |                                                                                                                                                                      |
| 1.4                     | Design, Sample Size Justification                                                                                                                                    |
| 1.5                     | Interim Analysis Plan                                                                                                                                                |
| 1.6                     | Accrual Justification                                                                                                                                                |
| 1.7                     | DATA AND Safety Monitoring .                                                                                                                                         |
| 12.0                    | DISCIPLINE REVIEW                                                                                                                                                    |
| 12.1                    | Radiology Review .                                                                                                                                                   |
| 13.0                    | REGISTRATION GUIDELINES                                                                                                                                              |
| 13.1                    | Registration Timing                                                                                                                                                  |
| 13.2                    | Investigator/Site Registration .                                                                                                                                     |
| 14.0                    | DATA SUBMISSION SCHEDULE .                                                                                                                                           |
| 14.1                    | Data Submission Requirements .                                                                                                                                       |
| 14.2                    | Master Forms .                                                                                                                                                       |
| 14.3                    | Data Submission Procedures .                                                                                                                                         |
| 14.4                    | Data Submission Overview and Timepoints                                                                                                                              |
| 15.0                    | SPECIAL INSTRUCTIONS                                                                                                                                                 |
| 15.1                    | SWOG Specimen Tracking System (STS)                                                                                                                                  |
| 15.2                    | Correlative Studies and Banking  (Optional for Patients) .                                                                                                           |
| 15.3                    | treatment initiation)                                                                                                                                                |
| 15.4                    | Specimen Flow Diagram                                                                                                                                                |
| 15.5                    | Radiology Review (Required) ...............................................................................................................................76        |
| 16.0                    | ETHICAL AND REGULATORY CONSIDERATIONS                                                                                                                                |
| 16.1                    | Serious Adverse Event Reporting Requirements ............................................................................................79                          |
| 17.0                    | BIBLIOGRAPHY                                                                                                                                                         |
| 18.0                    | APPENDIX                                                                                                                                                             |
| 18.5                    | PD-L1 22C3 IHC Assay .                                                                                                                                               |
| 18.1                    | New York Heart Association Classification                                                                                                                            |
| 18.2                    | Instructions for the SWOG Biospecimen Bank ...........................................................................................................90             |
| 18.3                    | CC                                                                                                                                                                   |
| 18.4                    | Live Vaccines Examples ...........................................................................................................................................92 |
| 18.5                    | PD-L1 22C3 IHC Assay .                                                                                                                                               |  
| PROTOCOL CONTACT INFORMATION  Patient Advocate:                                              | Judy Johnson, MBA E-mail: judyjohnson.519@gmail.com Phone: 314/477-6139 SWOG Statistics and Data Management Center   |
|----------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|
| Eligibility, RAVE, Data Submission:                                                          | E-mail: LUNGMAPquestion@crab.org Phone: 206/652-2267 SWOG Operations Office                                          |
| Regulatory, Protocol, Informed Consent:                                                      | E-mail: protocols@swog.org Phone: 210/614-8808                                                                       |
| Medical Queries (treatment or toxicity related                                               | E-mail: S1800AMedicalQuery@swog.org                                                                                  |
| questions): Investigational Drug questions:                                                  | See Protocol Section 3.0                                                                                             |
| Requests for Investigator's Brochures:                                                       | See Protocol Section 3.4f for ramucirumab CTMM@lilly.com                                                             |
| Temperature Excursion Reports:                                                               | See Protocol Section 3.5f for pembrolizumab                                                                          |
| Specimen Tracking System (STS) Amendments,  Errors, Connectivity Issues and Technical issues | technicalquestion@crab.org                                                                                           |
| with the SWOG CRA Workbench: Foundation Medicine, Inc. (for ordering ctDNA                   | FMI Client Services                                                                                                  |
| blood collection kits only):                                                                 | E-mail: lung.map@FoundationMedicine.com                                                                              |
| Cancer Therapy and Evaluation Program -                                                      | To review CTEP-IAM account (new requests,                                                                            |
| Identity and Access Management (CTEP-IAM):                                                   | reset passwords): https://ctepcore.nci.nih.gov/iam/index.jsp                                                         |
| Access to iMedidata Rave or Delegation of Task                                               | See Protocol Section 14.3 or contact                                                                                 |
| Log (DTL):                                                                                   | CTSU Help Desk: Phone: 1-888-823-5923 or Email:  ctsucontact@westat.com                                              |
| Questions related to                                                                         | See LUNGMAP Protocol Section 13.2 or contact                                                                         |
| Oncology Patient Enrollment Network (OPEN):                                                  | CTSU Help Desk: Phone: 1-888-823-5923 or Email:  ctsucontact@westat.com                                              |
| Patient Transfers:                                                                           | patienttransfer@crab.org                                                                                             |
| TRIAD installations:                                                                         | https://triadinstall.acr.org/triadclient/ Questions: TRIAD-Support@acr.org                                           |
| Adverse Event Reporting questions:                                                           | See Protocol Section 8.7 E-mail: adr@swog.org                                                                        |
| Source Documentation Portal - Central Monitoring:                                            | centralmonitorquestion@crab.org                                                                                      |  
| CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION CONTACT INFORMATION For regulatory requirements: For patient enrollments: For study data  submission: Regulatory documentation must be  submitted to the CTSU via the  Regulatory Submission Portal. Refer to the patient enrollment  section of the protocol for  instructions on using the  Oncology Patient Enrollment  Network (OPEN). Data collection for this study  will be done exclusively  through Medidata  Rave. Refer to the data  submission section of the  protocol for further  instructions.  (Sign in at www.ctsu.org, and  select the Regulatory > Regulatory  Submission.)  OPEN is accessed at  https://www.ctsu.org/OPEN_SYS TEM/ or https://OPEN.ctsu.org. Institutions with patients waiting  that are unable to use the Portal  should alert the CTSU Regulatory  Office immediately at 1-866-651- 2878 to receive further instruction  and support. Other Tools and Reports: Institutions participating  through the CTSU continue  to have access to other tools  and reports available on the  SWOG CRA Workbench via  the SWOG website  (www.swog.org). Contact the CTSU Help Desk  with any OPEN-related questions  by phone or email: 1-888-823- 5923, or ctsucontact@westat.com. Contact the CTSU Regulatory Help  Desk at 1-866-651-2878 for  regulatory assistance. The most current version of the study protocol and all supporting documents must be downloaded  from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Access to the CTSU members' website is managed through the Cancer Therapy and Evaluation  Program - Identity and Access Management (CTEP-IAM) registration system and requires user log in with a CTEP-IAM username and password. For patient eligibility or data submission questions contact the SWOG Statistics and Data  Management Center (SDMC) by phone or email: 206/652-2267 LUNGMAPQuestion@crab.org For treatment or toxicity related questions contact S1800AMedicalQuery@swog.org. For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data  submission) Contact the CTSU Help Desk by phone or e-mail: CTSU General Information Line: 888-823-5923 S1400contact@westat.com All calls and correspondence will be triaged to the appropriate CTSU representative.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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registration o

Screening Study testing for determining Sub-Study Assignment Arm B
Investigator's Choice of Standard of Care ¥
(Cycle length = 21 days)
Ramucirumab plus Pembrolizumab (MK-3475)
(Cycle length = 21 days)
Progression  
  
Progression Ω See **LUNGMAP** Section 5.1 for registration information. Note: Patients may have been enrolled on the legacy **S1400** screening/pre-screening study.  
€ Notification of sub-study assignment will be provided by the SWOG Statistics and Data Management Center (SDMC) (see **LUNGMAP** Section 11.0 for details).  
Δ See Section 11.0 for a more detailed statistical design. ¥ This is the Investigator's Choice of Standard of Care as outlined in Section 7.2a.
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1.0 objectives

1.1 Primary Objective To compare overall survival 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).  
1.2 Secondary Objectives a. To compare response rates between the arms, including complete response (CR)
and partial response (PR) (confirmed and unconfirmed).  
b. To compare the disease control rate (CR, PR, confirmed and unconfirmed and SD) c. To evaluate the duration of response (DoR) among responders within each arm.
d. To evaluate the frequency and severity of toxicities within each arm.  
e. To compare IA-PFS between the arms.
f. To evaluate the clinical outcomes (OS, IA-PFS, response) by randomization stratification factors (See Section 6.0) by comparing outcomes within the ramucirumab and pembrolizumab (MK-3475) arm, performing a sub-group analysis of the arms, and by evaluating an interaction between the factors and treatment arm.  
1.3 Translational Medicine Objectives a. To evaluate if PD-L1 expression levels are associated with clinical outcomes (OS,
IA-PFS, and response).  
b. To evaluate if tumor mutation burden (TMB) as determined by the FMI Foundation One panel is associated with clinical outcomes.  
c. To collect, process, and bank cell-free (cfDNA) at baseline and progression for future development of a proposal to evaluate comprehensive next-generation sequencing of circulating tumor DNA (ctDNA).
Note: The proposal to use these specimens would be submitted as an amendment to CTEP for approval prior to SDMC reviewing the results.  
d. To establish a tissue/blood repository to pursue future studies.
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2.0 background 2.1 lung-map

The Lung-MAP study is an umbrella protocol which contains a screening component and multiple independently conducted and analyzed treatment sub-studies for patients with previously treated stage IV or recurrent NSCLC. This protocol is specifically designed for patients not eligible for one of the biomarker-driven sub-studies in Lung-MAP who have previously received (and progressed during or following) both platinum-based chemotherapy and immune checkpoint inhibitor therapy.  
2.2 General Background The therapeutic landscape in metastatic NSCLC has dramatically changed with approvals of immunotherapy agents in both treatment-naïve and previously treated cancer and irrespective of histology. *(1, 2, 3, 4, 5)* Tumors may modulate and evade the host immune response through several mechanisms, including down regulation of tumor-specific antigen expression and presentation, secretion of anti-inflammatory cytokines, and upregulation of inhibitory ligands. T-cell checkpoint regulators such as cytotoxic T-lymphocyte antigen 4
(CTLA-4) and programmed death-1 (PD-1, CD279) are cell surface molecules that play a critical role in down-regulating T-cell activation and proliferation. T-cell checkpoint inhibitors' anti-tumor activity depends on disruption of immune tolerance to tumor cell antigens. Following on the success of CTLA-4 and anti-PD-1 pathway-targeted agents in several cancers, the field of tumor immunotherapy is rapidly expanding with several new promising approaches. Overall, enhancement of the magnitude and potency of tumor antigen-specific adaptive cellular responses by CD8 and CD4 T cells is now considered a major goal in cancer immunotherapy. Knowing that single-agent immunotherapies have already demonstrated activity, it is plausible, that combination therapies could lead to a greater depth of response, and an increase in overall survival (OS) as has been noted with the combination of anti-PD-1 and anti-CTLA-4 in subjects with previously untreated NSCLC. (6) In addition, the biggest current need is for those patients with primary or acquired resistance.
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2.3 study design

We now understand that the kinetics of immune-mediated anti-tumor activity may be delayed compared to that of cytotoxic chemotherapy or targeted therapy. Immunotherapy mediates tumor regression indirectly through activation of immune responses and/or inhibition of suppressive immune elements. This may result in delayed tumor regression, with some patients even experiencing the progression of existing disease or the appearance of new lesions prior to eventual disease regression. Furthermore, many immunotherapy agents do not impact PFS, but are associated with significant improvements in overall survival. *(7)*
Knowing that single-agent immunotherapies have already demonstrated activity, it is plausible that combination therapies could lead to a greater depth of response, and/or an increase in overall survival (OS) as has been noted with the combination of anti-PD-1 and anti-CTLA-4 in subjects with previously untreated NSCLC. *(8)*
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2.4 ramucirumab and pembrolizumab (mk-3475)

An immunosuppressive tumor microenvironment exists within lung tumors. Vascular Endothelial Growth Factor (VEGF) has been shown to modulate the tumor immune microenvironment. CD25+ FOXP3+ CD4+ T cells (Treg) play an important role in developing immune tolerance within tumors. VEGF impedes T cell extravasation by limiting T cell adhesion to the luminal surfaces of blood vessels, inhibits the proliferation and cytotoxicity of cytotoxic T lymphocytes (CTLs), and stimulates the proliferation of T regulatory (Treg) cells. *(9)* VEGF also induces programmed death ligand 1 (PDL1) expression on dendritic cells. VEGFR2 has been shown to be expressed by FOXP3 high Treg and exists in peripheral blood mononuclear cells and lymphocytes within malignant effusions. Therefore, inhibition of VEGFR may inhibit the immunosuppressive function of Treg. *(10)* VEGFR2 has also been shown to reduce tumor induced Treg proliferation. *(11)* In a transgenic breast cancer model, VEGFR inhibition led to modulation of cytokines related to tumor cell infiltration. In addition, VEGFR2 inhibition decreased infiltration of suppressive immune cells while increasing mature dendritic cells. *(12)* VEGF has a systemic effect on myeloid-derived suppressor cells (MDSCs) and suppresses dendritic cell maturation. VEGF drives the recruitment and infiltration of angiogenic and immunesuppressive MDSCs and macrophages. MDSCs and macrophages then produce reactive oxygen species, nitric oxide, and arginase to suppress T cell proliferation, viability, and activity. High levels of VEGF have been associated with the accumulation of immature myeloid DC in cancer patients. *(13)* By contrast, inhibition of VEGF restores many of these phenotypes. *(14)* Sunitinib is a multi-kinase inhibitor that has multiple targets including VEGFR and c-kit. Treatment with sunitinib led to a 50% reduction in the peripheral blood levels of MDSC in renal cell cancer patients. The decline was associated with improved Th1 lymphocyte function and decreased numbers of Tregs. *(15)* Furthermore, the simultaneous blockade of PD1 and VEGFR2 synergistically inhibited tumor growth by reducing tumor neovascularization and resulted in upregulation of proinflammatory cytokines. *(16)* Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR2), blocking VEGF binding and receptor activation. *(17)* In a Phase III trial in patients with advanced NSCLC, the combination of ramucirumab and docetaxel demonstrated improved overall response rate (ORR), progression free survival and overall survival compared to docetaxel alone. *(18)*
Such benefit was also seen in patients who progressed rapidly on first-line therapy who historically would have a poor prognosis in the second line setting in a post-hoc analysis.  
(19) In advanced renal cell carcinoma, the combination of axitinib and pembrolizumab
(MK-3475) resulted in a 71% ORR. *(20)* In an early Phase I a/b trial, 27 NSCLC patients who previously progressed on chemotherapy received the combination of ramucirumab and pembrolizumab (MK-3475), which demonstrated a 30% ORR with 77% of evaluable patients experiencing some tumor shrinkage. *(21)* The doublet demonstrated encouraging antitumor activity independent of PD-L1 and histology, numerically better than anti-PD-1 monotherapy. In an updated presentation at ASCO 2018 by Roy Herbst et al, data in the NSCLC cohort was reported by PDL1 status. *(22)* Overall response rate was 18% in PDL1
<1% and 45% in ≥1% with duration of response not reached in either group, and disease control rate was 82% versus 91% in PDL1 <1% and ≥1%, respectively. For patients with PDL1 <1%, progression free survival (PFS) was 9.7 months and overall survival (OS) was 17 months. For those with PDL1 ≥1%, PFS was 6.9 months and OS was not reached. Toxicity in the NSCLC subgroup showed 26% with grade 3/4 adverse events, 7% with hypertension, 4% with fatigue, 4 % with infusion reaction and 4% with proteinuria. Dual blockade with ramucirumab and pembrolizumab (MK-3475) may lead to improved tumor responses and prolonged survival in patients with metastatic lung cancer. In addition, a study evaluating maintenance nivolumab with or without bevacizumab following first-line platinum-based doublet chemotherapy was evaluated in patients with advanced NSCLC.  
the median OS survival was not reached in either arm. In the combination arm, median PFS was 37.1 weeks, while nivolumab alone resulted in median PFS of 16 weeks for squamous cell carcinoma and 21.4 weeks for nonsquamous NSCLC. *(23)* The combination was well tolerated. The preclinical rationale in addition to early clinical data support the evaluation of this combination.
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2.5 pd-l1 test

Testing for Programmed death-ligand 1 (PD-L1) expression by Immunohistochemistry
(IHC) was performed on all fresh tumor biopsies and archival tumor materials on LUNGMAP screening protocol, prior to LUNGMAP Revision \#4. This was done by Foundation Medicine utilizing the 22C3 pharmDx (Dako) antibody which is already FDA approved and a reliable biomarker for selection of patients that are more likely to benefit from checkpoint inhibitor therapy.
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2.6 circulating tumor dna (ctdna)

In addition, the detection rates of mutations observed in ctDNA isolated from patient plasma at baseline and progression will be evaluated in comparison to mutations observed in tumor tissue. It is expected that mutations identified in plasma will be synonymous with those detected in tissue, with the following exceptions: a subset of patients may have insufficient amounts of ctDNA in circulation for detection, and secondly, a subset of patients may have additional mutations detected in plasma that are associated with metastases and not present in the original tissue biopsy. The overarching goal of the Lung-MAP liquid biopsy program, planned across multiple sub-studies, is to assess whether positive identification of mutations in ctDNA can be utilized for molecular assignment. In this substudy, the primary objective is to correlate detection frequencies between tissue and plasma.  
2.7 Inclusion of Women and Minorities and Planned Enrollment Report This study was designed to include women and minorities but was not designed to measure differences of intervention effects. The anticipated accrual in the ethnicity/race and sex categories is shown in the table below.  
| DOMESTIC PLANNED ENROLLMENT REPORT Ethnic Categories   | Total              |        |      |    |     |
|--------------------------------------------------------|--------------------|--------|------|----|-----|
| Not Hispanic or  Latino                                | Hispanic or Latino |        |      |    |     |
| Female                                                 | Male               | Female | Male |    |     |
| American Indian/ Alaska  Native                        | 0                  | 1      | 0    | 0  | 1   |
| Asian                                                  | 1                  | 3      | 0    | 0  | 4   |
| Native Hawaiian or Other  Pacific Islander             | 0                  | 1      | 0    | 0  | 1   |
| Black or African American                              | 5                  | 6      | 0    | 0  | 11  |
| White                                                  | 55                 | 69     | 1    | 2  | 127 |
| More Than One Race                                     | 0                  | 0      | 0    | 0  | 0   |
| Total                                                  | 61                 | 80     | 1    | 2  | 144 |
| Racial Categories                                      |                    |        |      |    |     |
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3.0 drug information investigator brochures

For information regarding Investigator's Brochures, please refer to SWOG Policy 15. For **S1800A**,
the investigational drugs are ramucirumab (Arm B only) and pembrolizumab (MK-3475) and are being provided under an IND held by SWOG. [Note: Ramucirumab will be supplied for both Arm A
(Investigator's Choice of Standard of Care) and Arm B (Investigational Combination).] of For INDs filed by SWOG, the protocol serves as the Investigator Brochure for the performance of the protocol. In such instances, submission of the protocol to the IRB should suffice for providing the IRB with information about the drug. However, in cases where the IRB insists on having the official Investigator Brochure from the company, requests may be submitted to the CTSU website by completing the CTSU Request for Clinical Brochure.  
3.1 Docetaxel (Taxotere®) (NSC-628503)
[Commercially Available Drug]
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a. pharmacology

Mechanism of Action: Docetaxel promotes the assembly of microtubules and stabilizes their formation by inhibiting depolymerization. This stabilization creates a microtubule which is non-functional. Cell death is promoted by the disruption of normal cell shape, motility, attachment, and intracellular transport. Docetaxel is cytotoxic predominately in the S-phase of the cell cycle.
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b. pharmacokinetics

1. Absorption: Intravenous administration of docetaxel results in 100%
bioavailability. Area under the curve (AUC) of docetaxel was dose proportional following doses of 70 mg/m2 to 115 mg/m2 with infusion times of 1 to 2 hours.  
2. Distribution: The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin, and lipoproteins.  
3. Metabolism: Docetaxel is primarily metabolized in the liver by cytochrome P450 3A4 and 3A5 isoenzymes (CYP3A4/5).  
4. Elimination: Docetaxel elimination follows a three-compartment model with an initial distribution half-life of 3 to 5 minutes, an intermediate elimination half-life of 36 to 60 minutes, and a terminal half-life of 10 to 18 hours. Mean total body clearance was 21 L/h/m2.Approximately 6% of unchanged drug is eliminated by the kidney in 24 hours, with the majority
(80%) of excretion occurring in feces at 7 days.
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c. adverse effects

1. Possible Side Effects of Docetaxel: The most common adverse effects occurring in > 20% of people receiving docetaxel include: fluid retention, alopecia, nail disorders, skin reactions (rash, pruritis), nausea, vomiting, diarrhea, constipation, mucositis, infections, anemia, asthenia, neutropenia, neuropathy, fever, amenorrhea, erythema of the extremities with edema, pain and lacrimation with or without conjunctivitis.  
Adverse effects occurring in ≤ 20% of people receiving docetaxel include:
cutaneous skin reactions, abdominal pain, thrombocytopenia, febrile neutropenia, hepatotoxicity, venous thromboembolism, pulmonary embolism, myalgia, anorexia, dysgeusia, dyspnea, and cardiac dysrhythmias.  
Rare (< 3%) but potentially serious adverse effects include:
hypersensitivity reactions (rash/erythema, hypotension, wheezing, shortness of breath, swelling of the face or throat), acute myeloid leukemia, and interstitial lung disease or pneumonia.  
Patients receiving docetaxel infusions may experience alcohol intoxication from the ethanol included in the formulation. Refer to the current FDA-approved package insert for the most comprehensive and up to date information on adverse reactions.  
2. Pregnancy and Lactation: Pregnancy Category D. Excretion in breast milk is unknown and breast feeding is not recommended during treatment.  
3. Drug Interactions: Cytochrome P450 3A4/5 inducers, inhibitors, or substrates may alter docetaxel metabolism. In patients receiving treatment with docetaxel, close monitoring for toxicity and a docetaxel dose reduction could be considered if systemic administration of a potent CYP3A inhibitor cannot be avoided. Patients should use caution with sleep aids or narcotic analgesics due to possible additive sedation from the alcohol present in the docetaxel formulation. Due to potential drug interactions, a complete patient medication list, including docetaxel, should be screened prior to initiation of and during treatment with docetaxel.  
d. DOSING & ADMINISTRATION
See treatment plan in Section 7.0.  
e. HOW SUPPLIED
Docetaxel is commercially available and will not be supplied. Refer to the current FDA-approved package insert.
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f. storage preparation & stability

Refer to the current FDA-approved package insert.  
3.2 Gemcitabine hydrochloride (Gemzar®) (NSC-613327)
[Commercially Available Drug]
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a. pharmacology

Mechanism of Action: Gemcitabine (2'-Deoxy-2', 2'-difluorocytidine monohydrochloride), like cytarabine, is a nucleoside analog of deoxycytidine. This antimetabolite, a pyrimidine analog inhibiting both DNA and RNA viruses, is cellcycle-specific in blocking the cells at the G1/S and is retained in human tumor cells for long periods. Studies suggest that gemcitabine is activated by deoxycytidine kinase. Deoxycytidine has been shown to reverse the growth inhibitory activity of gemcitabine.
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b. pharmacokinetics

1. Distribution: Gemcitabine plasma protein binding is negligible. The volume of distribution is increased with the infusion length. In a pharmacokinetics study of patients with various solid tumors, the volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes. For long infusions (70 to 285 minutes), the volume of distribution rose to 370 L/ m2.  
2. Metabolism: Gemcitabine is metabolized intracellularly to form active gemcitabine di- and tri-phosphates. The gemcitabine di- and triphosphates do not appear to circulate in plasma in measurable amounts.  
Gemcitabine is metabolized by the liver to form the inactive uracil derivative, 2'-deoxy-2',2'-difluorouridine (dFdU). The inactive metabolite does not appear to accumulate with weekly dosing; however, it is excreted by the kidneys and may accumulate in patients with decreased renal function.  
3. Elimination: Following a single 1,000 mg/m2/30 min [14C]-gemcitabine infusion, 92% to 98% of the dose was recovered within 1 week after gemcitabine administration. Urinary excretion of the parent drug and the dFdU metabolite accounted for 99% of the excreted dose, and less than 1% of the dose was excreted in feces. The renal clearance of gemcitabine is less than 10%; therefore, the parent drug appears to be almost completely metabolized to the inactive dFdU.  
Clearance of gemcitabine is affected by age and gender and is lower in women and the elderly. Differences in either clearance or volume of distribution based on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Studies showed that gemcitabine half-life for short infusions ranged from 42 to 94 minutes, for long infusions it varied from 245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions. The terminal phase half-life for the active metabolite, gemcitabine triphosphate, in mononuclear cells ranges from 1.7-19.4 hours.
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c. adverse effects 1. possible

Refer to the current FDA-approved package insert for the most comprehensive and up to date information on adverse reactions.  
Adverse effects reported in >20% to 100% of subjects treated with gemcitabine include: flu-like symptoms, nausea, vomiting, rash, alopecia, infection, myelosuppression including anemia, leukopenia, neutropenia, and thrombocytopenia, muscle weakness, hematuria, paresthesia, sensory neuropathy, fatigue, somnolence, hearing loss, peripheral edema.  
Adverse effects reported in 4% to 20% of subjects include: diarrhea, constipation, stomatitis, dyspnea, capillary leak syndrome, posterior reversible encephalopathy syndrome (PRES).  
Adverse effects reported in 3% or less of subjects include: arrhythmias, supraventricular arrhythmias, congestive heart failure, myocardial infarction, desquamation and bullous skin eruptions, gangrene, cerebrovascular accident, hepatic failure, adult respiratory distress syndrome (ARDS), anaphylaxis, renal failure, pulmonary fibrosis, pulmonary edema, and, Interstitial, pneumonitis.  
2. Pregnancy and Lactation: Category D. Gemcitabine may cause fetal harm when administered to a pregnant woman. This agent has produced teratogenic effects in mice and rabbits when administered at a dose of <
2 mg/m2. Adverse effects included decreased fetal viability, weight and morphologic defects. There is no data on gemcitabine administration during human pregnancy, and it is not currently known if metabolites are excreted in human milk. However, many drugs are excreted in human milk, and there is a potential for adverse effects in nursing infants.  
Therefore, the use of gemcitabine should be avoided in pregnant or nursing women because of the potential hazard to the fetus or infant.  
3. Drug Interactions: Per gemcitabine package insert, no formal drug interaction studies have been performed to date. When gemcitabine was administered with carboplatin or paclitaxel there was minimal or no effect on the pharmacokinetics of the studied drugs.  
d. DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan
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e. how supplied

Gemcitabine is commercially available and will not be supplied. Refer to the current FDA-approved package insert for the most comprehensive and up to date information.  
f. STORAGE, PREPARATION & STABILITY
Refer to the current FDA-approved package insert.  
3.3 Pemetrexed (Alimta®) (NSC 698037)
[Commercially Available Drug]
NOTE: Pemetrexed is not FDA-approved for squamous cell NSCLC and should not be used to treat patients with squamous cell NSCLC.
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a. pharmacology

Mechanism of Action: Pemetrexed for injection is a folate analog metabolic inhibitor that exerts its action by disrupting folate dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentrationdependent process that occurs in tumor cells and is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
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b. pharmacokinetics

1. Absorption: The pharmacokinetics of pemetrexed administered as a single-agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.  
2. Distribution: Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
3. Metabolism: Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration.  
4. Elimination: The clearance of pemetrexed decreases, and exposure
(AUC) increases, as renal function decreases. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).
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c. adverse effects

1. Possible Side Effects of Pemetrexed: Refer to the current FDA-approved package insert for the most comprehensive and up to date information on adverse reactions. Adverse effects reported in > 20% of subjects treated with pemetrexed include: anemia, fatigue, constipation, nausea, vomiting, mucositis/stomatitis, thrombocytopenia, bleeding, infection, neutropenia, and desquamation.  
Adverse effects reported in 4% to 20% of subjects include: diarrhea, edema, increased serum creatinine, increased serum ALT, increased serum AST, interstitial pneumonitis, pulmonary fibrosis, pruritus, rash, and erythema multiforme.  
Serious adverse effects reported in ≤ 3% of subjects include: bowel obstruction, neuropathy, alopecia, and thrombosis/embolism.  
2. Pregnancy and Lactation: Pregnancy Category D. Pemetrexed can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If pemetrexed is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with pemetrexed. Due to the potential for serious adverse reactions in the nursing infant, a decision should be made to discontinue pemetrexed or to discontinue breast-feeding during therapy, taking into account the benefits of treatment to the mother.  
3. Drug Interactions: Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with pemetrexed in patients with normal renal function (creatinine clearance
≥80 mL/min). No dose adjustment of pemetrexed is needed with concomitant non-steroidal anti-inflammatory drugs (NSAIDs) in patients with normal renal function. Caution should be used when administering NSAIDs concurrently with pemetrexed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g.,
meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following pemetrexed administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.  
Due to potential drug interactions, a complete patient medication list, including pemetrexed, should be screened prior to initiation of and during treatment with pemetrexed. See Section 8.0 Toxicities to be Monitored and Dosage Modifications.
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d. dosing & administration see

e. HOW SUPPLIED
Pemetrexed is commercially available and will not be supplied. Refer to the current FDA-approved package insert for the most comprehensive and up to date information.
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f. storage preparation & stability

Refer to the current FDA-approved package insert.  
3.4 Ramucirumab (Cyramza™, IMC-1121B, LY3009806) (NSC 749128, IND 143217)
[Investigational Drug]
Ramucirumab will be supplied for both Arm A (Investigator's Choice of Standard of Care) and Arm B (Investigational Combination). See Section 3.4e for additional details.
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a. pharmacology

Mechanism of Action: Ramucirumab is a recombinant human IgG1 monoclonal antibody that specifically binds to vascular endothelial growth factor receptor 2
(VEGFR2). The binding of ramucirumab to VEGFR2 prevents its interaction with activating ligands (VEGF-A, VEGF-C, and VEGF-D) and as a result, ramucirumab inhibits ligand-stimulated activation of VEGF Receptor 2 and its downstream intracellular signaling components, including Erk1/Erk2, neutralizing ligandinduced proliferation and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an *in vivo* animal model.
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b. pharmacokinetics

4. Absorption: Ramucirumab is given via intravenous infusion.  
5. Distribution: In population pharmacokinetic models involving 2,820 patients, the mean volume of distribution (Vd) of ramucirumab at steady state was 4.47 L.  
6. Metabolism: As a monoclonal antibody, ramucirumab is largely confined to the extracellular space, and elimination is primarily by catabolism.  
7. Elimination: The mean clearance of ramucirumab was 0.0132 L/hour. The mean terminal half-life was 10.2 days.
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c. adverse effects

1. Adverse Effects: The below summary is based on patients receiving single-agent ramucirumab for gastric cancer (N=236). The type and frequency of adverse events observed vary when ramucirumab is administered in combination with other antineoplastic agents. Refer to the current FDA-approved package insert for the most comprehensive and up to date information on adverse reactions.  
2.  
Version: April 2022  
| Version: April 2022                                                                                                                                                                                                                                                       |                                                                                                                                 |                  |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|------------------|
| Adverse Events with                                                                                                                                                                                                                                                       |                                                                                                                                 |                  |
| Possible Relationship to Ramucirumab                                                                                                                                                                                                                                      |                                                                                                                                 |                  |
| Likely (> 20%)                                                                                                                                                                                                                                                            | Less Likely                                                                                                                     | Rare but Serious |
| (4 - ≤ 20%)                                                                                                                                                                                                                                                               | (≤ 3%)                                                                                                                          |                  |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia* Neutropenia CARDIAC DISORDERS Hypertension*                                                                                                                                                                                  | Arterial  thromboembolic  events (myocardial  infarction, cardiac  arrest,  cerebrovascular  accidents, and  cerebral ischemia) |                  |
| GASTROINTESTINAL DISORDERS Abdominal pain* Diarrhea*                                                                                                                                                                                                                      | Intestinal obstruction Gastrointestinal  perforation                                                                            |                  |
| METABOLISM AND NUTRITION DISORDERS Hypokalemia* Hyponatremia* NERVOUS SYSTEM DISORDERS Headache* RENAL AND URINARY DISORDERS Proteinuria  RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Epistaxis SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash * Serious events reported |                                                                                                                                 |                  |  
Important adverse events, including serious adverse events, observed with ramucirumab across clinical trials and disease states: hemorrhage, infusion related reactions, gastrointestinal hemorrhage, impaired wound healing, Posterior Reversible Encephalopathy Syndrome (PRES), nephrotic syndrome, thyroid dysfunction, and worsening of pre-existing hepatic impairment.  
3. Pregnancy and Lactation:
There are no available data on ramucirumab use in pregnant women. Based on its mechanism of action, ramucirumab can cause fetal harm. Avoid the use of ramucirumab in pregnant women and advise a pregnant woman of the potential risk to a fetus. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. Contraception should be used during treatment and for at least three months after the last dose of ramucirumab. Based on animal models, ramucirumab may potentially impair female fertility.  
Studies have not been conducted to assess ramucirumab's impact on milk production, its presence in breast milk, or its effects on the breast-fed child.  
Ramucirumab is excreted in human milk and, due to potential risks to the nursing infant, do not breastfeed during treatment with ramucirumab and avoid breastfeeding for 2 months after the last dose of ramucirumab.  
4. Drug Interactions: No clinically meaningful changes in the exposure of either ramucirumab or its concomitant drugs in the currently approved combinations, including paclitaxel, docetaxel, irinotecan (or its active metabolite, SN-38), and erlotinib were observed in patients with solid tumors. Studies indicate that it is unlikely for drug-drug interactions with concomitant administration of ramucirumab and durvalumab.
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d. dosing & administration see

Ramucirumab is administered through a separate infusion line. The use of a protein sparing 0.22 micron in-line filter is recommended. The line should be flushed with sterile sodium chloride (0.9%) solution for injection at the end of the infusion. Do not administer as an intravenous push or bolus.
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e. how supplied

1. Ramucirumab will be supplied free of charge. It will be provided by Eli Lilly and Company and distributed by CTEP PMB. Sites will be provided a commercially labeled ramucirumab for investigational use.  
2. Ramucirumab is supplied in single-use, 50-mL glass vials. Each vial contains 500 mg of ramucirumab at a concentration of 10 mg/mL in a sterile, preservative-free solution. Each vial is stoppered with a chlorobutyl elastomer stopper laminated with FluroTec® (West Pharmaceutical Services, Inc., Exton, PA), and secured with an aluminum 2-piece flip-top seal.
Ramucirumab formulated in an aqueous solution at a concentration of 10 mg/mL. The buffer contains 10mM histidine, 75mM sodium chloride, 133mM glycine, and 0.01% polysorbate 80.  
Ramucirumab is a clear to slightly opalescent and colorless to slightly yellow liquid without visible particles. The pH is 6.0.  
All excipients used for the manufacture of ramucirumab are of pharmacopeial grade. Ramucirumab molecular weight is 146.8 kDa.  
See Section 3.6 for Drug Ordering and Accountability.  
1. Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use.  
Keep the vial in the outer carton in order to protect from light. DO NOT
FREEZE OR SHAKE the vial. In case of temperature excursion outside of the storage range at the site, contact CTMM@lilly.com to obtain the Temperature Excursion Data Collection Form (TEDCF). Complete and submit the TEDCF to the location indicated on the form within one business day of resolution of the temperature excursion. Please use the following information when filling out the form:
- Trial Alias: I4T-US-I015
- Site Number: 101
- Site monitor name(s) and e-mail: This should be a person at the site level to contact with outcome (i.e. research coordinator).  
Determine the cause of the excursion and implement preventive actions to prevent future occurrence. Study drug should be returned to acceptable storage conditions and segregated from active stock. Clearly mark the material as quarantined and do not dispense/use (note directly on package) until further instruction is provided by Eli Lilly and Company.  
2. Preparation:
- Inspect vial contents for particulate matter and discoloration prior to dilution. If particulate matter or discolorations are identified, discard the vial.  
- Withdraw the required volume of ramucirumab and further dilute with only 0.9% Sodium Chloride Injection in an intravenous infusion container to a final volume of 250 mL. DO NOT use dextrose containing solutions.  
- Gently invert the container to ensure adequate mixing. DO NOT
FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medications.  
- Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F
to 46°F) or 4 hours at room temperature (below 25°C [77°F]).  
- Discard vial with any unused portion of ramucirumab, as the product contains no preservatives.
3. Compatibility information: DO NOT mix with dextrose containing solutions or infuse with electrolyte solutions or other medications.  
3.5 Pembrolizumab (MK-3475) (NSC-776864) (IND 143217)
[Investigational Available Drug]
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a. pharmacology

Mechanism of Action: Pembrolizumab (MK-3475) is a humanized MAb of the IgG4/kappa isotype. The programmed cell death 1 (PD-1) receptor is an inhibitory receptor expressed by T cells. When bound to either of its ligands, PD-L1 or PDL2, activated PD-1 negatively regulates T-cell activation and effector function. The pathway may be engaged by tumor cells expressing PD-1 ligands to suppress immune control. Pembrolizumab (MK-3475) blocks the negative immune regulatory signaling by binding to the PD-1 receptor, inhibiting the interaction between PD-1 and its ligands and thereby promoting the host immune system to recognize tumor cells as foreign bodies to be eliminated.
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b. pharmacokinetics

1. Absorption: N/A
2. Distribution: Limited distribution and protein binding (Vd= ~7.5 liters)
3. Metabolism: Pembrolizumab (MK-3475) follows general protein degradation pathways in the body. Cytochrome p450 enzymes are not involved in metabolism.
4. Elimination: Elimination half-life after IV administration was approximately 26 days. Steady state concentration levels were achieved within ~18 weeks of repeated dosing, with ~2.2-fold accumulation in exposure during administration Q3W relative to exposure observed following single dose administration. In the dose range studied for efficacy (2 to 10 mg/kg),
pembrolizumab (MK-3475) exposure increases in a dose-proportional manner, with clearance being independent of time or pembrolizumab (MK3475) concentration.
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c. adverse effects 1. adverse

The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE)
associated with an agent using a uniform presentation of events by body system. Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ aeguidelines.pdf for further clarification. *Frequency is provided based on* 3793 patients. Below is the CAEPR for pembrolizumab (MK-3475).  
Version 2.6, July 15, 20211  
| Adverse Events with Possible                                                                                                                                                                                                                                                                       |                     |                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|------------------------|
| Relationship to pembrolizumab (MK-3475) (CTCAE 5.0 Term) [n= 3793]                                                                                                                                                                                                                                 |                     |                        |
| Likely (>20%)                                                                                                                                                                                                                                                                                      | Less Likely (<=20%) | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Blood and lymphatic system  disorders - Other (immune  thrombocytopenic purpura)2 CARDIAC DISORDERS Myocarditis2 Pericarditis2 ENDOCRINE DISORDERS Adrenal insufficiency2 Endocrine disorders - Other (thyroiditis)2 Hyperthyroidism2Anemia2 Lymph node pain2 |                     |                        |  
| Adverse Events with Possible                                       |                     |                        |
|--------------------------------------------------------------------|---------------------|------------------------|
| Relationship to pembrolizumab (MK-3475) (CTCAE 5.0 Term) [n= 3793] |                     |                        |
| Likely (>20%)                                                      | Less Likely (<=20%) | Rare but Serious (<3%) |
| Hypophysitis2 Hypopituitarism2 Hypothyroidism2                     |                     |                        |
| EYE DISORDERS                                                      | Uveitis2 Eye disorders - Other (VogtKoyanagi-Harada  syndrome)                     |                        |
| GASTROINTESTINAL DISORDERS Abdominal pain Colitis2 Diarrhea2 Mucositis oral2 Nausea Pancreatitis2 Small intestinal  mucositis2 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Chills2 Fever2 HEPATOBILIARY DISORDERS Hepatobiliary disorders - Other (autoimmune  hepatitis)2 Hepatobiliary disorders - Other (sclerosing cholangitis) IMMUNE SYSTEM DISORDERS Immune system  disorders - Other  (pseudoprogression/tum or inflammation)2 Immune system  disorders - Other  (sarcoidosis)2 Anaphylaxis2 Cytokine release syndrome2 Immune system disorders - Other (acute graft-versushost-disease)2,3 Immune system disorders - Other (hemophagocytic  lymphohistiocytosis)2 Serum sickness2 INFECTIONS AND INFESTATIONS Infection4 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Infusion related reaction INVESTIGATIONS Alanine  aminotransferase  increased2 Alkaline phosphatase  increased Aspartate  aminotransferase  increased2 GGT increased Serum amylase increased                                                                    |                     |                        |  
| Adverse Events with Possible                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                      |                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|------------------------|
| Relationship to pembrolizumab (MK-3475) (CTCAE 5.0 Term) [n= 3793]                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                      |                        |
| Likely (>20%)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Less Likely (<=20%)                                                                                                  | Rare but Serious (<3%) |
| Blood bilirubin  increased CPK increased                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                      |                        |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Metabolism and nutrition                                                                                             |                        |
| Hyponatremia                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | disorders - Other (diabetic  ketoacidosis)2 Metabolism and nutrition  disorders - Other (type 1  diabetes mellitus)2 |                        |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia2 Arthritis2 Avascular necrosis2 Back pain Joint effusion2 Joint range of motion  decreased Musculoskeletal and  connective tissue  disorder - Other  (tenosynovitis)2 Myalgia2 Myositis2 NERVOUS SYSTEM DISORDERS Guillain-Barre syndrome2 Nervous system disorders - Other (myasthenic  syndrome)2 Nervous system disorders - Other (neuromyopathy)2 Nervous system disorders - Other (non-infectious  encephalitis)2 Nervous system disorders - Other (non-infectious  meningitis)2 Nervous system disorders - Other (non-infectious  myelitis) Nervous system disorders - Other (polyneuropathy)2 Paresthesia Peripheral motor  neuropathy2 RENAL AND URINARY DISORDERS Renal and urinary disorders  - Other (autoimmune |                                                                                                                      |                        |  
| Relationship to pembrolizumab (MK-3475) (CTCAE 5.0 Term) [n= 3793]                                                                                                                                                                                                                                                                                                                                                                                               |                     |                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|------------------------|
| Likely (>20%)                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Less Likely (<=20%) | Rare but Serious (<3%) |
| nephritis)2                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                     |                        |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough Pleuritic pain2 Pneumonitis2 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Bullous dermatitis2 Erythroderma Pruritus2 Rash acneiform2 Rash maculo-papular2 Skin and subcutaneous  tissue disorders - Other  (dermatitis)2 Skin hypopigmentation2 Urticaria2 Erythema multiforme2 Palmar-plantar  erythrodysesthesia  syndrome Stevens-Johnson syndrome2 Toxic epidermal necrolysis VASCULAR DISORDERS Vasculitis2 |                     |                        |  
  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Immune-mediated adverse reactions have been reported in patients receiving pembrolizumab (MK-3475). Adverse events potentially related to pembrolizumab (MK-3475) may be manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse reactions were reversible and managed with interruptions of pembrolizumab (MK-3475), administration of corticosteroids and supportive care.  
3Acute graft-versus-host disease has been observed in patients treated with pembrolizumab (MK-3475) who received hematopoeitic stem cell transplants.  
4Infection includes all 75 sites of infection under the INFECTIONS AND
INFESTATIONS SOC. Adverse events reported on pembrolizumab (MK-3475) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that pembrolizumab (MK-3475) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (pancytopenia); Disseminated intravascular coagulation; Hemolysis CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia
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eye disorders - eye pain

GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal hemorrhage; Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; Rectal hemorrhage; Small intestinal perforation; Upper gastrointestinal hemorrhage; Vomiting GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema limbs; Facial pain; Gait disturbance; General disorders and administration site conditions - Other (general physical health deterioration);
Generalized edema; Malaise; Non-cardiac chest pain; Pain INVESTIGATIONS - Cholesterol high; Creatinine increased; Fibrinogen decreased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell decreased METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle weakness; Musculoskeletal and connective tissue disorder -
Other (groin pain); Pain in extremity NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders - Other (brainstem herniation);
Seizure; Syncope; Tremor PSYCHIATRIC DISORDERS - Agitation; Confusion RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal and urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal inflammation; Pleural effusion; Pneumothorax; Respiratory failure SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous tissue disorders - Other (drug eruption)
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event Note: Pembrolizumab (MK-3475) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
2. Pregnancy and Lactation: The central function of the PD-1/PD-L1 pathway is to maintain immune tolerance to the fetal allograft, and its important role in maintaining pregnancy has been recently emphasized in literature. The PD-L1 molecule expressed at the uteroplacental interface effectively protects the concepti from maternal T cell-mediated immunity. Blockade of PD-L1 signaling has been shown in murine models of allogeneic pregnancy to abrogate feto-maternal tolerance to the concepti and to result in an increase in fetal resorption. The evidence from these experimental results indicates that there is a theoretical risk associated with the administration of pembrolizumab (MK-3475) to women of childbearing potential (WOCBP). It is therefore anticipated that the inhibition of PD-1 by treatment with anti-PD-1 monoclonal antibody (i.e., pembrolizumab) during pregnancy would have detrimental effects that might include increased rates of abortion and stillbirth.  
It is not known whether pembrolizumab (MK-3475) is excreted in human milk. Because of the potential for drugs to be excreted in human milk, the risk to the nursing infant cannot be excluded and therefore pembrolizumab
(MK-3475) should not be administered to nursing mothers.  
Contraception should be used during treatment and for at least four months after the last dose of pembrolizumab (MK-3475).  
3. Drug Interactions: No studies on pharmacodynamic drug interactions have been performed. Due to potential drug interactions, a complete patient medication list, including pembrolizumab (MK-3475), should be screened prior to initiation of and during treatment with pembrolizumab (MK-3475). See Section 8.0 Toxicities to be Monitored and Dosage Modifications.  
d. DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan
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e. how supplied

1. Pembrolizumab (MK-3475) will be supplied free of charge. It will be provided by Merck & Co., Inc. and distributed by Pharmaceutical Management Branch (PMB), CTEP/DCTD/NCI (PMB).  
2. Pembrolizumab (MK-3475) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use.  
Each vial contains 100 mg of pembrolizumab (MK-3475) in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab (MK3475) and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg),
sucrose (70 mg), and Water for Injection, USP.
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f. storage preparation & stability

1. Refer to the package label for expiration.  
2. Pembrolizumab (MK-3475) should be stored under refrigeration at 2°C -
8°C (36°F - 46°F) and protected from light in the original box. Do not freeze or shake the vials.
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solution

- Prepare the IV infusion using aseptic technique in a biological safety cabinet or hood.  
- Pembrolizumab (MK-3475) should be prepared in 0.9%
Sodium Chloride Injection, USP (normal saline) with a final concentration between 1mg/mL and 10mg/mL.  
- Pembrolizumab (MK-3475) is compatible with the following bags: PVC plasticized with DEHP, non-PVC (polyolefin),
EVA, PE lined polyolefin.  
- After adding the required amount of drug into the infusion bag, gently invert the bag 10-15 times to mix the solution.  
- Pembrolizumab (MK-3475) should NOT be mixed with other reconstitution diluents. Pembrolizumab (MK-3475) is infused over 30 minutes and is to be administered through a sterile, low protein-binding 0.2 to 5 micron in-line filter. The following infusion set materials are compatible with pembrolizumab
(MK-3475): PVC plasticized with DEHP, PVC and TOTM, polyethylene lined PVC, PVC plasticized with DEHT or polyurethane sets. Maximum rate of infusion should not exceed 6.7ml/min using an infusion pump. Lines may be primed with normal saline.  
- Administer prepared solutions immediately after preparation.  
If not administered immediately, prepared solutions may be stored refrigerated for up to 24 hours. Pembrolizumab (MK3475) solutions may be stored at room temperature for a cumulative time of up to 6 hours. This includes room temperature storage of liquid drug product solution in vials, room temperature storage of infusion solution in the IV bag, and the duration of infusion. If refrigerated, allow the IV
admixture to come to room temperature prior to use.  
- Parenteral drug product should be visually inspected for particulate matter and discoloration prior to administration.  
Discard the drug product vial if extraneous particulate matter other than translucent to white proteinaceous particles is observed.  
- Discard any unused portion of pembrolizumab (MK-3475)
vials immediately as the vials do not contain preservatives.  
- Do not administer the product as an IV push or bolus.  
3. If a storage temperature excursion is identified, promptly return pembrolizumab to between 2-8°C (36°F - 46°F) and quarantine the supplies. Contact Merck Sharp & Dohme Corp., by referencing the phone number listed on the commercial package insert, to obtain instructions and clinical complaint form.  
4. Do not co-administer other drugs through the same infusion line.  
5. Repackaging or other specific dispensing requirements: None 3.6 DRUG ORDERING & ACCOUNTABILITY FOR INVESTIGATIONAL AGENTS
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for commercial agents

Commercial agents are labeled with an expiration date and that date should be followed.  
a. Drug Ordering Investigational Agents provided by PMB
Confirmation of patient's enrollment is required for initial drug supply.  
Drug ordering: NCI-supplied agents may be requested by the Principal Investigator
(or their authorized designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained). The CTEP assigned protocol number (**S1800A**) must be used for ordering all CTEP
supplied investigational agents. The responsible investigator at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 and a CV. If there are several participating investigators at one institution, CTEP-supplied investigational agents for the study should be ordered under the name of one lead investigator at that institution. Active CTEP-registered investigators and investigator-designated shipping designees and ordering designees can submit agent requests through the PMB
Online Agent Order Processing (OAOP) application < https://eappsctep.nci.nih.gov/OAOP/pages/login.jspx >. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of an "active" account status and a "current" password. For questions about drug orders, transfers, returns, or accountability, call 240/276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime.
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b. drug handling and accountability

1. Drug Accountability: The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, disposition, and return of all drugs received from the PMB using the Drug Accountability Record Form available on the NCI home page (http://ctep.cancer.gov).  
2. Electronic logs are allowed as long as a print version of the log process is the exact same appearance as the current NCI DARF.
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c. drug return and/or disposition

1. All undispensed drug supplies should be returned to the PMB. When it is necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock recovery letter), investigators should return the study drug to the PMB using the NCI Return Agent Form available on the NCI home page (http://ctep.cancer.gov).  
2. Drug Expiration: PMB will send a stock recovery letter when the agent is no longer suitable for use
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d. contact information and useful

Questions about drug orders, transfers, returns or accountability should be addressed to the PMB by calling 240/276-6575 Monday through Friday between 8:30 am and 4:30 pm Eastern Time or by email: PMBAfterHours@mail.nih.gov.  
- CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ - NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov
- PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm
- PMB Online Agent Order Processing (OAOP) application:
https://ctepcore.nci.nih.gov/OAOP
- CTEP Identity and Access Management (IAM) account:
https://ctepcore.nci.nih.gov/iam/
- CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov
- PMB email: PMBAfterHours@mail.nih.gov
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4.0 staging criteria

Patients must have Stage IV or recurrent disease as outlined below (AJCC Cancer Staging Manual, 8th Edition, 2017):  
Stage IVA Any T Any N M1a  
Any T Any N M1b  
Stage IVB Any T Any N M1c  
Primary Tumor (T)  
TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy T0 No evidence of primary tumor
Tis Carcinoma in situ Squamous cell carcinoma in situ (SCIS) Adenocarcinoma in situ (AIS): adenocarcinoma with pure lepidic pattern, ≤ 3 cm in greatest dimension T1 Tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)
T1mi Minimally invasive adenocarcinoma: adenocarcinoma (≤ 3 cm in greatest dimension) with a predominantly lepidic pattern and ≤ 5 mm invasion in greatest dimension T1a Tumor ≤ 1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.  
T1b Tumor ˃ 1 cm but ≤ 2 cm in greatest dimension T1c Tumor ˃ 2 cm but ≤ 3 cm in greatest dimension T2 Tumor ˃ 3 cm but ≤ 5 cm or having any of the following features:
- Involves the main bronchus regardless of distance to the carina, but without involvement of the carina
- Invades visceral pleura (PL1 or PL2) - Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung T2 tumors with these features are classified as T2a if ≤ 4 cm or if the size cannot be determined and T2b if ˃ 4 cm but ≤ 5 cm.  
T2a Tumor ˃ 3 cm but ≤ 4 cm in greatest dimension T2b Tumor ˃4 cm but ≤ 5 cm in greatest dimension T3 Tumor ˃ 5 cm but ≤ 7 cm in greatest dimension or directly invading any of the following:
parietal pleural (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium, or separate tumor nodule(s) in the same lobe as the primary T4 Tumor ˃ 7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary
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regional lymph nodes (n)

Distant Metastasis (M) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M0 No distant metastasis M1 Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or malignant pleural or pericardial effusion. nodules or malignant pleural (or pericardial) effusion. **
M1b Single extrathoracic metastasis in a single organ (including involvement of a single nonregional node)
M1c Multiple extrathoracic metastases in a single organ or in multiple organs ** Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is non-bloody and is not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
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5.0 eligibility criteria

Each of the criteria in the following section must be met in order for a patient to be considered eligible for registration. For each criterion requiring test results and dates, please record this information on the Onstudy Form and submit via Medidata Rave® (see Section 14.0). Any potential eligibility issues should be addressed to the Statistics and Data Management Center (SDMC) in Seattle at 206/652-2267 or LUNGMAPquestion@crab.org prior to randomization. NCI policy does not allow for waiver of any eligibility criterion
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm).  
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28. This allows for efficient patient scheduling without exceeding the guidelines. If Day 7, 14, 21, 28 or 42 falls on a weekend or holiday, the limit may be extended to the next working day. 5.1 Disease Related Criteria a. Patients must have been assigned to **S1800A** by the SWOG Statistics and Data Management Center (SDMC). Patients who were screened under **S1400** (legacy screening/pre-screening study) must have had prior PD-L1 testing by the Dako 22C3 PharmDx IHC assay, and must have results available for stratification purposes.  
b. Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK
gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy.  
c. Patients must not have an active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.  
d. Patients must not have any history of primary immunodeficiency. e. Patients must not have experienced the following:
- Any Grade 3 or worse immune-related adverse event (irAE). Exception:
asymptomatic nonbullous/nonexfoliative rash.  
- Any unresolved Grade 2 irAE. - Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1 immunotherapy.  
Exception to the above: Toxicities of any grade that requires replacement therapy and has stabilized on therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are allowed.  
f. Patients must not have any history of organ transplant that requires use of immunosuppressives.  
g. Patients must not have clinical signs or symptoms of active tuberculosis infection. h. Patients must not have history of (non-infectious) pneumonitis that required steroids or current pneumonitis/interstitial lung disease.  
i. Patients must not have had a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to sub-study randomization.  
j. Patients must not have a history of gastrointestinal perforation or fistula within six months prior to sub-study randomization.  
k. Patients must not have Grade 3-4 gastrointestinal bleeding (defined by NCI
CTCAE v5) within three months prior to sub-study randomization.  
l. Patients must not have any known allergy or reaction to any component of the investigational formulations.
If there is a known allergy or reaction to standard of care formulations, patients must be able to safely receive at least one of the standard of care options.  
m. Patients must not have any Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within six months prior to sub-study randomization, or serious uncontrolled cardiac arrhythmia (see **S1800A** Section 18.1).  
Patients must not have experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within six months prior to sub-study randomization.  
n. Patients must not have documented evidence of acute hepatitis or have an active or uncontrolled infection.  
o. Patients with known human immunodeficiency virus (HIV) infection are eligible, provided they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to randomization.  
p. Patients with evidence of chronic hepatitis B virus (HBV) infection are eligible provided viral load is undetectable on suppressive therapy, if indicated.
q. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.  
r. Patients must not have undergone major surgery within 28 days prior to sub-study randomization, or subcutaneous venous access device placement within 7 days prior to randomization. Any patient with postoperative bleeding complications or wound complications from a surgical procedure performed in the last two months should be excluded. The patient must not have elective or planned major surgery to be performed during the course of the clinical trial.  
s. Patients must not have gross hemoptysis within two months of sub-study randomization (defined as bright red blood or ≥1/2 teaspoon) or with radiographic evidence of intratumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer.  
t. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years.  
u. Patients must not have been diagnosed with venous thrombosis less than 3 months prior to randomization. Patients with venous thrombosis diagnosed more than 3 months prior to randomization must be on stable doses of anticoagulants.  
v. Patients must not have any of following:
- cirrhosis at a level of Child-Pugh B (or worse) (See Appendix 18.3); - cirrhosis (any degree) and a history of hepatic encephalopathy; or
- clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.
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5.2 prior/concurrent therapy criteria

a. Patients must have received at least one line of anti-PD-1 or anti-PD-L1 therapy for Stage III, IV or recurrent disease and at most one line of anti-PD-1 or anti-PDL1 therapy for Stage IV or recurrent disease, given alone or in combination with platinum-based chemotherapy, an anti-CTLA4 therapy, or other immunemodulatory therapy. Patients must have experienced disease progression during or after this regimen. Disease progression during or after anti-PD-1 or anti-PD-L1 therapy must have occurred more than (>) 84 days following initiation (Cycle 1 Day 1) of anti-PD-1 or PD-L1 therapy (combination or monotherapy). Patients who received consolidation anti-PD-1 or anti-PD-L1 therapy following concurrent chemoradiation for Stage III disease as their only line of anti-PD-1 or anti-PD-L1 therapy, are eligible if they experienced disease progression more than
(>) 84 days but less than (<) 365 days from their first date of anti-PD-1 or anti-PDL1 therapy.  
Patients must have been exposed to platinum-based chemotherapy for Stage IV
or recurrent disease and experienced disease progression during or after this regimen, with the following exception: patients that received adjuvant platinumbased chemotherapy post-surgical resection for Stage I-III disease meet this criterion if disease progression occurred within one year from the last dose that the patient received that therapy.  
Prior tyrosine kinase inhibitor therapy for patients with targetable alterations is allowed if criteria 5.2a above is also met.  
b. Patients must have progressed (in the opinion of the treating investigator) following the most recent line of therapy.  
c. Patients must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to substudy randomization. Patients must have recovered (≤ Grade 1) from any side effects of prior therapy, except for alopecia. Patients must not have received any radiation therapy within 14 days prior to sub-study randomization. (See Section 5.3 for criteria regarding therapy for CNS metastases).  
d. Patients must not have received nitrosoureas or mitomycin-c within 42 days prior to sub-study randomization.  
e. Patients must not have received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within seven days prior to sub-study randomization. Inhaled or topical steroids, and adrenal replacement doses ≤ 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.  
f. Patients must not have received a live attenuated vaccination within 28 days prior to sub-study randomization. (See Appendix 18.4)
g. Patients must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.  
h. Patients must not be receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents within 7 days prior to randomization. Once-daily aspirin use (maximum dose 325 mg/day) is permitted.  
i. Patient must not have received radiotherapy within 14 days before the first dose of study treatment or received lung radiation therapy of >30 Gy within 6 months before the first dose of study treatment.
Note: Participants must have recovered from all radiation-related toxicities to Grade 1 or less, not require corticosteroids, and not have had radiation pneumonitis.
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5.3 clinical/laboratory criteria

a. Patients must have measurable disease (see **S1800A** Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document only non-measurable disease unless it is of diagnostic quality as defined in **S1800A**
Section 10.1c. Measurable disease must be assessed within 28 days prior to substudy randomization. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to sub-study randomization. All disease must be assessed and documented on the Baseline Tumor Assessment Form. Patients whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator)
prior to sub-study randomization. See **S1800A** Section 15.0 and **LUNGMAP**
Section 15.6 for guidelines and submission instructions for required central radiology review. CT and MRI scans must be submitted for central review via TRIAD.  
b. Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to sub-study randomization. Patient must not have leptomeningeal disease, spinal cord compression or brain metastases unless: (1)
metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 14 days following treatment, and prior to sub-study randomization, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least seven days prior to sub-study randomization.  
c. Patients must be able to safely receive at least one of the investigator's choice of standard of care regimens described in Section7.3a, per the current FDA-approved package insert(s).  
d. Patients must have an ANC ≥ 1,500/mcl, platelet count ≥ 100,000 mcl, and hemoglobin ≥ 9 g/dL obtained within 28 days prior to sub-study randomization.  
e. Patients must have adequate hepatic function as defined by serum bilirubin ≤
Institutional Upper Limit of Normal (IULN) and either ALT or AST ≤ 2 x IULN within 28 days prior to sub-study randomization (if both ALT and AST are done, both must be < 2 IULN). For patients with liver metastases, bilirubin and either ALT or AST
must be ≤ 5 x IULN (if both ALT and AST are done, both must be ≤ 5 x IULN).  
f. Patients must have a serum creatinine ≤ the IULN or calculated creatinine clearance ≥ 50 mL/min using the following Cockroft-Gault Formula. This specimen
must have been drawn and processed within 28 days prior to sub-study randomization.  
Calculated Creatinine Clearance = (140 - age) X (weight in kg†)
72 x serum creatinine* Multiply this number by 0.85 if the patient is a female. † The kilogram weight is the patient weight with an upper limit of 140% of the IBW. * Actual lab serum creatinine value with a minimum of 0.8 mg/ dL. Creatinine Calculator: https://crawb.crab.org/TXWB/CreatinineClearanceCalculator.aspx g. Patients' urinary protein must be ≤1+ on dipstick or routine urinalysis (UA).  
Random analysis of urine protein with a normal value is sufficient. If urine dipstick or routine analysis indicated proteinuria ≥2+, then a 24-hour urine is to be collected and demonstrate <1000 mg of protein in 24 hours to allow participation in the study.  
h. Patients must not have a history of uncontrolled or poorly-controlled hypertension defined as SBP > 150 mmHg or DBP > 90 mmHg within 28 days prior to sub-study randomization. Patients are permitted to be receiving multiple anti-hypertensive medications (unless otherwise indicated in the study). All blood pressure measurements within the 14 days prior to registration must be SBP < 150 and DBP
< 90. An exception can be made by a healthcare provider for a patient with a single blood pressure elevation who upon rechecking has a normal blood pressure.  
i. For patients where an International Normalized Ratio (INR) is clinically indicated, INR must be ≤ 1.5 seconds above the institutional upper limit of normal (IULN) (unless receiving anticoagulation therapy) documented within 28 calendar days prior to sub-study randomization. For patients where a partial thromboplastin time
(PTT) is clinically indicated, PTT must be ≤ 5 seconds above the institutional upper limit of normal (IULN) (unless receiving anticoagulation therapy) documented within 28 calendar days prior to sub-study randomization.  
j. If receiving warfarin, the patient must have an INR ≤3.0. For warfarin, heparin and low molecular weight heparin (LMWH) there should be no active bleeding (that is, no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices).  
k. Patients must have Zubrod performance status 0-1 (see **S1800A** Section 10.4)
documented within 28 days prior to sub-study randomization.
l. Pre-study history and physical exam must be obtained within 28 days prior to substudy randomization.  
m. Patients must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective contraceptive method during the study and 4 months after completion of study treatment. A woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures during the study and 4 months after study completion.  
5.4 Specimen Submission Criteria a. Patients must agree to have blood specimens submitted for circulating tumor DNA
(ctDNA) as outlined in Section 15.3.
b. Patients must also be offered participation in banking and in the correlative studies for collection and future use of specimens as described in **S1800A** Section 15.0.  
5.5 Regulatory Criteria a. As a part of the OPEN registration process (see **LUNGMAP** Section 13.4 for OPEN
access instructions) the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.  
b. Patients with impaired decision-making capacity are eligible as long as their neurological or psychological condition does not preclude their safe participation in the study (e.g., tracking pill consumption and reporting adverse events to the investigator).  
c. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
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6.0 stratification factors

Randomization between treatment arms will be performed using a dynamic balancing algorithm.  
Randomization will be stratified based on the following factors:
a. PD-L1 Status 1. negative (<1%) versus;  
2. positive (>= 1%) or unknown PD-L1 status
Provided by PD-L1 testing performed at FMI as part of the **LUNGMAP** screening protocol unless patient was screened under the **S1400** (legacy screening/pre-screening study). The S1400 patients must have had prior PD-L1 testing by the Dako 22C3 PharmDx IHC assay and must have results available for stratifying.
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b. histology

1. Patients with squamous cell lung cancer, including mixed histology with any squamous component.  
2. Patients with non-squamous cell lung cancer (adenocarcinoma, large cell, NSCLC
NOS).
c. If patient is randomized to standard of care arm, does the planned treatment include ramucirumab? _ Yes
_ No
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7.0 treatment plan

For treatment or dose modification questions, please contact Drs. Karen L. Reckamp and Konstantin H. Dragnev at S1800AMedicalQuery@swog.org. For dosing principles or questions, please consult the SWOG Policy \#38 "Dosing Principles for Patients on Clinical Trials" at https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf.  
7.1 Disease Assessment See Section 9.0 for disease assessment time points. Disease assessment timing is to be based on calendar timing counted as weeks after registration, not based on cycles or drug administration. Disease Assessment During Treatment
- For patients on Arm A: CT or MRI (the same method used at pre-study to meet the eligibility criteria in Section 5.3) must be repeated every 6 weeks (± 7 day window),
for the first year regardless of treatment delays, then every 12 weeks until disease progression. The 6 weeks should start from Cycle 1 Day 1.  
- For patients on Arm B: CT or MRI (the same method used at pre-study to meet the eligibility criteria in Section 5.3) 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.
Pre-study Brain CT/MRI is required 42 days prior to randomization per Section 5.3. If patient has brain metastases at baseline, scans must use the same modality as baseline and be repeated every 12 weeks (± 7 day window) while on treatment.  
Disease Assessment During Off Protocol Treatment, Prior to Progression After off protocol treatment prior to progression, disease assessments must continue every 12 weeks (± 7 day window) until progression.  
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.  
7.2 Pre-Medication and Supportive Care Pre-medication associated with standard drug administration and supportive care (including anti-diarrheals, antibiotics, diuretics, growth factors, or other medications) may be given as indicated by the current American Society of Clinical Oncology (ASCO)
guidelines. Pre-medication with a histamine H1 antagonist is recommended prior to infusion of ramucirumab. Recommended premedication agents include an intravenous histamine H1 antagonist such as diphenhydramine hydrochloride (or equivalent). Additional premedication may be provided at investigator discretion. For patients who have experienced a Grade 1 or 2 infusion-related reaction, pre-medication antihistamine (e.g. diphenhydramine) in addition to dexamethasone and acetaminophen may be used prior to infusion on subsequent infusions. Dosing and administration route of pre-medications may be given per institutional policy. Intranasal and inhaled corticosteroids are allowed during protocol therapy. Corticosteroids to manage immune-related adverse events during protocol therapy will be permitted.  
7.3 Treatments
Patients will be randomized to one of the following treatment arms: Arm A: Investigator's Choice of Standard of Care Arm B: Ramucirumab plus Pembrolizumab (MK-3475)
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a. arm a investigator's choice

Treating Investigator and patient will choose the appropriate SoC drug (docetaxel, gemcitabine, pemetrexed, or ramucirumab plus docetaxel) based on patient's previous therapy and disease.
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note

- Pemetrexed is only FDA-approved for non-squamous cell NSCLC. - Patients who take docetaxel or ramucirumab plus docetaxel, must have adequate hepatic function per the current FDA-approved package insert.  
- Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to Cycle 1 Day 1.
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1. docetaxel

Agent Dose Route Day Schedule*  
Dexamethasone 8 mg  
BID **  
Oral,  
beginning 24 hours  
prior to  
docetaxel  
Docetaxel 75 mg/m2 IV Day 1 Q 21 days  
Day 0-2 Q 21 days  
* NOTE: A cycle of treatment is 21 days. Disease assessment must occur every 6 weeks. Treatment will continue until any criteria in Section 7.3 is met.  
**Dexamethasone may be administered per local institutional guidelines.  
Recommended dose listed above.
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2. gemcitabine hydrochloride

* NOTE: A cycle of treatment is 21 days. Disease assessment must occur every 6 weeks. Treatment will continue until any criteria in Section 7.3 is met.
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3. pemetrexed

| Agent       | Dose              | Route     | Day       | Schedule*   |
|-------------|-------------------|-----------|-----------|-------------|
| Gemcitabine | 1000              | IV        |           |             |
| mg/m2       | 30 (± 5)  minutes | Days 1, 8 | Q 21 days |             |  
Page 38 Version Date 8/4/2022  
Agent Dose Route Day Schedule* Folic Acid 400-1000  
mcg  
Oral, Daily; beginning 7  
days before  
first dose of  
pemetrexed and continuing until 4  
weeks after the  
last dose of pemetrexed  
| Agent         | Dose          | Route                                           | Day   | Schedule*   |
|---------------|---------------|-------------------------------------------------|-------|-------------|
| Folic Acid    | 400-1000  mcg |                                                 |       |             |
| Vitamin B12   | 1 mg **       | Intramuscular                                   | Day   |             |
| Dexamethasone | 4 mg BID**    | Oral,  beginning 24  hours prior to  pemetrexed |       |             |
| Pemetrexed    | 500 mg/m2     | IV 10  minutes                                  |       |             |
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notes

* Pemetrexed is not FDA-approved for squamous cell NSCLC and should not be used to treat patients with squamous cell NSCLC.
A cycle of treatment is 21 days. Disease assessment must occur every 6 weeks. Treatment will continue until any criteria in Section 7.3 is met.  
| days before  first dose                                                                                                                          | of   |
|--------------------------------------------------------------------------------------------------------------------------------------------------|------|
| pemetrexed and  continuing until 4  weeks after the  last dose of  pemetrexed Q 63 days -7 (every 3rd cycle) Day  Q 21 days 0-2 Day  Q 21 days 1 |      |  
**Dexamethasone and Vitamin B12 may be administered per local institutional guidelines. Recommended dose listed above.
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4. ramucirumab plus docetaxel

Agent Dose Route Day Schedule b Ramucirumab a 10 mg/kg IV over 3060 minutes d  
Day 1 Q 21 days  
| Ramucirumab a   | 10 mg/kg                                 | IV over 30- 60 minutes d   |
|-----------------|------------------------------------------|----------------------------|
| Dexamethasone   | 8 mg                                     | Oral,                      |
| BID c           | beginning  24 hours  prior to  docetaxel |                            |  
Docetaxel 75 mg/m2 e IV Day 1 Q 21 days  
Day 0-2 Q 21 days  
NOTES:  
a Pre-medication with a histamine H1 antagonist is recommended prior to infusion of ramucirumab. Recommended premedication agents include an intravenous histamine H1 antagonist such as diphenhydramine hydrochloride (or equivalent). Additional premedication may be provided at investigator discretion.  
b A cycle of treatment is 21 days. Disease assessment must occur every 6 weeks. Treatment will continue until any criteria in Section 7.3 is met.  
c Dexamethasone may be administered per local institutional guidelines.  
Recommended dose listed above.  
d Ramucirumab will be administered over an approximately 60-minute intravenous (IV) infusion. If the first infusion is tolerated, all subsequent ramucirumab infusions may be administered over 30 minutes. Please refer to the package insert for the administration of ramucirumab
The actual doses of ramucirumab administered will be determined by measuring the patient's weight at the beginning of each cycle. If the patient's weight fluctuates by more than 10% from the weight used to calculate the dose at baseline, the dose must be recalculated using the most recent weight and this weight will become the baseline weight going forward. Recalculation of the ramucirumab dose for weight fluctuations of <10% is permitted but not required.  
e Docetaxel may be administered per local institutional guidelines.  
Recommended dose listed above, but the use of a starting dose of 60 mg/m2 is allowed at treating investigator's discretion. Ramucirumab is administered prior to docetaxel consistent with FDA-approved package labeling for ramucirumab. Per a study noted in the ramucirumab package insert "Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m every 3 weeks." Sites should provide a justification in the patient's chart for using a starting dose of docetaxel at 60 mg/m2.
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b. arm b ramucirumab plus

Note that women of childbearing potential must have a negative serum pregnancy test within 7 days prior to Cycle 1 Day 1.  
| Agent         | Dose     | Route                                   | Day   | Schedule b         |
|---------------|----------|-----------------------------------------|-------|--------------------|
| Ramucirumab a | 10 mg/kg | IV over 30-60                           | Day 1 | Q 21 days          |
| minutes c     |          |                                         |       |                    |
| Pembrolizumab | 200 mg   | IV over 30                              | Day 1 | Q 21 days or up to |
| (MK-3475)     | minutes  | 35 cycles without  disease  progression |       |                    |
| NOTES:        |          |                                         |       |                    |  
a Pre-medication with a histamine H1 antagonist is recommended prior to infusion of ramucirumab. Recommended premedication agents include an intravenous histamine H1 antagonist such as diphenhydramine hydrochloride (or equivalent).  
Additional premedication may be provided at investigator discretion.  
b A cycle of treatment is 21 days. Disease assessment must occur every 6 weeks.  
Treatment will continue until any criteria in Section 7.3 is met.  
c Ramucirumab will be administered prior to pembrolizumab (MK-3475), over an approximately 60-minute intravenous (IV) infusion. If the first infusion is tolerated, all subsequent ramucirumab infusions may be administered over 30 minutes. Please refer to the package insert for the administration of ramucirumab.
The actual doses of ramucirumab administered will be determined by measuring the patient's weight at the beginning of each cycle. If the patient's weight fluctuates by more than 10% from the weight used to calculate the dose at baseline, the dose must be recalculated using the most recent weight and this weight will become the baseline weight going forward. Recalculation of the ramucirumab dose for weight fluctuations of < 10% is permitted but not required. Pembrolizumab (MK-3475) 200 mg (fixed dose) will be administered over a 30minute IV infusion. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted (that is, infusion time is between 25 and 40 minutes).  
The first 2 cycles will require a 1-hr observation period i) between ramucirumab and pembrolizumab (MK-3475) administration, and ii) after pembrolizumab (MK3475) infusion. For all cycles thereafter, no observation period will be required unless clinically indicated.  
Patients will receive 35 cycles of pembrolizumab (MK-3475). Maintenance ramucirumab may continue for patients past 35 cycles until reaching a discontinuation criterion (Section 7.3), as long as the participant is receiving benefit.  
7.4 Criteria for Removal from Protocol Treatment  
a. Progression of disease as defined in Section 10.2 in **S1800A**. However, a patient on Arm B may continue protocol treatment as long as the patient is continuing to clinically benefit from treatment in the opinion of the treating investigator. Patients should still be removed from protocol treatment for criteria below.  
* Upon progression, the Request for New Sub-Study Assignment Form may be submitted under the patient's screening (LUNGMAP or **S1400**) to receive a new sub-study assignment (see Section 14.0).  
b. Symptomatic deterioration (as defined in Section 10.2 of **S1800A**).  
c. Unacceptable toxicity.  
d. Treatment delay for any reason > 84 days (or as noted in Section 8.0)
e. The patient may withdraw from this study at any time for any reason.
7.5 Discontinuation of Treatment All reasons for discontinuation of treatment must be documented in the Off Protocol Treatment Notice.  
7.6 Follow-Up Period All patients will be followed until death or 3 years after sub-study randomization, whichever occurs first.  
Note: Patients who enroll on a new sub-study following progression must continue followup on this sub-study, in addition to follow-up on the new sub-study.
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8.0 toxicities to be monitored

8.1 NCI Common Terminology Criteria for Adverse Events This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for toxicity and Serious Adverse Event reporting. A copy of the CTCAE Version 5.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate treatment areas should have access to a copy of the CTCAE Version 5.0.  
8.2 General Considerations
a. Patients on Arm B will receive pembrolizumab (MK-3475) for up to 35 cycles.  
b. If multiple toxicities are experienced, dose modifications will be based on the toxicity requiring the largest dose reduction.  
c. Dose reductions are allowed on ramucirumab only. Dose re-escalations are not allowed.  
d. Dose interruptions and discontinuations are allowed to manage toxicity. If the toxicity is clearly related to only one of the drugs, the other agent may be continued. If the relationship cannot be established, there should be an option to hold both.  
e. If one drug is discontinued due to toxicity, patient may remain on other study drugs as long as the remaining therapy is well tolerated and according to the treating physician the patient is still deriving clinical benefit.  
f. The maximum dose delay for any reason is 84 days.
8.3 Dose Modifications for Chemotherapy Treatment and dose modifications are at the discretion of the treating investigator.  
NOTE: Pemetrexed is not FDA-approved for squamous cell NSCLC and should not be used to treat patients with squamous cell NSCLC.  
8.4 Dose Modifications for Ramucirumab Dose modifications should be made based on the observed toxicity, as summarized in the tables below.
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table 1 dose reductions for

DRUG DOSE LEVEL DOSE  
Ramucirumab Full 10 mg/kg  
-1 Level 8 mg/kg  
-2 Level 6 mg/kg  
-3 Level 5 mg/kg  
-4 Level Discontinue  
Note: Once a dose reduction is applied, the reduced dose is maintained unless further dose reduction is needed.  
| Table 2: Dose Interruptions for Ramucirumab Toxicity Grade Dose  Interruptions                                                                                                                                                                                                                                                                                                                                                 | Toxicity Management                                                                                                                                                                                                                                     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Manage per institutional standard  at the discretion of treating  investigator. Monitor patients for signs and  symptoms of infusion-related  reactions (e.g., fever and/or  shaking chills, flushing and/or  itching, alterations in heart rate  and blood pressure, dyspnea or  chest discomfort, skin rashes  etc.) and anaphylaxis (e.g.,  generalized urticaria,  angioedema, wheezing,  hypotension, tachycardia, etc.). |                                                                                                                                                                                                                                                         |
| Any Grade                                                                                                                                                                                                                                                                                                                                                                                                                      | The infusion rate  of study  drug/study  regimen may be  decreased by  50% or  temporarily  interrupted until  resolution of the  event. Subsequent  infusions may be  given at 50% of  the initial infusion  rate.                                     |
| InfusionRelated  Reactions                                                                                                                                                                                                                                                                                                                                                                                                                                | Acetaminophen and/or  antihistamines may be  administered per institutional  standard at the discretion of the  investigator.                                                                                                                           |
| < Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                      | Consider premedication per  institutional standard prior to  subsequent doses.  Manage severe infusion-related  reactions per institutional  standards (e.g., IM epinephrine,  followed by IV diphenhydramine  and ranitidine, and IV  glucocorticoid). |
| Permanently  discontinue                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                         |
| > Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                      | ramucirumab.                                                                                                                                                                                                                                            |
| Table 3: Dose Modifications for Ramucirumab Toxicity Grade                                                                                                                                                                                                                                                                                                                                                                     | Dose Modifications                                                                                                                                                                                                                                      |
| No dose modification. Consider  increased BP monitoring; start  anti-hypertensive medication if  appropriate.                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                         |
| Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                        | No dose modification. Begin  anti-hypertensive therapy and  continue ramucirumab.                                                                                                                                                                       |
| Grade 2 Asymptomatic                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                         |
| Hypertension                                                                                                                                                                                                                                                                                                                                                                                                                   | Hold ramucirumab until  symptoms resolve. Start or  adjust anti-hypertensive  medication.                                                                                                                                                               |
| Grade 2 Symptomatic                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                         |  
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| Toxicity                                                                | Grade                                                                                                                                                                                                                                                                                                                                                                       | Dose Modifications     |
|-------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|
| Hold ramucirumab until                                                  |                                                                                                                                                                                                                                                                                                                                                                             |                        |
| Grade 3                                                                 | resolution of symptoms and  returns to Grade 2.                                                                                                                                                                                                                                                                                                                             |                        |
| Grade 4                                                                 | Permanently discontinue  ramucirumab. No dose modification. Therapy  with ramucirumab can be  continued while treatment for  the thyroid disorder is instituted.                                                                                                                                                                                                            |                        |
| Hypothyroidism                                                          | Grade 2-4                                                                                                                                                                                                                                                                                                                                                                   |                        |
| Prior to planned                                                        | Withhold ramucirumab 28 days                                                                                                                                                                                                                                                                                                                                                |                        |
| surgery                                                                 | prior.. Do not administer ramucirumab  for at least 14 days following  major surgical procedure and  until adequate wound healing.  The safety of resumption after  resolution of wound healing has  not been established.                                                                                                                                                  |                        |
| After surgery                                                           |                                                                                                                                                                                                                                                                                                                                                                             |                        |
| Impaired Wound Healing                                                  | Do not administer ramucirumab  for at least 14 days following  major surgical procedure and  until adequate wound healing.  The safety of resumption after  resolution of wound healing has  not been established.                                                                                                                                                          |                        |
| Wound-healing  complications  developed during  study treatment Grade 1 | No dose modification. Check 24-hour urine protein  levels.  - If > 2 gram/24 hours, hold  ramucirumab until  resolution to < 2 gram/24  hours. Restart  ramucirumab at the next  lower dose.  - If the protein level ≥2 g/24  hours reoccurs, interrupt  ramucirumab and reduce  the dose to the next lower  level once the urine protein  level returns to <2 g/24  hours. |                        |
| Grade 2                                                                 |                                                                                                                                                                                                                                                                                                                                                                             |                        |
| 2+ proteinuria on urine  dipstick                                       |                                                                                                                                                                                                                                                                                                                                                                             |                        |
| Proteinuria                                                             | Permanently discontinue  ramucirumab. If patient  experiences nephrotic  syndrome, permanently  discontinue ramucirumab.                                                                                                                                                                                                                                                    |                        |
| > Grade 3                                                               |                                                                                                                                                                                                                                                                                                                                                                             |                        |
| > 3.5 gram/24 hours                                                     | Hold ramucirumab until                                                                                                                                                                                                                                                                                                                                                      |                        |
| Non-life threatening and  reversible                                    | Grade 3                                                                                                                                                                                                                                                                                                                                                                     | resolved to Grade 0-1. |  
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Grade   | Dose Modifications   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|----------------------|
| - If resolved to Grade 0-1, may  reduce ramucirumab by one  dose level. If NOT resolved to Grade 0-1  within 21 days, discontinue  ramucirumab at treating  investigator's discretion. Permanently discontinue  ramucirumab immediately, with  the exception of Grade 4 fever  or Grade 4 laboratory  abnormality, in which case: First occurrence: Delay  ramucirumab until resolved to  Grade 0-1. - If resolved to Grade 0-1, may  resume ramucirumab original  dose at the discretion of the  treating investigator. - If NOT resolved to Grade 0-1  within 21 days, discontinue  ramucirumab at treating  investigator's discretion. Second occurrence: Delay  ramucirumab until resolved to  Grade 0-1.  - If resolved to Grade 0-1,  reduce ramucirumab by one  dose level. If NOT resolved to Grade 0-1  within 21 days, discontinue  ramucirumab at treating  investigator's discretion. |         |                      |
| Other Adverse Events                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Grade 4 |                      |  
| Table 4: Dose Discontinuations for Ramucirumab Toxicity Grade   | Dose Discontinuation   |                                       |
|-----------------------------------------------------------------|------------------------|---------------------------------------|
| Arterial Thromboembolic  Events,                                | Any Grade              | Permanently discontinue  ramucirumab. |
| Gastrointestinal Perforation                                    | Any Grade              | Permanently discontinue  ramucirumab. |
| Gastrointestinal  Hemorrhage/Bleeding                           | ≥ Grade 3              | Permanently discontinue  ramucirumab. |
| Reversible posterior                                            | Any Grade              | Permanently discontinue               |
| leukoencephalopathy                                             | ramucirumab.           |                                       |
| syndrome Congestive heart failure                               | ≥ Grade 3              | Permanently discontinue  ramucirumab. |  
| Liver injury/liver failure or  Hepatic encephalopathy   | Any Grade    | Permanently discontinue               |
|---------------------------------------------------------|--------------|---------------------------------------|
| and/or hepatorenal syndrome                             | ramucirumab. |                                       |
| resulting from liver cirrhosis Fistula formation        | Any Grade    | Permanently discontinue  ramucirumab. |  
8.5 Dose Modifications for Pembrolizumab (MK-3475)
Adverse events (both non-serious and serious) associated with pembrolizumab (MK-3475)
exposure may represent an immunologic etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last dose of pembrolizumab treatment and may affect more than one body system simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce complications. Based on existing clinical study data, most irAEs were reversible and could be managed with interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose modification and toxicity management guidelines for irAEs associated with pembrolizumab are provided in the following tables.  
NOTE: Due to the possible effect of treatment with pembrolizumab (MK-3475)on the immunologic response to infectious disease vaccines, patients must not have had any infectious disease vaccination (e.g., standard influenza, H1N1 influenza, pneumococcal, meningococcal, tetanus toxoid) 1 week before or after any dose of pembrolizumab (MK-3475).  
| General instructions: 1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive  treatment should begin if the irAEs are not controlled by corticosteroids.  2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12  weeks of the last pembrolizumab treatment. 3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. irAE Management with  corticosteroids and/or other  Monitor and follow-up therapies Toxicity Grade Action with  (CTCAE V5.0) Pembrolizumab Grade 2 or 3 Withhold  - Monitor participants for signs and symptoms of enterocolitis  (ie, diarrhea, abdominal pain, blood or mucus in stool with or  without fever) and of bowel perforation (ie, peritoneal signs  and ileus). - Participants with ≥ Grade 2 diarrhea suspecting colitis should  consider GI consultation and performing endoscopy to rule out  colitis.  - Participants with diarrhea/colitis should be advised to drink  liberal quantities of clear fluids. If sufficient oral fluid intake is  not feasible, fluid and electrolytes should be substituted via IV  infusion. - Administer corticosteroids  (initial dose of 1-2 mg/kg  prednisone or equivalent)  followed by taper Diarrhea/ Colitis Recurrent  Grade 3 or Grade 4 Permanently  discontinue - Administer corticosteroids  (initial dose of 0.5-1 mg/kg  prednisone or equivalent)  followed by taper - Monitor with liver function tests (consider weekly or more  frequently until liver enzyme value returned to baseline or is  stable) Grade 3 b or 4 c Permanently  discontinue Grade 2 a Withhold AST or ALT evaluation or  Increased  Bilirubin - Administer corticosteroids  (initial dose of 1-2 mg/kg  prednisone or equivalent)  followed by taper   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| irAE Management with                                                                          |                                                                                    |                                                                                                      |                                                                                                         |
|-----------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------|
| corticosteroids and/or other                                                                  | Monitor and follow-up                                                              |                                                                                                      |                                                                                                         |
| therapies                                                                                     |                                                                                    |                                                                                                      |                                                                                                         |
| Toxicity                                                                                      | Grade                                                                              | Action with                                                                                          |                                                                                                         |
| (CTCAE V5.0)                                                                                  | Pembrolizumab                                                                      |                                                                                                      |                                                                                                         |
| New onset  T1DM or  Grade 3 or 4  hyperglycemia  associated  with evidence  of β-cell failure | - Initiate insulin replacement  therapy for participants with  T1DM  - Administer antihyperglycemic in participants with hyperglycemia                                                                                    |                                                                                                      |                                                                                                         |
| Type 1 diabetes  mellitus (T1DM)  or  Hyperglycemia                                           | - Monitor participants for hyperglycemia or other signs and  symptoms of diabetes. |                                                                                                      |                                                                                                         |
| Withhold d                                                                                    |                                                                                    |                                                                                                      |                                                                                                         |
| Grade 2                                                                                       | Withhold                                                                           | - Administer corticosteroids  and initiate hormonal  replacements as clinically  indicated           | - Monitor for signs and symptoms of hypophysitis (including  hypopituitarism and adrenal insufficiency) |
| Hypophysitis                                                                                  | Withhold or                                                                        |                                                                                                      |                                                                                                         |
| Grade 3 or 4                                                                                  | permanently  discontinue d                                                         |                                                                                                      |                                                                                                         |
| Grade 2                                                                                       | Continue                                                                           | - Treat with non-selective  beta-blockers (eg,  propranolol) or thionamides  as appropriate          |                                                                                                         |
| Hyperthyroidis m                                                                              | - Monitor for signs and symptoms of thyroid disorders                              |                                                                                                      |                                                                                                         |
| Withhold or                                                                                   |                                                                                    |                                                                                                      |                                                                                                         |
| Grade 3 or 4                                                                                  | permanently  discontinue d                                                         | - Initiate thyroid replacement  hormones (eg, levothyroxine  or liothyronine) per standard  of care. | - Monitor for signs and symptoms of thyroid disorders                                                   |
| Hypothyroidism                                                                                | Grade 2, 3, 4                                                                      | Continue                                                                                             |                                                                                                         |
| Grade 1 or 2                                                                                  | Withhold                                                                           | - Based on severity of AE  administer corticosteroids                                                | - Ensure adequate evaluation to confirm etiology and/or exclude  other causes                           |
| Grade 3 or 4                                                                                  | Permanently  discontinue                                                           |                                                                                                      |                                                                                                         |
| Myocarditis                                                                                   |                                                                                    |                                                                                                      |                                                                                                         |  
| irAE Management with                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                  |                                                                                                          |                                                                                                                   |                                                            |                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|-----------------------------------|
| corticosteroids and/or other                                                                                                                                                                                                                                                                                                                                                                                                                                              | Monitor and follow-up                                            |                                                                                                          |                                                                                                                   |                                                            |                                   |
| therapies                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                  |                                                                                                          |                                                                                                                   |                                                            |                                   |
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Grade                                                            | Action with                                                                                              |                                                                                                                   |                                                            |                                   |
| (CTCAE V5.0)                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Pembrolizumab                                                    |                                                                                                          |                                                                                                                   |                                                            |                                   |
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Withhold                                                         | - Administer corticosteroids  (initial dose of 1 - 2 mg/kg  prednisone or equivalent)  followed by taper | -                                                                                                                 | Monitor participants for signs and symptoms of pneumonitis |                                   |
| Pneumonitis                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Recurrent                                                        | -                                                                                                        | Evaluate participants with suspected pneumonitis with  radiographic imaging and initiate corticosteroid treatment |                                                            |                                   |
| Grade 2, Grade 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Permanently  discontinue                                         | - Add prophylactic antibiotics  for opportunistic infections                                             |                                                                                                                   |                                                            |                                   |
| Nephritis:  grading  according to  increased  creatinine or  acute kidney  injury                                                                                                                                                                                                                                                                                                                                                                                         | Grade 2                                                          | Withhold                                                                                                 | - Administer corticosteroids  (prednisone 1 - 2 mg/kg or  equivalent) followed by  taper.                         | -                                                          | Monitor changes of renal function |
| Grade 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Permanently  discontinue                                         |                                                                                                          |                                                                                                                   |                                                            |                                   |
| Persistent  Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Withhold Withhold or                                             | -                                                                                                        | Ensure adequate evaluation to confirm etiology and/or                                                             |                                                            |                                   |
| discontinue                                                                                                                                                                                                                                                                                                                                                                                                                                                               | exclude other causes.                                            |                                                                                                          |                                                                                                                   |                                                            |                                   |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | based on the  event e                                            |                                                                                                          |                                                                                                                   |                                                            |                                   |
| Recurrent  Grade 3 or  Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                  |                                                                                                          |                                                                                                                   |                                                            |                                   |
| All Other  Immune Related  AEs                                                                                                                                                                                                                                                                                                                                                                                                                                            | - Based on type and severity  of AE administer  corticosteroids. |                                                                                                          |                                                                                                                   |                                                            |                                   |
| Permanently  discontinue                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                  |                                                                                                          |                                                                                                                   |                                                            |                                   |
| a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x  baseline if baseline abnormal c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; |                                                                  |                                                                                                          |                                                                                                                   |                                                            |                                   |  
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal  
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x  
baseline if baseline abnormal  
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal  
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or  
≤ Grade 2, pembrolizumab may be resumed.  
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson Syndrome and toxic epidermal  
necrolysis.
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8.6 dose modification contacts

For treatment or dose modification questions, please contact Drs. Karen L. Reckamp and Konstantin H. Dragnev at S1800AMedicalQuery@swog.org. For dosing principles or questions, please consult the SWOG Policy \#38 "Dosing Principles for Patients on Clinical Trials" at https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf.  
8.7 Adverse Event Reporting Toxicities (including suspected reactions) that meet the expedited reporting criteria as outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study Coordinator and NCI via CTEP-AERS, and to the IRB per local IRB requirements.