Protocol: Lung Map Sub Study – SWOG-S1800D

SCHEMA S1800D

Please Note: Below is brief eligibility, for full eligibility requirements, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810) 762-8038. Thank you!

Eligibility:

1. Participants must have been assigned to S1800D by the SWOG Statistics and Data Management Center (SDMC). Assignment to S1800D is determined by the
   LUNGMAP or S1400 protocol.
2. Participants must have measurable or non-measurable disease documented by CT or MRI.
3. Participants must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to sub-study randomization.
4. Participants with spinal cord compression or brain metastases must have received local treatment to these metastases and remained clinically controlled and
   asymptomatic for at least 7 days following stereotactic radiation and/or 14 days following whole brain radiation, and prior to sub-study randomization.
5. Participants must not have any history of organ transplant that requires use of immunosuppressives.
6. Participants must not have an active or uncontrolled infection in the opinion of the treating investigator.
7. Participants must not have a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of
   the investigational regimen.
8. Participants must have progressed (in the opinion of the treating investigator) following the most recent line of therapy for NSCLC.
9. Participants with a known sensitizing mutation for which an FDA-approved targeted therapy for NSCLC exists (e.g. EGFR, ALK gene fusions, ROS1, BRAF,
   RET, NTRK, and MET sensitizing mutations), must have previously received at least one of the approved therapy(s).
10. Participants must have received exactly one line of anti-PD-1 or anti-PD-L1 therapy for advanced disease given alone or in combination with platinum-based
    chemotherapy. Participants must have experienced disease progression during or after this regimen.
11. Participants must not have received anti-CTLA4 therapy (e.g. ipilimumab, tremelimumab), or other immune-modulatory therapy (e.g. anti-TIM-3, anti-LAG-3,
    anti-GITR, IL-2, IL-15).
12. Participants must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to substudy randomization.
13. Participants must not have received any radiation therapy within 14 days prior to sub-study randomization.
14. Participants must not have received nitrosoureas or mitomycin-c within 42 days prior to sub-study randomization.
15. Participants must not have received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications
    within 7 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.
16. Participants must not have received a live attenuated vaccination within 28 days prior to sub-study randomization.
17. Participants must not have had a major surgery within 14 days prior to sub-study randomization. Participant must have fully recovered from the effects of prior
    surgery in the opinion of the treating investigator.
18. Zubrod performance status must be 0-1.

Protocol: Alliance – A171901

SCHEMA Alliance A171901

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810) 762-8038. Thank you!

Eligibility:

1. Documentation of Disease: Histologic or cytologic diagnosis of non-small cell lung cancer (adenocarcinoma). Stage IV or recurrent metastatic non-small cell lung
   cancer. No planned initiation of definitive (potentially curative) concurrent chemo-radiation.
2. Planning to begin MK-3475 (pembrolizumab) treatment within 14 days of registration, with or without combination chemotherapy. Treating physician considers pembrolizumab as appropriate and plans to proceed with one of the following treatment schedules: (a) MK-3475 (pembrolizumab) 200 mg IV flat dose every 21 days or 400 mg IV flat dose every 42 days. (b) MK-3475 (pembrolizumab) 200 mg IV/ 400 mg IV + carboplatin AUC=5 + pemetrexed 500 mg/m2 (20% chemotherapy dose reduction is permitted per the discretion of the treating physician).
3. Patients will be ineligible if they are post-organ transplantation or are receiving ongoing immunosuppression treatment. Patients will be ineligible if they have
   an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Note: Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients who require inhaled corticosteroids would not be excluded from the study. Patients with vitiligo or resolved childhood asthma/atopy would not be excluded from the study. Patients who require local steroid injections (for example, a steroid injection to a joint) would not be excluded from the study
4. Prior adjuvant therapy is allowed and must have been completed at least 6 months prior to registration.
5. No planned radiation or other cancer treatment in the 3 months following registration.
6. No untreated brain metastases. Patients must be off oral and IV corticosteroids for this condition and asymptomatic at registration.
7. Age ≥ 70 years of age.

Protocol: Alliance – A081801

SCHEMA Alliance A081801

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and (810) 762-8038. Thank you!

Eligibility:

1. Previously registered to A151216
2. Central and/or local testing of EGFR with no EGFR exon 19 deletion of EGFR L858 R mutation (applicable to non-squamous patients only).
3. Central and/or local testing of ALK with no ALK rearrangement (failed testing is considered negative) (applicable to non-squamous patients only).
4. Central and/or local testing of PD-L1 IHC using one of the following assays: DAKO 22C3, DAKO 28-8, EIL3N or SP263. Note: Local testing results of EGFR and ALK by a local CLIA certified laboratory is acceptable. The report must indicate the result as well as the CLIA number of the laboratory that performed the assay. Local result of PD-L1 by DAKO 22C3, Dako 28-8, EIL3N or SP263 are acceptable for enrollment on A081801. Patients with local results for EGFR, ALK and PD-L1 still need to be registered to A151216 and follow all the submissions requirements but do NOT need to wait for the results to proceed to A081801 registration.
5. Completely resected stage IIA, IIB IIIA or IIIB (T3-4N2) NSCLC (squamous or non-squamous) with negative margins. Note: Patients with pathologic N2 disease, completely resected, are eligible. However, patients known to have N2 disease prior to surgery are not eligible; guidelines do not recommend up-front surgery for this population.
6. No prior neoadjuvant or adjuvant therapy for current lung cancer diagnosis.
7. No prior allogeneic tissue/solid organ transplant.
8. Age ≥18 years.
9. ECOG PS: 0-1

Protocol: SWOG – S1914

SCHEMA SWOG S1914

Please Note:  Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810) 762-8038. Thank you!

Eligibility:

1. Patient must have histologically or cytologically proven Stage I-IIA or limited T3N0M0 non-small cell lung cancer (NSCLC) without radiographic evidence of nodal or distant involvement (N0M0). Patient may have
   T3 disease with the exclusion of multifocal tumors and pericardial involvement.
2. Disease must have one or more of the following high-risk features:
   • Tumor diameter ≥ 2 cm as assessed by diagnostic CT
   • Tumor SUV max ≥ 6.2 as assessed by FDG PET/CT
   • Moderately differentiated, poorly differentiated, or undifferentiated histology.
3. Patient must not have evidence of hilar or mediastinal nodal involvement. Any patient with radiographically suspicious hilar or mediastinal nodes (including features such as non-calcified nodes with a short axis diameter > 1 cm, abnormal
   morphology, and/or elevated FDG avidity) must undergo cytologic sampling of suspicious nodes to rule out involvement prior to randomization. Mediastinal nodal sampling for other patients is optional.
4. Patient must be medically or surgically inoperable as documented by a board certified thoracic surgeon or multi-disciplinary tumor board consensus OR patient’s unwillingness to undergo surgical resection must be clearly documented.
5. Patient must not have received any prior treatment for the current NSCLC diagnosis.
6. Patient must not have undergone prior radiation to overlapping regions of the chest that, in the opinion of the treatment physician, will interfere with protocol treatment.
7. Patient must not have received treatment with systemic immunostimulatory or immunosuppressive agents, including corticosteroids, within 14 days prior to randomization.
8. Must be at least 18 years of age.
9. Zubrod Performance Status 0-2.
10. Patients must not have a prior or concurrent malignancy whose natural history or treatment has the potential (in the opinion of the treating physician) to interfere with the safety or efficacy assessment of the investigational regimen.

Protocol: SWOG – S1900E

SCHEMA SWOG S1900E

Please Note:  Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or   (810) 762-8038. Thank you!

Eligibility:  Sub-Study of Lung Map

1. Participants must have confirmed Stage IV or recurrent non-squamous non-small cell lung cancer (NSCLC). Mixed histology NSCLC with less than 50% squamous component is allowed.
2. Participants must have measurable disease. Measurable disease must be assessed within 28 days prior to sub-study registration.
3. Participants must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to sub-study registration.
4. Participants with EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS1 gene rearrangement, or BRAF V600E mutation must have progressed following all standard of care targeted therapy.
5. Participants must have received at least one line of systemic treatment for Stage IV or recurrent NSCLC.
6. Participants must have progressed (in the opinion of the treating physician) following the most recent line of systemic therapy for NSCLC.
7. Participants must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub study registration.
8. Participants must not have received any radiation therapy within 14 days prior to sub-study registration, with the exception of stereotactic radiation to CNS metastases which must have been completed at least 7 days prior to sub-study
   registration.
9. Participants must not have received prior sotorasib (AMG 510) or other KRASG12C specific inhibitor.
10. Participants must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study.
11. Participants must not have had a major surgery within 14 days prior to sub-study registration.
12. Participants must be able to swallow tablets whole.
13.  Zubrod performance status must be 0-1.
14. Participants must not have a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.

Protocol: ECOG – EA5191

SCHEMA ECOG EA5191

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or    (810) 762-8038. Thank you!

Eligibility:

1. Must be at least 18 years of age.
2. Patient must have pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC).
3. Patient must have Stage IV disease (includes M1a, M1b, or recurrent earlier stage disease), according to the 8th edition of the lung cancer TNM classification system.
4. Patient must have predominant non-squamous histology (patients with NSCLC NOS are eligible). Mixed tumors will be categorized by the predominant cell type. If small cell elements are present the patient is ineligible.
5. Patient’s tumor(s) must be tested and known negative for EGFR TKI sensitizing mutations (EGFR Exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements (by FISH, NGS, or IHC) by routine CLIA-certified clinical testing methods. Negative circulating tumor DNA results alone are not acceptable. Prior testing for tumor PD-L1 status is not required.
6. Patients WITHOUT tumors with known molecular alterations in ROS1, MET, RET (see below), or must have progressed radiographically (per local investigator assessment) following one, but only one, line of platinum-based chemotherapy AND one, but only one, line of prior immunotherapy. Lines of therapy are defined by clinical or radiographic progression. Patients may have received chemotherapy and immunotherapy either concurrently or sequentially in either order. Patient must have received at least 2 prior doses of checkpoint inhibitor therapy in an every 2, 3, or 4 week schedule. No submission of molecular testing is required and patients may be registered for Step 0 then proceed directly to Step 1 screening.  OR  Patients with tumors with known molecular alterations in ROS1, MET, and RETmust have progressed radiographically (per local investigator clinical assessment) on atleast one line of prior chemotherapy or targeted therapy, but there is no limit on number of prior number of therapies. Reciept of prior immunotherapy is allowed but not required.
7. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen (in the opinion of the treating physician) are eligible for this trial.
8. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
9. Patients with new or progressive brain metastases (active brain metastases) are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of study treatment.

Protocol: ECOG – EA5181

SCHEMA ECOG EA5181

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810) 762-8038. Thank you!

Eligibility:

1. Must be at least 18 years of age.
2. Patient must have one of the following: Newly diagnosed stage IIIA/B/C NSCLC (per the AJCC 8th Edition) that is unresectable and is histologically and/or cytologically confirmed.  Nodal recurrence after surgery for early stage NSCLC.
3. ECOG Performance Status 0-1
4. Body weight > 30 kg of patients.
5. Patient must not have unintentional weight loss > 10% within 30 days prior to registration.
6. Patient must have measurable disease.
7. Patients with nodal recurrence after surgery for early-stage NSCLC are eligible if the following criteria are met: No prior chemotherapy or radiation was ever administered for this lung cancer originally or for recurrence prior to entering this protocol. Prior curative-intent surgery was at least 90 days prior to the nodal recurrence. No prior radiation was administered to the region of study cancer that would cause overlap of treatment fields.
8. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this
   trial. Patients must not have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration.

PROTOCOL: Lung Map

SCHEMA LUNGMAP

Please Note: Below is partial list of eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810) 762-8038. Thank you!

ELIGIBILITY:

Step 0:

1. Patients with adequate archival tissue should be registered directly to Step 1, without registering to Step 0. Patients who need a fresh biopsy to obtain adequate tumor tissue must also submit whole blood for ctDNA testing. These patients must be registered to Step 0 to obtain a patient ID number for the submission.
2. Patients registered to Step 0 are not registered to the LUNGMAP protocol. To participate in LUNGMAP, patients must be registered to Step 1 after evaluation of patient eligibility, including tumor tissue adequacy.

Step 1:

1. Patients must have pathologically proven non-small cell lung cancer (all histologic types) confirmed by tumor biopsy and/or fine-needle aspiration. Disease must be Stage IV or recurrent. All histologies, including mixed, are allowed.
2. Patients must either be eligible to be screened at progression on prior treatment or to be pre-screened prior to progression on current treatment.
3. Screening at progression on prior treatment:
   To be eligible for screening at progression, patients must have received at least one line of systemic therapy for any stage of disease (Stages IIV) and must have progressed during or following their most recent line of therapy.
   1. For patients whose prior systemic therapy was for Stage I-III
      disease only (i.e. patient has not received any treatment for
      Stage IV or recurrent disease), disease progression on platinum based chemotherapy must have occurred within one year from
      the last date that patient received that therapy. For patients treated with consolidation anti-PD-1 or anti-PD-L1 therapy for Stage III disease, disease progression on consolidation anti-PD1 or anti-PD-L1 therapy must have occurred within one year from
      the date of initiation of such therapy.
   2. For patients whose prior therapy was for Stage IV or recurrent disease, the patient must have received at least one line of a
      platinum-based chemotherapy regimen or anti-PD-1/PD-L1 therapy, alone or in combination (e.g. Nivolumab or
      Pembrolizumab).
4. Pre-Screening prior to progression on current treatment:
   To be eligible for pre-screening, current treatment must be for Stage IV or recurrent disease and patient must have received at least one dose of the current regimen. Patients must have previously received or currently be receiving a platinum-based chemotherapy regimen or anti-PD-1/PDL1 therapy, alone or in combination (e.g. Nivolumab or Pembrolizumab). Patients on first-line treatment are eligible upon receiving Cycle 1, Day 1 infusion. Note: Patients will not receive their sub-study assignment until they progress and the LUNGMAP Notice of Progression is submitted.
5. Patients must have adequate tumor tissue available, defined as ≥ 20% tumor cells and ≥ 0.2 mm3 tumor volume.
   • The local interpreting pathologist must review the specimen.
   • The pathologist must sign the LUNGMAP Local Pathology Review Form confirming tissue adequacy prior to Step 1 registration.
6. Patients must agree to have this tissue submitted to Foundation Medicine for common broad platform CLIA biomarker profiling and PD-L1. If archival tumor material is exhausted, then a new fresh tumor biopsy that is formalin-fixed and paraffin-embedded (FFPE) must be obtained. Patients who need the fresh biopsy must also submit whole peripheral blood for ctDNA testing. A tumor block or FFPE slides 4-5 microns thick must be submitted. Bone biopsies are not allowed. If FFPE slides are to be submitted, at least 12
   unstained slides plus an H&E stained slide, or 13 unstained slides must be submitted. However, it is strongly recommended that 20 FFPE slides be submitted. Note: Previous next-generation DNA sequencing (NGS) will be repeated if done outside this study for sub-study assignment.
7. Patients must agree to have any leftover tissue (tissue that remains after biomarker testing) retained for the use of correlative studies outlined in the substudy treatment consents.
8. Patients with known EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, or BRAF V600E mutation are not eligible unless they have progressed following all standard of care targeted therapy. EGFR/ALK/ROS/BRAF testing is not required prior to Step 1 registration, as it is included in the Foundation One testing for screening/prescreening.
9. Patients must have Zubrod performance status 0-1.
10. Patients must be ≥ 18 years of age.

PROTOCOL: ECOG-EA5163

SCHEMA ECOG EA5163

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810) 762-8038. Thank you!

ELIGIBILITY:

1. Patients must have histologically or cytologically confirmed stage IV non-squamous NSCLC (includes M1a, M1b, and M1c stage disease. Patients with Stage IIIB and IIIC disease are eligible if they are not candidates for combined chemotherapy and radiation.
2. Patients must have PD-L1 expression Tumor Proportion Score (TPS) ≥ 1% in tumor cells. If PD-L1 expression TPS is unevaluable or the testing could not be completed, the patients are not eligible. The assay must have been performed by a CLIA (or equivalent) certified laboratory.
3. Patients must have measurable or non-measurable disease.
4. Must be at least 18 years of age.
5. ECOG Performance Status 0-1
6. Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Patients treated with any prior checkpoint inhibitors for metastatic lung cancer are ineligible. Chemotherapy for non-metastatic disease (e.g.
   adjuvant therapy) or immunotherapy for locally advanced Stage III disease is allowed if at least 6 months have elapsed between the last dose of the prior therapy and study registration. Local therapy, e.g. palliative radiation, is
   allowed as long as a period of 14 days has passed between completion of local therapy and study registration. Registration prior to treatment during the 14 days is allowed. Palliative radiation must be to non-target lesions.
7. Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 14 days prior to date of registration will be allowed. Other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required.
8. Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600) or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors are excluded.
9. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
10. Patients with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
11. Patients must not receive any other investigational agents during the course of therapy.

PROTOCOL: ECOG-E4512

SCHEMA ECOG E4512

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810) 762-8038. Thank you!

ELIGIBILITY:

1. Must be at least 18 years of age.
2. Patients must have undergone complete surgical resection of their stage IIA, IIB, IIIA or IIIB non-squamous or squamous b and have had negative margins. N3 disease is not allowed.
3. ECOG Performance Status 0-1
4. Positive for translocation or inversion events involving the ALK gene locus (e.g. resulting in EML4-ALK fusion) as defined by a CLIA approved test including: (1) translocation or inversion events involving
   the ALK gene locus (e.g. resulting in EML4-ALK fusion) as determined by the Vysis Break Point FISH assay; (2) ALK protein expression by immunohistochemistry (IHC); or (3) ALK rearrangement identified by
   Next Generation (NexGen) sequencing.
5. Patients must have completed any prior adjuvant chemotherapy or radiation therapy 2 or more weeks (6 or more weeks for mitomycin and nitrosoureas) prior to randomization and be adequately recovered at the time of randomization.
6. Patients must not have any history of locally advanced or metastatic cancer requiring systemic therapy within 5 years from randomization, with the exception of in-situ carcinomas and non-melanoma skin cancer. Patients must have no previous primary lung cancer diagnosed concurrently or within the past 2 years.
7. Patients may not be receiving any other investigational agents while on study.

PROTOCOL: Alliance-A151216

SCHEMA Alliance A151216

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810) 762-8038. Thank you!

ELIGIBILITY:

1. For pre-surgical patients:
   1. Suspected diagnosis of resectable non-small cell lung cancer. Cancers with a histology of “adenosquamous” are considered a type of adenocarcinoma and thus a “non-squamous” histology. Patients with squamous cell carcinoma are eligible.
   2. Suspected clinical stage of IIIA, II (IIA or IIB) or large IB (defined as size ≥4cm). Note: IB tumors <4cm are NOT eligible. Stage IB cancer based on pleural invasion is not eligible unless the tumor size is ≥4cm.
2. For post-surgical patients:
   1. Completely resected non-small cell lung cancer with negative margins (R0). Patients with squamous cell carcinoma are eligible only if they have not received adjuvant therapy.
   2. Pathologic stage IIIA, II (IIA or IIB) or large IB (defined as size ≥4 cm). Note: IB tumors <4cm are NOT eligible. Stage IB cancer based on pleural invasion is not eligible unless the tumor size is ≥4cm. The 7th edition of AJCC staging will be utilized.
3. ECOG Performance Status 0-1.
4. Age ≥ 18 years.
5. No patients who have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer.
6. No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration. No secondary primary lung cancer diagnosed concurrently or within 2 year prior to registration.
7. No prior treatment with agents targeting EGFR mutation, ALK rearrangement, and PD1/PD-L1/CTLA-4.
8. Patients who have had local genotyping are eligible, regardless of the local result.
9. No patients with recurrence of lung cancer after prior resection.
10. Note: Post-surgical patients should proceed to registration immediately following pre-registration.
11. Tissue available for the required analyses (either clinical tissue block or slides and scrolls.
12. Completely resected NSCLC with negative margins (R0). Cancers with a histology of “adenosquamous” are considered a type of adenocarcinoma and thus a “nonsquamous” histology.
13. Pathologic stage IIIA, IIA or IIB, or large IB (defined as size ≥ 4cm). Note: IB tumors <4cm are NOT eligible. Stage IB cancer based on pleural invasion is not eligible unless the tumor size is ≥4cm.
14. Patients with squamous cell carcinoma are eligible only if they have not received adjuvant therapy.