**Credentialing must be completed prior to enrollment to main ALCHEMIST screening study (A151216)**

*DTL Required- Physicians must sign toxicity grid
CURRENT SITES CREDENTIALED:
Genesys, SJMH, Saginaw, Sparrow, St. Alphonsus, Lehigh, SJMO, St. Marys

-Patients must have undergone complete surgical resection of their stage IB (at least 4cm), II, or IIIA NSCLC and have had negative margins
-Patients must have no evidence of disease
-ECOG PS must be 0-1
-Patients must be registered to the ALCHEMIST-SCREEN (A151216)
-Non-squamous tumors must be EGFR and ALK wild-type
-Tumors must have PD-L1 status tested centrally
-Must not have prior treatment with an immune checkpoint inhibitor (anti-PD-L1, anti-CTLA4 monoclonal antibody)
-Patients must have adequately recovered from surgery and prior chemotherapy (grade 1 or less with exception of alopecia, ototoxicity and neuropathy)
-Patients must not require systemic corticosteroids equivalent to more than 10mg prednisone/d or other immunosuppressive meds

-Participants must have a pathologically-confirmed diagnosis of non-small cell lung cancer
-Participants must have advanced disease - either stage IV disease, stage IIIB disease not amenable to definitive multi-modality therapy, or recurrent disease after a prior diagnosis of stage I-III disease.
-An EGFR exon 20 insertion mutation must be detected in the tumor tissue.
-Patients must have previously received at least one line of therapy for their advanced lung cancer. There are no restrictions on the maximum number of prior therapies allowed.
-Participants may not have received any prior treatment with therapies targeting PDL1, PD1 or CTLA4.
-ECOG performance status ?1
-Participants may not have clinically symptomatic brain metastases or leptomeningeal disease

-Patients must have histologically or cytologically confirmed stage IV non-squamous NSCLC (includes M1a, M1b, and M1c stage disease, AJCC 8th edition). Patients with T4NX disease (Stage IIIB) with nodule in ipsilateral lung lobe are eligible if they are not candidates for combined chemotherapy and radiation.

-Patients must have PD-L1 expression Tumor Proportion Score (TPS = 1% in tumor cells. The assay must have been performed by a CLIA (or equivalent) certified laboratory.

-Patients must have measurable or non-measureable disease as defined in Section 6.1.2. Presence of malignant pleural fluid alone is allowed as study eligibility.

-Patients must have an ECOG Performance Status of 0 to 1

-Patients must NOT have received the following:

---Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Patients treated with any prior checkpoint inhibitors for 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 since the prior therapy and registration. Local therapy, e.g. palliative radiation, is allowed as long as a period of 14 days has passed since completion.

---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.

-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.

-Patients with symptomatic brain metastases are excluded. Patients with treated or asymptomatic brain metastases are eligible if off steroids for at least 14 days prior to protocol treatment. Anticonvulsants are allowed.

-Patients with another active malignancy within the last 2 years are excluded. 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 are permitted.

-Patients must not have known pre-existing and clinically active interstitial lung disease, or a known history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.

-Patients must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn’s disease, malabsorption,etc.)

-Patients must not have history of auto-immune condition requiring ongoing or intermittent systemic treatment in the past 2 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, etc.) is not considered a form of systemic

treatment.

-Patients must not have history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure, NYHA classification of 3, unstable angina or poorly controlled

arrhythmia, or myocardial infarction within 6 months prior to registration.

*Credentialing required. Please check your site's credentialing status.*
CURRENT SITES CREDENTIALED: SJMH, Livonia, Genesys, Sparrow, Saginaw, SJMO, Holy Cross

Eligibility Criteria:

Step 1 Eligibility Criteria – Concurrent Therapy

• Patient must be = 18 years old
• 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. Please see Section 3.1.11 for associated requirements.
• Patient must have an ECOG Performance Status of 0 or 1.
• Body weight > 30 kg of patients.
• Patient should have a life expectancy greater than 12 weeks.
• Patient must have a baseline ECG obtained within 6 weeks of registration. 
• Patient must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version v1.1, as defined in Section 6.1. Baseline imaging assessments and measurements used to evaluate all measurable or non-measurable sites of disease must be done within 4 weeks prior to registration.
• Absolute neutrophil count (ANC) = 1500 cells/uL
• White blood cells (WBC) counts = 2500/uL
• Platelet count = 100,000/uL
• Hemoglobin = 9.0 g/dL
• Total bilirubin = 1.5 x upper limit of normal (ULN) with the following exception: patients with known Gilbert disease who have serum bilirubin level < 3 x ULN may be enrolled.
• Aspartate aminotransferase (AST) and alanine transaminase (ALT) = 3.0 x ULN.
• Patient must have acceptable organ and marrow function as defined below. These values must be obtained = 7 days prior to registration.
• Serum creatinine = 1.5 x ULN or creatinine clearance = 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation (see Appendix VI).
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) = 1.5 x ULN.
• Patient must have pulmonary function tests (PFTs) with both FEV1 and DLCO = 40% of predicted, obtained within 5 months of registration.
• Patient should be expected to have Lung V20 of = 35%.
• 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.
• 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.
• Patients who are Human Immunodeficiency Virus (HIV) positive may participate in the study IF they meet all of the following eligibility requirements:
• They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective.
• They must have a CD4 count of greater than 250 cells/mcL.
• They must not be receiving prophylactic therapy for an opportunistic infection.
• 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.
• Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and until 90 days after the last dose of study treatment. All females of childbearing potential must have a negative blood test or urine study, with a minimum sensitivity 50 mlU/L or equivalent units of HCG, within 7 days prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months).
• Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use accepted and highly effective method(s) of contraception during sexual intercourse for at least one week prior to the start of treatment, during protocol treatment, and continue for 90 days after the last dose of protocol treatment.
• Patient must not have any active, known or suspected autoimmune disease and neuromuscular paraneoplastic syndromes including, but not limited to myasthenia gravis, Lambert-Eaton myasthenic syndrome, limbic encephalitis, myositis, Guillain-Barré, systemic lupus erythematosus, and systemic sclerosis. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia), not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are eligible.
• Patient must not have a history of active hepatitis B (chronic or acute) or hepatitis C infection. Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for hepatitis C virus ribonucleic acid (HCV RNA).
• Patient must not have a known active tuberculosis infection.
• Patient must not have any severe infections within 4 weeks prior to registration including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
• Patient must not have signs or symptoms of severe infection (sepsis) within 2 weeks prior registration.
• Patient must not have been treated with systemic immunostimulatory agents (including but not limited to interferon-a [IFN-a], interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to registration; or treated with an investigational agent within 4 weeks prior to registration (or within five half-lives of the investigational agent, whichever is longer).
• Unstable angina and/or congestive heart failure requiring hospitalization within 180 days prior to registration.
• Uncontrolled cardiac arrhythmia within 180 days prior to registration. weeks prior to registration (or within five half-lives of the investigational agent, whichever is longer).
• Patient must not have a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Patient must not have been treated with systemic immunosuppressive medications (equivalent to > 10 mg prednisone per day) or other immunosuppressive medications within 7 days of registration. Inhaled or topical steroids and adrenal replacement steroid doses equivalent to > 10 mg prednisone per day are permitted in the absence of active autoimmune disease.
• Patient must not have had a prior allogeneic bone marrow transplantation or prior solid organ transplantation.
• Patient must not have a history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan within 4 weeks of registration.
• Patient must not have had any prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.
• Patient with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. For example, patients must not have the following:
• Unstable angina and/or congestive heart failure requiring hospitalization within 180 days prior to registration.
• Uncontrolled cardiac arrhythmia within 180 days prior to registration.
• Patient must not have an uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• Patient must not have received a live, attenuated vaccine within 4 weeks prior to registration.
• Patient must not have unintentional weight loss > 10% within 30 days prior to registration.
• Patient must not have had past radiation to the current intended treatment site.
• Patient must not donate blood while on study treatment.

Step 2 Eligibility Criteria – Consolidation

• Patients must not receive any non-protocol anti-cancer therapy after the end of chemo/radiation or during consolidation.
• Patients with any > Grade 2 non-hematologic or > Grade 3 hematologic toxicities must recover to grade 2 (or less) within 45 days after the end of concurrent chemo/radiation, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Patients with suspected cases of = Grade 2 pneumonitis (non-infectious) are not eligible for consolidative MEDI4736 (durvalumab) and will proceed onto follow-up instead.
• Patients must not have disease progression on the first post-treatment (for concurrent chemo/radiation) chest CT scan, which must be obtained within 14 days after the last dose of radiation therapy. If so, the patient is not eligible for consolidative MEDI4736 (durvalumab) and will proceed onto follow-up instead.

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Canton, Chelsea), St. Mary's Livonia, Genesys, Hurley, St. John, Macomb, LVHN, Sparrow, Oakland, Saginaw, Holy Cross

Eligibility Criteria:

Patient must have a pathologically-confirmed diagnosis of non-squamous, non-small cell lung cancer (NSCLC).

- Patient must have advanced disease, defined as - either stage IV disease, stage IIIB disease not amenable to definitive multi-modality therapy, or recurrent disease after a prior diagnosis of stage I-III disease. All staging is via the American Joint Committee on Cancer (AJCC)/IASLC 8th edition staging criteria.

- Patient must have somatic activating sensitizing mutation in EGFR (e.g. but not limited to Exon 19 deletion, L858R, G709X, G719X, exon 19 insertions, L861Q, S768I). Patients with non-sensitizing mutations in EGFR (EGFR exon 20 insertions) are not eligible. Test results originating from a CLIA-certified or similarly accredited laboratory are acceptable; no specific assay is mandated. If there is any question as to whether an EGFR mutation is sensitizing, please contact the primary study team.

- Patient must not have received any prior treatment with an EGFR TKI or with an anti-VEGF agent.

-Patients that have received prior radiation therapy are eligible. Radiation (WBRT or stereotactic radiation) must have been completed at least two weeks prior to study registration.

- Patient must not have any risk factors for anti-VEGF administration, specifically, hemoptysis, active cardiovascular disease, uncontrolled hypertension, significant proteinuria (screening urine dipstick >3+) and tumor invading major blood vessels.

- Patient must have measurable disease as defined in Section 6.1.2. Baseline measurements of sites of disease must be obtained within 4 weeks prior to study registration. If a potential target lesion is previously irradiated without subsequent growth and/or is radiated after the imaging from which baseline measurements are obtained, they cannot be included as target lesions, and additional target lesions are required to meet criteria for measurable disease.

- Patient must not have had any prior systemic treatment for metastatic disease.

-Patient must be = 18 years of age.

- Patient must have an ECOG Performance status of 0 to 2

- Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.

All females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.

A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Women of childbearing potential and sexually active males must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for 2 weeks prior to the start of treatment, while on study treatment, and for

• 6 weeks after the last dose of protocol treatment for female patients on the AZD9291 (osimertinib) alone arm
• 4 months after the last dose of protocol treatment for male patients on AZD9291 (osimertinib) alone arm
• 6 months after the last dose of protocol treatment for all patients on AZD9291 (osimertinib) plus bevacizumab combination arm

NOTE: Female patients should also not breastfeed while on treatment and for 6 months after the last dose bevacizumab.

- Patient must have adequate organ and marrow function as defined below (must be obtained =14 days prior to registration):

Leukocytes = 3,000/mcL

Absolute neutrophil count = 1,500/mcL

Platelets = 100,000/mcL

Hemoglobin = 9 g/dL

Total bilirubin and creatinine = 1.5 x institutional upper limit of normal (ULN)

AST(SGOT)/ALT(SGPT) = 2.5 × institutional ULN

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

- 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.

- Patients with treated brain metastases are eligible if neurologically stable without glucocorticoid therapy after the stated washout period from RT or surgery provided the metastatic lesions are non-hemorrhagic.

 -Patients with untreated brain metastases or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required provided the metastatic lesions are non-hemorrhagic and are neurologically stable without glucocorticoid therapy.

- 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 with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

- Patient must have the ability to understand and the willingness to sign a written informed consent document and comply with study requirements

- Patient must not have had treatment with any investigational drug within five half-lives or 3 months (whichever is greater), prior to study initiation.

- Patient must not be currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (see Appendix VII). For any patient currently receiving such inducers of CYP3A4, they must discontinue use prior to first dose of study treatment. All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.

-Patient must not have any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of registration, with the exception of alopecia and grade 2 prior platinum-therapy–related neuropathy.

- Patient must not have any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it challenging for the patient to participate in the study. Screening for chronic conditions is not required.

- Patient must not have refractory nausea and vomiting, chronic gastrointestinal diseases, the inability to swallow the osimertinib tablets or previous significant bowel resection that would preclude adequate absorption of osimertinib.

- Patient must not have a medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.

-Patient must not have a history of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.

- Patient must not have mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value.

-Patient must not have any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second-degree heart block.

- Patient must not have any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: potassium < LLN; magnesium < LLN; calcium < LLN), congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes.

Eligibility Criteria:

Eligibility Criteria for Step 0 (Pre-Registration)

- Patient must be = 18 years of age on day of consent.

- Patient must have pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC)

- 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.

- 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.

- 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.

- 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. (See note in Section 3.2 for patients who received prior adjuvant chemotherapy or chemoradiation.) 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. See note in Section 3.2 for patients who received prior adjuvant chemotherapy or chemoradiation.

• Known molecular alterations in ROS1, MET, and RET are defined as below ROS1 gene rearrangement by FISH or DNA analysis. In addition to above requirements, these patients must have progressed on at least one prior ROS1 TKI therapy
• MET exon 14 splice mutations on DNA analysis. In addition to above requirements, prior MET directed TKI therapy is optional.
• MET mutations predicted to be sensitive to MET inhibitor. In addition to above requirements, prior MET directed TKI therapy is optional.
• High MET amplification by FISH (characterized by a fluorescence in situ hybridization MET/CEP7 ratio of 5 or greater); OR MET amplification by DNA NGS CLIA certified assay. In addition to above requirements, prior MET directed TKI therapyis optional.

RET gene rearrangement by FISH or DNA analysis. In addition to above requirements, prior RET directed TKI therapy is optional.

NOTE:

During Step 0 screening, CLIA reports of the testing results must be submitted via Medidata Rave for central review (see section 4.2.4) for instructions.The central review will be performed by the Study Chair, Co-Chair, Biology Co-Chair, and/or a delegate to determine that the results indicate a patient’s eligibility for targeted therapy. CLIA reports that contain information pertaining to any of the above mutations will be uploaded to Medidata Rave for central review of documentation for determination of patient eligibility for targeted therapy (Arm T). Central testing of tissue will not be performed. Institutions will be notified of the patient’s eligibility status for Arm T within two (2) business days of submission of the molecular testing reports. Patients with tumors with the above known

molecular alterations are eligible for cohort Arm Z following Step 1 eligibility review.

Patients without tumors with the above known molecular alterations are eligible for randomization to Arm A, B or C following Step 1 eligibility review

NOTE: 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.

- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents (such as anthracycline or HER2-directed antibody therapy, but not prior checkpoint inhibitor therapy), must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2B or better. (Appendix XI)

- Patient must have ECOG performance status 0-1

Eligibility Criteria for Step 1 (Randomization/Registration) for All Treatment Arms

- Patient must have met the eligibility criteria outlined in Section 3.1

- Patient must have measurable disease as defined by RECIST v1.1 criteria in Section 6. Measurements must be obtained within 4 weeks prior to randomization/registration.

Patient must have an anticipated life expectancy greater than 3 months.

- Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to randomization/registration:

- Chemotherapy/targeted oral therapy administered in a daily or weekly schedule must be completed = 1 week prior to randomization/registration

- Any chemotherapy administered in an every 2 week or greater schedule must be completed = 2 weeks prior to randomization/registration.

- Additionally, patient should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (as determined by the treating physician).

- Patient must not have had any prior radiation therapy for bone metastasis within 2 weeks, or any other radiation therapy within 4 weeks prior to randomization/registration.

- Patient must have acceptable bone marrow, renal, hepatic, and coagulation function, obtained within 2 weeks prior to randomization/registration as defined below:

ULN = institutional upper limit of normal; LLN = institutional lower limit of normal
• Leukocytes = 3,000/mcL

• Absolute neutrophil count = 1,500/mcL
• Platelets = 100,000/mcL
• Hemoglobin = 9 g/dL
• Total bilirubin = 1.5 x institutional ULN
• AST(SGOT) and ALT(SGPT) = 2.5 × ULN

• Creatinine = 1.5 x ULN
OR
Calculated (Crockoft-Gault formula) or measured creatinine clearance = 50 mL/min/1.73m2 (normalized to BSA) for patients with creatinine levels greater than 1.5 times the institutional normal Creatinine = 1.5 X ULN or creatinine clearance = 50ml/min/1.73m2

- Women must not be pregnant or breast-feeding due to the unknown effects of cabozantinib and nivolumab on human development and for the potential risk for adverse events in nursing infants with the treatment regimens being used.

All females of childbearing potential must have a blood test or urine study within 14 days prior to randomization/registration to rule out pregnancy.

A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

- Women of childbearing potential and sexually active males must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for up to 7 months after completion of treatment on the study (see Appendix VI).

- Patient must not have history of the following:

- Clinically significant gastrointestinal bleeding within 6 months prior to randomization/registration.

- Pulmonary hemorrhage or hemoptysis of = 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to randomization/registration.

- Any grade drug induced pneumonitis within 3 months prior to randomization/registration. Prior immune mediated pneumonitis of grade 3 or 4 are not eligible regardless of time window.

- Current radiographic evidence of cavitating pulmonary lesion(s).

- Current radiographic evidence of tumor invading any major blood vessels.

- Evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or mainstem endobronchial tumor within 28 days prior to randomization/registration.

- Peptic ulcer disease, inflammatory bowel, known malabsorption syndrome, bowel obstruction or gastric outlet obstruction (PEG tube placement) within 3 months prior to randomization/registration.

- Abdominal fistula, GI perforation, intra-abdominal abscess within 6 months prior to randomization/registration.

- Grade 3 or greater infection, or infection requiring intravenous systemic treatment within 28 days prior to randomization/registration. Patients should be off antibiotics at the time of randomization/registration.

- Serious non-healing wound/ulcer/bone fracture within 28 days prior to randomization/registration.

- History of organ transplant.

- Concurrent symptomatic untreated hypothyroidism within 7 days prior to randomization/registration.

- History of major surgery (within 3 months, with wound healing within 28 days, prior to randomization/registration), minor surgery (within 28 days prior to randomization/registration), other minor procedures (within 7 days prior to randomization/registration) or clinically relevant ongoing complications from prior surgery.

• Unstable angina pectoris
• Clinically-significant cardiac arrhythmias

• Stroke (including TIA, or other ischemic event)
• Myocardial infarction
• Thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose.
  

- Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic within 7 days of registration despite optimal antihypertensive treatment

- History of the following within 6 months prior to therapy:

-NOTE: Subjects with a diagnosis of DVT (but not PE) within 6 months are allowed if stable, asymptomatic, and treated with LMWH for at least 2 weeks before first dose

Patient must not receive concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel) within 7 days prior to randomization/registration. Allowed anticoagulants are the following:

- Low-dose aspirin (100 mg po daily or less) is permitted.

- Anticoagulation with therapeutic doses of LMWH is allowed in patients who are on a stable dose of LMWH for at least 6 weeks prior to study randomization/registration, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor within this time period.

- Patient must not receive concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone (> 1 mg daily dosing), phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s Wort) within 7 days prior to randomization/registration.

- Patient must have corrected QT interval calculated by the Fridericia formula (QTcF) = 500 ms within 28 days prior to randomization/registration.

- Patient must be able to swallow tablets.

- Patient must not be on systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to randomization/registration, with the following exceptions:

- Inhaled or topical steroids and adrenal replacement doses = 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

- Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).

- Physiologic replacement doses of systemic corticosteroids are permitted, if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.

- Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.

-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.

- Patient must meet one of the following criteria with respect to brain metastases:

Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study randomization/registration not demonstrating brain metastases

-OR-

Patients with known brain metastases must have baseline brain imaging and completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery; or complete neurosurgical resection = 3 months prior to randomization/registration) = 4 weeks prior to randomization/registration. They must be clinically stable. Known leptomeningeal disease is not allowed.

- Patient must not have known active autoimmune disease or known history of autoimmune disease for which recurrence may affect vital organ function or require immune suppressive treatment including systemic corticosteroids (e.g., immune-related neurologic disease, multiple sclerosis, autoimmune neuropathy, Guillian-Barre syndrome, etc.).

- Known human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.

- For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy at time of registration/randomization, if indicated.

- Patients with a known 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 at time of registration/randomization.

- Additional Eligibility Criteria for Step 1 (Randomization) Arms A-C

- Patient must not be eligible for the targeted therapy arm (Arm T) per one of the following criteria

• Patient did not have a known molecular alteration in ROS1, RET, or MET and did not have central review of tissue
• Central review report the patient is not eligible for Arm T based on molecular report.
  

- Patient must have progressed radiographically (per local investigator clinical assessment) following one, and only one, line of platinum-based chemotherapy AND one, and only one, line of prior immunotherapy. Patients may have received these lines of treatment together or sequentially. Patient must have received at least 2 prior doses of checkpoint inhibitor therapy (of only one type), in an every 2, 3, or 4 week schedule.

-NOTE: The requirement for prior chemotherapy will be met if patients have recurrence within 6 months after prior adjuvant platinum based chemotherapy for early stage disease, or recurrence within 6 months after prior radiotherapy plus platinum based chemotherapy for locally advanced disease.

-NOTE: Patients with unresectable stage III A/B NSCLC who have received chemo and radiation then consolidation durvalumab, followed by progression pts are eligible if progression happens while on after >2 doses of durvalumab. Prior bevacizumab with chemo is also allowed.

- Patient must not have had any prior anti-MET therapy, such as crizotinib or cabozantinib.

- Patient must not have had any prior allergic reaction or hypersensitivity to study drug components or related drugs (multitargeted small molecule tyrosine kinase inhibitors or checkpoint inhibitor monoclonal antibodies).

- Patients must not have had history of life-threatening toxicity related to prior immune therapy (eg.anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hypo/hyperthyroidism)

Additional Eligibility Criteria for Step 1 (Registration) Targeted Arm T

- Patient was registered to Step 0, Targeted Arm and central review results report the patient is eligible for Arm T

- Patients with ROS1 gene rearrangements must have progressed on at least one prior ROS1 targeted therapy such as crizotinib.

- Patient must have progressed radiographically (per local investigator clinical assessment) on at least one line of prior chemotherapy or targeted therapy, but there is no limit on number of prior number. Prior immunotherapy is allowed but not required. Prior bevacizumab with chemo is allowed.

NOTE: The requirement for prior chemotherapy will be met if patients have recurrence within 6 months after prior adjuvant platinum based chemotherapy for early stage disease, or recurrence within 6 months after prior radiotherapy plus platinum based chemotherapy for locally advanced disease.

NOTE: Patients with unresectable stage III NSCLC who have received chemo and radiation then consolidation durvalumab, followed by progression are eligible if progression happens after >2 doses of durvalumab. Prior bevacizumab with chemo is also allowed.

STEP 2 Eligibility Criteria (Crossover Arm Z)

- Patients must have met all eligibility requirements for Step 1 (see Section 3.2) at time of registration to Step 1 to be eligible for Step 2.

- Patients must have radiographic progressive disease per RECIST criteria (see Section 6.1.4) after = 2 cycles of therapy on Arm C.

- Patients must not have intervening anticancer treatment or major surgical procedure(s) between Step 1 and Step 2, except palliative radiation to the bone finishing = 1 week prior to registration to Step 2.

- Patients may not have central nervous system progression, but patients with stable CNS disease are allowed.

- Patients must be registered to Step 2 within 4 weeks of the last dose of treatment administration from Step 1.

- Patients must have an ECOG performance status between 0-2 (see Appendix V)

- Patients must have recovered to baseline (pre-Step 1) or CTCAE v.5.0 = Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.

-Patient must have acceptable bone marrow, renal, hepatic, and coagulation function, obtained within 2 weeks prior to randomization/registration as defined below:

ULN = institutional upper limit of normal; LLN = institutional lower limit of normal

- Leukocytes = 3,000/mcL

- Absolute neutrophil count = 1,500/mcL

- Platelets = 100,000/mcL

- Hemoglobin = 9 g/dL

- Total bilirubin = 1.5 x institutional ULN

- AST(SGOT) and ALT(SGPT) = 2.5 × ULN

- Creatinine =1.5 x ULN

OR

- Calculated (Crockoft-Gault formula) or measured creatinine clearance = 50 mL/min/1.73m2 (normalized to BSA) for patients with creatinine levels greater than 1.5 times the institutional normal Creatinine = 1.5 X ULN or creatinine clearance

= 50ml/min/1.73m2

- Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) = 500 ms within 28 days before registration.

- No intercurrent illness or disease complication that the investigator believes would limit the ability to safely tolerate the combination of cabozantinib and nivolumab.

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: Trinity Health IHA (AA-MI349, Brighton-MI350, Chelsea-MI351, Canton-MI352), Livonia, Oakland, Sparrow, Genesys, Hurley, holy cross

Eligibility Criteria:

 Eligibility Criteria (Step 1 Registration)

-Patient must be ≥ 70 years of age.

- Patient must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with PD-L1 TPS range of 1-49%.

- Patient must have Stage IIIB, IIIC or IV disease and not be candidates for combined chemo-radiation. NOTE: Prior chemo-RT for stage III with recurrence is allowed.

-Patient must have a tumor that is negative for EGFR mutation/ALK translocations or other actionable first line mutations in which patients would receive first-line oral tyrosine kinase inhibitors. -Patient must have an ECOG Performance Status of 2.

-Patient must agree not to father children while on study and for 6 months after the last dose of protocol treatment.

- Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision\u0002making capacity (IDMC) who have a legally authorized representative.

-Patient must have adequate organ and marrow function as defined below (these labs must be obtained within 14 days prior to Step 1 registration) 

Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months of Step 1 registration are eligible for this trial.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

- 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 undetectable HCV viral.

- 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.

- Patient must be English or Spanish speaking to be eligible for the QOL component of the study. 

Eligibility Criteria (Step 2 Randomization)

- Patient must have completed the baseline Geriatric Assessment (GA) as outlined in Section 7.3, after Step 1 registration and prior to Step 2 randomization 

**Please see the current version of the protocol for the complete eligibility list.** 

*Credentials Required. Check your site's credentialing status. Note that the investigator registering must have completed training- check your investigator's specific status.
CURRENT SITES CREDENTIALED:
SJMH, Genesys Hurley, St. Alphonsus, Sparrow

Eligibility Criteria Step 1:
-ECOG Performance status: 0 or 1
-Patients must have unresectable stage III or stage IV disease.
-Patients must have measurable disease. All sites of disease must be evaluated within 4 weeks prior to randomization.
-Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive.
-Patients must have BRAFV600E or BRAFV600K mutations, identified by an FDA-approved test at a CLIA-certified lab.
-Patients may have had prior systemic therapy in the adjuvant setting; however this adjuvant treatment must not have included a CTLA4 or PD1 pathway blocking antibody or a BRAF/MEK inhibitor. Also, patients may not have had any prior systemic treatment for advanced (measurable metastatic) disease. -Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting at least 4 weeks prior to entering the study and recovered from adverse events due to those agents. Mitomycin and nitrosoureas must have been discontinued at least 6 weeks prior to entering the study. Patients must have discontinued radiation therapy at least 2 weeks prior to entering the study and recovered from any adverse events associated with treatment. Prior surgery must be at least 4 weeks from registration and patients must be fully recovered from post surgical complications.
-Patients are ineligible if they have any currently active CNS metastases. Patients must not have taken any steroids within 14 days prior to randomization for the purpose of managing their brain metastases. Patients with only Whole Brain irradiation for treatment of CNS metastases are ineligible.
-Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study.

Eligibility Criteria Step 2 (Crossover arm for patients that have progressive disease):
-The patient must have met all eligibility criteria in step 1 (except as detailed below) at the time of crossover.
- RECIST defined measurable disease is not required
-Only prior systemic therapy as part of step 1 is allowed.
-malabsorption, swallowing difficulty, or other conditions that would interfere with the ingestion or absorption of dabrafenib or trametinib, or history of retinal vein occlusion are acceptable for patients crossing over to ipilimumab + nivolumab treatment.
-history of autoimmune disease, excluding interstitial lung disease or pneumonitis, is allowed in patients crossing over to dabrafenib/trametinib therapy
-Patients can be less than 4 weeks from surgery or SRS to CNS metastases
-Patients with a history of cardiovascular risks that developed during step 1 of therapy should be discussed with study PI at time of crossover.
-Patients must have melanoma that is metastatic and clearly progressive on prior therapy.
-Patients must be at least 2 weeks and within 12 weeks from documented PD on Step 1 of current study. All sites of disease must be evaluated within 4 weeks prior to registration.
-Patients must have recovered from adverse events (toxicities resolved to grade 1 or less) of prior therapy. Patients with immune related toxicities from ipilimumab + nivolumab may continue onto Step 2 even if still on steroids to control side effects, so long as toxicity has resolved to grade 1 or less.
-Patients must have discontinued radiation therapy at least 2 weeks prior to registering to Step 2 of the study and recovered from any adverse events associated with treatment. Prior surgery must be at least 2 weeks from registration to Step 2 and patients must be fully recovered from post-surgical complications

 **EA Ipilimumab Investigator Training required** Check your site's credentialing status.
CURRENT SITES CREDENTIALED:
SJMH, Genesys Hurley, St. Alphonsus, Sparrow, Saginaw, Livonia, SJMO

-ECOG Performance status must be 0-1
-Patient must have known BRAF mutational status of tumor; Wild-type (WT) or mutated, prior to randomization
-Patients must have unresectable stage III or stage IV melanoma. Patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive.
-Patients must have measurable disease.
-Patients may have had prior systemic therapy in the adjuvant setting (e.g. interferon, BRAF, or MEK agents). Patients may have had prior anti-CTLA-4 in the adjuvant setting, if at least one year from last dose of treatment has passed prior to beginning treatment. Patients may NOT have had any prior ipilimumab or PD-1/ PD-L1 agent in the adjuvant setting.
-Patients are ineligible if they have any currently active CNS mets. Patients must not have taken any steroids less than or equal to 14 days prior to randomization for the purpose of managing their brain mets. Patients with only Whole brain irradiation for treatment of CNS mets will be ineligible.
-Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (e.g., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids. 

CREDENTIALING REQUIRED. Please check your site's credentialing status.

Sites Currently Credentialed: SJMH (Ann Arbor, Canton, Chelsea), LVHN , St. Mary's Livonia, Holy Cross, St. John, St. John Macomb

Eligibility Criteria:

3.1.1 Age = 18 years.

3.1.2 Patients must have an ECOG performance Status: 0, 1, or 2 (However, those patients with a performance state of 3 because they are wheel chair bound due to congenital or traumatic events more than one year before the diagnosis of Merkel cell carcinoma are eligible)

3.1.3 Women must not be pregnant or breast-feeding due to the unknown effects of the study drug in this setting.

All women of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.

A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

3.1.4 Women of childbearing potential and sexually active males on Arm A MK-3475 (Pembrolizumab) must use accepted and effective method(s) of contraception or abstain from sex from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment. For patients on Arm B only receiving radiation therapy, contraception use should be per institutional standard.

3.1.5 Patient must have a histological confirmation of diagnosis of Merkel cell carcinoma (MCC), pathologic stages (AJCC version 8) I-IIIb.

• Stage I patients with negative sentinel lymph node biopsy are ineligible. Patients who have a positive biopsy or for whom no biopsy was done are eligible.

• Patients with distant metastatic disease (stage IV) are not eligible.

• The primary tumor must have grossly negative margins. (Microscopically positive margins are allowed).

• Cancers of unknown primary that have regional disease only can be included.

• Complete nodal dissection is not required for eligibility.

3.1.6 Patients with all macroscopic Merkel cell carcinoma (either identified by physical exam or imaging) have been completely resected by surgery within 16 weeks before registration.

3.1.7 Patient may not have a history of distant metastatic disease.

NOTE: loco-regional recurrent disease is acceptable, as long as this is not metastatic (prior surgery with or without radiation therapy is acceptable).

3.1.8 For patients with initial presentation of Merkel cell carcinoma, patient must have no previous systemic therapy or radiation therapy prior to surgery for Merkel cell carcinoma and cannot have completed adjuvant radiation therapy for Merkel Cell Carcinoma more than 6 weeks prior to registration. Patients actively undergoing radiation therapy or having completed adjuvant radiation therapy within 6 weeks of registration are eligible, as long as resection date is within 16 weeks of registration.

3.1.9 Patient must have the following required values for initial laboratory tests obtained within 4 weeks prior to registration.

3.1.9.1 White Blood Count = 2000/uL

3.1.9.2 Absolute neutrophil count (ANC) = 1000/uL

3.1.9.3 Platelets = 75 x 103/uL

3.1.9.4 Hemoglobin = 8 g/dL (= 80 g/L; may be transfused)

3.1.9.5 Creatinine = 2.0 x ULN

3.1.9.6 AST and ALT = 2.5 x ULN

3.1.9.7 Total Bilirubin = 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)

3.1.10 Patients who are HIV+ with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation.

3.1.11 Patients with HBV or HCV infection are eligible provided viral loads are undetectable. Patients on suppressive therapy are eligible.

3.1.12 Patients must not be on active immunosuppression, have a history of life threating virus, have had other (beside non-melanoma skin cancers, or recent indolent cancers e.g.: resected low grade prostate cancer) invasive cancer diagnoses in the last two years, or have had immunotherapy of any kind within the last 2 years.

3.1.13 Patients must not have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

3.1.14 Operative notes from patient’s surgical resection must be accessible.