Nivolumab and Ipilimumab With or Without Local Consolidation Therapy in Treating Patients With Stage IV Non-Small Cell Lung Cancer

Inclusion Criteria:

• Histologically or cytologically confirmed non-small cell lung cancer; if adiagnostic biopsy is available, a pre-treatment biopsy is not required. Patientswith a suspected lung cancer may be consented, but pathology must be confirmed priorto initiating treatment on study. Neuroendocrine carcinomas (e.g. small cell lungcancer [SCLC], carcinoid tumors) are not eligible. Carcinomas with neuroendocrinedifferentiation are eligible.

• Stage IV (according to the American Joint Committee on Cancer [AJCC] 8th edition)measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

• Signed and dated written or remote informed consent prior to admission to the studyin accordance with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines and to the local legislation.

• For lung adenocarcinoma patients, patients must not harbor any EGFR sensitizing orALK fusion where there are standard care therapy options available. For patientswith histologies other than adenocarcinoma, EGFR and ALK status is not required.Adenocarcinoma patients may be consented prior to the EGFR and ALK status beingknown, but EGFR and ALK status must be determined prior to initiating therapy. EGFRand ALK status may be determined using either tumor- or plasma-based, ClinicalLaboratory Improvement Amendments (CLIA)-certified assays. For patients withnon-small cell lung cancer (NSCLC), not otherwise specified (NOS), EGFR/ALK testingis not required, as the frequency of alterations is exceedingly rare in thishistology. Also, note that patients with ROS1/RET alterations can be enrolled, astyrosine kinase inhibitor such as crizotinib aren't established as first linetherapy for patients with these alterations.

• One prior line of chemotherapy and/or targeted agents for metastatic disease arepermitted. This chemotherapy can include maintenance therapy, as long as it wasgiven in the front line setting. In addition, prior antiangiogenic therapy (e.g.bevacizumab) is permitted if used as frontline treatment.

Patients must have organ and marrow function as defined below:

• Performance status of 0 or 1 if using Eastern Cooperative Oncology Group (ECOG)/Zubrod.

• Screening laboratory values must meet the following criteria and should be obtainedwithin 14 days prior to treatment initiation

• White blood cell (WBC ) >= 2000/uL

• Neutrophils >= 1500/uL (obtained within 14 days prior to randomization/registration)

• Platelets >= 100 x 10^3/uL (obtained within 14 days prior torandomization/registration)

• Hemoglobin > 9.0 g/dL (obtained within 14 days prior to randomization/registration)

• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 50 mL (if using the Cockcroft-Gault formula)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x ULN (obtainedwithin 14 days prior to randomization/registration)

• Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert syndrome, who can havetotal bilirubin < 3.0 mg/dL) (obtained within 14 days prior torandomization/registration)

• Women of childbearing potential (WOCBP) must use appropriate method(s) ofcontraception. Appropriate methods of contraception are as follows. Women will beinstructed to adhere to contraception for a period of 26 weeks after the last doseof investigational product. Men receiving nivolumab and who are sexually active withWOCBP will be instructed to adhere to contraception for a period of 35 weeks afterthe last week of nivolumab/ipilimumab (nivo/ipi). Note: WOCBP is defined as anyfemale who has experienced menarche and who has not yet undergone surgicalsterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in theabsence of other biological or physiological causes. In addition, women under theage of 55 must have a documented negative serum or urine test.

• Women of childbearing potential must have a negative serum or urine pregnancy testwithin 48 hours prior to the start of nivolumab.

• Men who are sexually active with WOCBP must use any contraceptive method with afailure rate of less than 1% per year. Men receiving nivolumab and who are sexuallyactive with WOCBP will be instructed to adhere to contraception for a period of 35weeks after the last dose of investigational product. Women who are not ofchildbearing potential (ie, who are postmenopausal or surgically sterile) as well asazoospermic men do not require contraception.

• Subjects with brain metastases are eligible if metastases are adequately treated andsubjects are neurologically stable (except for residual signs or symptoms related tothe central nervous system [CNS] treatment) for at least 2 weeks prior to the firstdose of nivolumab. In addition, subjects must be either off corticosteroids, or on astable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2weeks prior to the first dose of nivolumab. Patients with asymptomatic, small (e.g. =< 1 cm) brain metastases are 1) eligible provided that the patient is offcorticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (orequivalent) for at least 2 weeks prior to the first dose of nivolumab

• For cohort 1 subjects may receive radiotherapy for symptomatic metastases prior toenrollment provided that there is at least one other non-irradiated lesion amenableto LCT at the time of enrollment. When feasible, stereotactic body radiation therapy (SBRT) or other hypofractionated techniques are strongly encouraged.

Inclusion Criteria In Cohort 2:

• Patients must have disease progression per imaging radiologic studies prior torandomization in LONESTAR study (during induction phase)

• Patient in this cohort must start therapy with platinum doublet and immunecheckpoint inhibitor therapy no longer than 6 weeks after their last day of immunecheckpoint inhibitor therapy

• Patients must have organ and marrow function as defined below:

Performance Status of 0 or 1 if using ECOG/Zubrod. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to treatment initiation

WBC ≥ 2000/μL Neutrophils ≥ 1500/μL Platelets ≥ 100 x103/μL Hemoglobin > 9.0 g/dL

Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 50 mL (if using the Cockcroft-Gault formula below):

AST/ALT ≤ 3 x ULN Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

• Women of childbearing potential (WOCBP) must use appropriate method(s) ofcontraception. Appropriate methods of contraception are as follows. Women will beinstructed to adhere to contraception for a period of 26 weeks after the last doseof investigational product. Men receiving nivolumab and who are sexually active withWOCBP will be instructed to adhere to contraception for a period of 35 weeks afterthe last week of nivo/ipi. Note: WOCBP is defined as any female who has experiencedmenarche and who has not yet undergone surgical sterilization (hysterectomy orbilateral oophorectomy) or who is not postmenopausal. Menopause is definedclinically as 12 months of amenorrhea in a woman over 45 in the absence of otherbiological or physiological causes. In addition, women under the age of 55 must havea documented negative serum or urine test.

• Women of childbearing potential must have a negative serum or urine pregnancy testwithin 48 hours prior to the start of therapy.

• Men who are sexually active with WOCBP must use any contraceptive method with afailure rate of less than 1% per year. Men receiving nivolumab and who are sexuallyactive with WOCBP will be instructed to adhere to contraception for a period of 35weeks after the last dose of investigational product Women who are not ofchildbearing potential (ie, who are postmenopausal or surgically sterile as well asazoospermic men do not require contraception.Subjects with brain metastases areeligible if metastases are adequately treated (exception of ≤1 cm asymptomatic brainmetastases, as specified below) and subjects are neurologically stable (except forresidual signs or symptoms related to the CNS treatment) for at least 2 weeks priorto the first dose of nivolumab. In addition, subjects must be either offcorticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (orequivalent) for at least 2 weeks prior to the first dose of nivolumab. In addition,subjects must be either off corticosteroids or on stable or decreasing dose of ≤ 10mg daily prednisone (or equivalent) for at least 2 weeks prior to the first dose ofnivolumab. Patients with asymptomatic, small (e.g. ≤1 cm) brain metastases areeligible and do not require prior local therapy for eligibility, provided that thepatient is off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg dailyprednisone (or equivalent) for at least 2 weeks prior to the first dose ofnivolumab.

• Participants enrolled in the cohort 2 must be willing to undergo tumor biopsy priorto the initiation of therapy with immune checkpoint inhibitor and platinum doublettherapy and on treatment biopsies. In cases when such a biopsy is clinically unsafeto perform, archival (meaning obtained at earlier times) tumor biopsies may beaccepted the discretion of the study PI.

• For cohort 2 subjects may receive radiotherapy for symptomatic metastases at thetime of their progression prior to enrollment to cohort 2

Exclusion Criteria:

• Systemic immunotherapy for metastatic NSCLC. Immunotherapy agents include, but arenot limited to, agents targeting the PD1/PD-L1 axis (e.g. nivolumab, pembrolizumab,atezolizumab, durvalumab) or CTLA-4 (ipilimumab, tremelimumab) pathways.

• Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to the initiation of study treatment. The following exceptions areallowed: hormone-replacement therapy or oral contraceptives

• Women must not be breastfeeding.

• Patients excluded with any prior treatment of pneumonitis requiring corticosteroidswithin 60 days prior to the first dose of nivolumab

• Unwillingness or inability to follow the procedures required in the protocol.

• Any serious or uncontrolled medical disorder that, in the opinion of theinvestigator, may increase the risk associated with study participation or studydrug administration, impair the ability of the subject to receive protocol therapy,or interfere with the interpretation of study results.

• Prior malignancy active within the previous 2 years. Patients with locally curablecancers that have been apparently cured, such as basal or squamous cell skin cancer,superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breastwith local control measures (surgery, radiation) are eligible.

• Patients should be excluded if they have an active, known or suspected autoimmunedisease. Subjects are permitted to enroll if they have vitiligo, type I diabetesmellitus, residual hypothyroidism due to autoimmune condition only requiring hormonereplacement, psoriasis not requiring systemic treatment, or conditions not expectedto recur in the absence of an external trigger.

• Patients should be excluded if they have a condition requiring systemic treatmentwith either corticosteroids (> 10 mg daily prednisone equivalents) or otherimmunosuppressive medications within 14 days of study drug administration (i.e.disease-modifying antirheumatic drugs). Inhaled or topical steroids and adrenalreplacement doses > 10 mg daily prednisone equivalents are permitted in the absenceof active autoimmune disease. Note that subjects are permitted to use topical,ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimalsystemic absorption). Physiologic replacement doses of systemic corticosteroids arepermitted, even if >10 mg/day prednisone equivalents. A brief course ofcorticosteroids for prophylaxis (e.g. contrast dye allergy) or for treatment ofnon-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused bycontact allergen) is permitted.

• As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumabcombinations, drugs with a predisposition to hepatoxicity should be used withcaution.

• Patients should be excluded if they are known to be positive for hepatitis B virussurface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody)indicating acute or chronic infection.

• Patients should be excluded if they have known history of testing positive for humanimmunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

• History of allergy to study drug components.

• History of severe hypersensitivity reaction to any monoclonal antibody.

• Prisoners or subjects who are involuntarily incarcerated.

• Subjects who are compulsorily detained for treatment of either a psychiatric orphysical (infection disease) illness.

• Psychological, familial, sociological or geographical factors potentially hamperingcompliance with the study protocol and follow-up schedule.

• Any condition that, in the opinion of the investigator, would interfere with thestudy treatment or interpretation of the study results.