Nivolumab, Carboplatin and Pemetrexed Disodium, with or without Bevacizumab in Treating Patients with ALK-Rearranged or EGFR-Mutant Stage IIIB-IV Non-small Cell Lung Cancer

Inclusion Criteria

• Histologically or cytologically confirmed advanced (stage IIIB or IV) non-small-cell lung cancer (NSCLC) * ALK-rearranged NSCLC: ALK rearrangement as assessed by ALK fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or next-generation sequencing (NGS); for ALK FISH, rearrangements must be detected in > 15% of tumor cells * EGFR-mutant NSCLC: EGFR activating gene mutation (e.g., L858R, exon 19 deletion) per local testing
• Patients receiving bevacizumab (Cohorts E and F) must have non-squamous histology NSCLC
• Presence of at least one measurable lesion as defined by RECIST version (v)1.1; a previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the completion of irradiation
• Prior treatment with appropriate tyrosine kinase inhibitors (TKIs) as follows: * ALK-positive NSCLC (Cohorts F and H): Participants must have progressed on or after 1 or more next-generation ALK-TKI(s) * EGFR-mutant NSCLC (Cohorts E and G): Participants must have progressed on or after 1 or more third-generation EGFR-TKI(s)
• No prior systemic chemotherapy is allowed; NOTE: Prior adjuvant or neoadjuvant chemotherapy is allowed if received more than 12 months prior to the study; in addition, one prior cycle (dose) of chemotherapy is allowed if there was no evidence of disease progression following the dose
• Tumor tissue sample is required within 6 months prior to study enrollment; tissue sample may be fresh (core needle, excisional, or incisional biopsy), or archival if obtained within 6 months prior to enrollment; if a tissue sample is available but it has been > 6 months, the principal investigator may approve the sample after discussion; PD-L1 IHC testing will be performed on the tumor tissue, but positivity on the PD-L1 IHC testing is not required to enroll in the study
• Clinically asymptomatic and stable central nervous system (CNS) metastases are allowed (including untreated CNS metastases) if they have not required increasing doses of steroids or stable doses equivalent to prednisone > 10 mg daily within 2 weeks prior to study entry for CNS symptoms
• Prior palliative radiotherapy must have been completed at least 2 weeks prior to study entry
• Subjects must have been off any prior TKIs for at least 5 half-lives of that drug
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy >= 12 weeks
• White blood cell (WBC) >= 2.0 x 10^9/L
• Neutrophils >= 1.5 x 10^9/L
• Platelet >= 100 x 10^9/L
• Hemoglobin >= 9/dL
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance using Cockcroft-Gault formula >= 50 mL/min
• Total bilirubin =< 1.5 x ULN (except in patients with Gilbert’s syndrome who may have total bilirubin < 3.0 mg/dL)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN (or =< 5.0 x ULN if liver metastases are present)
• Females of child-bearing potential (defined as a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or has not been naturally post-menopausal for at least 24 consecutive months) must: * Have a negative serum or urine pregnancy test obtained within 24 hours prior to starting the investigational drug * Not be breastfeeding * Agree to use, and be able to comply with, highly effective contraception (failure rate less than 1% per year) without interruption while on study treatment plus 5 half-lives of nivolumab (half-life up to 25 days) plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment completion; complete abstinence is acceptable if it is in line with the preferred and usual lifestyle of the patient; period abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception; examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal implants, established and proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices; alternatively, two methods (e.g., two barrier methods from the options of diaphragm, cervical cap, vaginal sponge, and condom, or progesterone-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action) may be combined to achieve a failure rate of < 1% per year; barrier methods must always be supplemented with the use of a spermicide
• Male subjects agree to remain abstinent or use a condom plus an additional contraceptive method that result in a failure rate of < 1% per year during sexual contact with a female of childbearing potential while participating in the study, during dose interruptions, and for 31 weeks following the last dose of the study treatment, even if he has undergone a successful vasectomy; abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient; periodic abstinence and withdrawal are not acceptable
• Subject has the ability to understand and provide signed informed consent
• Subject has the willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

Exclusion Criteria

• Subjects previously treated with T cell immune-modulating antibodies, including anti-CTLA-4, anti-PD-1 and/or anti-PD-L1 agents
• Subjects with symptomatic brain metastases, carcinomatous meningitis, spinal cord compression, or intractable back pain due to compression of destructive mass
• Subjects with active, known, or suspected autoimmune disease; subjects 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 permitted to enroll
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization (unless used to treat investigational drug-related adverse events); inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Subjects with interstitial lung disease or interstitial pneumonitis that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• For Cohorts E and F (bevacizumab cohorts) only (not applicable to cohorts G and H): * Previous history of hemoptysis (expectoration of more than 2.5 mL of blood) within 3 months prior to enrollment * History of hemorrhagic central nervous system (CNS) metastases or intracranial hemorrhage * History of or genetic predisposition to a bleeding diathesis or coagulopathy * Therapeutic anticoagulation, including but not limited to: low-molecular weight heparin, heparin, or warfarin; anticoagulants must be discontinued 10 days prior to the first administration of bevacizumab; prophylactic use of anticoagulants is allowed * Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day) or other non-steroidal anti-inflammatories known to inhibit platelet function * Clinically significant heart disease (i.e., active), stroke or myocardial infarction within 6 months prior to enrollment, unstable angina pectoris, congestive heart failure of grade > II according to the New York Heart Association (NYHA), or cardiac arrhythmia requiring specific treatment during the study and that may interfere with the follow-up of the study treatment or poorly controlled by treatment * Arterial or venous thromboembolic events within 6 months of study enrollment * Poorly controlled arterial hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg), with or without antihypertensive medication; patients presenting with high blood pressure are eligible if the dose or adjustment of anti-hypertensives lowers blood pressure to meet the inclusion criteria of the study * Minor surgical intervention, including placement of a permanent catheter, within 24 hours prior to the first infusion of bevacizumab * Non-healing wound, active peptic ulcer, or untreated bone fracture * Previous history of abdominal fistula, tracheoesophageal fistula or other fistula with grade 4 severity, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to enrollment * Proteinuria at baseline; subjects unexpectedly found to have 2+ or greater proteinuria on a urine dipstick at baseline should undergo a 24-hour urine which must be an adequate collection and must demonstrate < 2 g of protein/24 hr to allow participation in the study * Patients who have received previous anti-angiogenic treatment (experimental or marketed: bevacizumab, thalidomide, CP-547632, sunitinib, sorafenib, or others)
• Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days prior to screening; no major surgery, other than diagnostic surgery, is allowed within 4 weeks prior to treatment in the study
• Co-administration of anti-cancer therapies other than those administered in the study
• Subjects with other active malignancy requiring concurrent intervention
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS); HIV-positive participants are ineligible
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
• Subjects with >= grade 2 peripheral neuropathy at enrollment per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
• Pregnant or lactating women
• Subjects currently enrolled in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices, or investigational drug
• History of allergy or hypersensitivity to any study drugs or their excipients
• Any known clinically significant concomitant medical condition, laboratory abnormality, or psychiatric illness that, in the investigator’s opinion, would prevent the subject from participating in the study, pose an unacceptable risk to the patient in this study, or interfere with the interpretation of safety results