Nivolumab in Combination With Chemotherapy, or Nivolumab in Combination With Ipilimumab, in Advanced EGFR-Mutant or ALK-Rearranged NSCLC

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 FISH, 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) as well as a T790M mutation per local testing.
• Presence of at least one measurable lesion as defined by RECIST v1.1. 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 B and D): Participants must have progressed on or after 1 or more next-generation ALK-TKI(s).
• EGFR-mutant NSCLC (cohorts A and C): Participants must have progressed on or after 1 or more third-generation, T790M mutant-selective EGFR-TKI(s).
• Prior systemic chemotherapy requirements are as follows:
• Nivolumab plus carboplatin and pemetrexed arms (cohorts A and B): NO prior systemic chemotherapy is allowed. NOTE: Prior adjuvant or neoadjuvant chemotherapy is allowed if received more than 12 months prior to the study.
• Nivolumab plus ipilimumab arms (cohorts C and D): Participants must have received a platinum-based combination chemotherapy for their advanced lung cancer and either progressed on/after this chemotherapy or are intolerant. Only ONE line of chemotherapy is allowed. NOTE: Prior adjuvant or neoadjuvant chemotherapy does not count as an additional line of chemotherapy if received more than 12 months prior to the study.
• Tumor tissue sample is required following the participant's last line of systemic therapy (TKI or chemotherapy). Tissue sample may be fresh (core needle, excisional, or incisional biopsy), or archival if obtained within 6 months prior to enrollment. There can have been no systemic therapy administered after the sample was obtained. If a tissue sample is available but it has been > 6 months and there has been no intervening therapy, 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 systemic anti-cancer treatment (including TKIs) for at least 5 half-lives of that drug.
• Age ≥ 18 years old.
• ECOG performance status of 0 or 1.
• Life expectancy ≥ 12 weeks.
• Screening laboratory values must meet the following criteria:
• WBC ≥ 2.0 x 109/L
• Neutrophils ≥ 1.5 x 109/L
• Platelet ≥ 100 x 109/L
• Hemoglobin ≥ 9/dL
• Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance using Cockcroft-Gault formula ≥ 50 mL/min
• Female CrCl = (140-age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL
• Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
• Total bilirubin ≤ 1.5 x ULN (except in patients with Gilbert's syndrome who may have total bilirubin 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 suspecte