A Master Protocol Of Phase 1/2 Studies Of Nivolumab In Advanced Nsclc Using Nivolumab As Maintenance After Induction Chemotherapy Or As First-Line Treatment Alone Or In Combination With Standard Of Care Therapies
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide, accounting for approximately 18% of all cancer deaths.1 Despite treatment with platinum-based chemotherapy, the standard of care for first-line therapy, patients with metastatic NSCLC have a median survival of approximately 10 months, and a 5-year survival rate of less than 5%. Immunotherapeutic approaches have demonstrated clinical efficacy in several cancer types, including melanoma, hormone-refractory prostate cancer, and lung cancer.3,4. Tumors may modulate and evade the host immune response through a number of mechanisms, including down regulation of tumor-specific antigen expression and presentation, secretion of anti-inflammatory cytokines, and up-regulation of inhibitory ligands. T-cell checkpoint regulators such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1, CD279) are cell-surface molecules that, when engaged by their cognate ligands, induce signaling cascades down-regulating T-cell activation and proliferation. One proposed model by which therapeutic T-cell checkpoint inhibitors derive antitumor activity is through breaking of immune tolerance to tumor cell antigens. Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype mAb that binds PD-1 on activated immune cells and disrupts engagement of the receptor with its ligands PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273), thereby abrogating inhibitory signals and augmenting the host antitumor response. In early clinical trials, nivolumab has demonstrated activity in several tumor types, including melanoma, renal cell cancer (RCC), and NSCLC.5 Nivolumab received FDA approval in December 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab treatment, and if BRAF V600 mutation-positive, a BRAF inhibitor. A second FDA labeled indication occurred in March 2015 for the treatment of metastatic squamous (SQ) NSCLC with progression on or after platinum-based chemotherapy. The approval of nivolumab in metastatic SQ NSCLC patients that have progressed on or after a platinum-based chemotherapy was based on the findings of 2 clinical trials. The first trial was a single-arm trial of nivolumab in subjects with metastatic SQ NSCLC (CA209063) in subjects that had progressed after receiving a platinum-based therapy and at least 1 additional systemic treatment. The second trial was a Phase 3 randomized trial (CA209017) of nivolumab versus docetaxel in patients with metastatic SQ NSCLC that had progressed on or after platinum-based chemotherapy which was stopped early after an interim analysis due to an improved overall survival (OS) benefit to patients on the nivolumab arm (see Section 1.4.6, Anti-Tumor Activity Summary).