US Food and Drug Administration Approval Summary: Nivolumab Plus Platinum-Doublet Chemotherapy for the Neoadjuvant Treatment of Patients With Resectable Non-Small-Cell Lung Cancer.

PURPOSE: On March 4, 2022, the US Food and Drug Administration (FDA) approved nivolumab plus platinum-doublet chemotherapy for the neoadjuvant treatment of patients with resectable non-small-cell lung cancer (NSCLC). We discuss the FDA's review of the key data and regulatory considerations supporting this approval. PATIENTS AND METHODS: The approval was based on the results of CheckMate 816, an international, multiregional, active-controlled trial that randomly assigned 358 patients with resectable NSCLC, stage IB (≥4 cm) to IIIA (N2) per the American Joint Committee on Cancer seventh staging edition to receive either nivolumab plus platinum-doublet or platinum-doublet chemotherapy alone for three cycles before planned surgical resection. The major efficacy end point that supported this approval was event-free survival (EFS). RESULTS: At the first planned interim analysis (IA), the hazard ratio (HR) for EFS was 0.63 (95% CI, 0.45 to 0.87; P = .0052; statistical significance boundary = .0262) favoring the nivolumab plus chemotherapy arm; the median EFS was 31.6 months (95% CI, 30.2 to not reached) in the nivolumab plus chemotherapy arm versus 20.8 months (95% CI, 14.0 to 26.7) in the chemotherapy-only arm. At the time of a prespecified IA for overall survival (OS), 26% of patients had died, and the HR for OS was 0.57 (95% CI, 0.38 to 0.87; P = .0079; statistical significance boundary = .0033). Eighty-three percent of patients in the nivolumab-containing arm versus 75% in the chemotherapy-only arm received definitive surgery. CONCLUSION: This approval, the first for any regimen for the neoadjuvant treatment of NSCLC in the United States, was supported by a statistically significant and clinically meaningful improvement in EFS with no evidence of detriment in OS or negative impact on patients' receipt and timing of surgery or surgical outcomes.

FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non-small Cell Lung Cancer, A Collaborative Project Orbis Review.

On May 26, 2020, the FDA approved nivolumab with ipilimumab and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. The approval was based on results from Study CA2099LA (CheckMate 9LA), an open-label trial in which 719 patients with NSCLC were randomized to receive nivolumab with ipilimumab and two cycles of chemotherapy (n = 361) or four cycles of platinum-doublet chemotherapy (n = 358). Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.1 months [95% confidence interval (CI), 13.2-16.2] compared with 10.7 months (95% CI, 9.5-12.5) for patients who received chemotherapy (HR, 0.69; 96.71% CI, 0.55-0.87; P = 0.0006). Progression-free survival and overall response rate per blinded independent central review were also statistically significant. This was the first NSCLC application reviewed under FDA's Project Orbis, in collaboration with Singapore's Health Sciences Authority, Australia's Therapeutic Goods Administration, and Health Canada. The benefit-risk analysis supports FDA's approval of nivolumab with ipilimumab and chemotherapy.

FDA Approval Summary: Lurbinectedin for the Treatment of Metastatic Small Cell Lung Cancer.

On June 15, 2020, the FDA granted accelerated approval to lurbinectedin for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was granted on the basis of the clinically meaningful effects on overall response rate (ORR) and duration of response (DOR), and the safety profile observed in a multicenter, open-label, multicohort clinical trial (PM1183-B-005-14, NCT02454972), referred to as Study B-005, in patients with advanced solid tumors. The trial included a cohort of 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. The confirmed ORR determined by investigator assessment using RECIST 1.1 in the approved SCLC patient population was 35% [95% confidence interval (CI): 26-45], with a median DOR of 5.3 (95% CI: 4.1-6.4) months. The drug label includes warnings and precautions for myelosuppression, hepatotoxicity, and embryo-fetal toxicity. This is the first drug approved by the FDA in over 20 years in the second line for patients with metastatic SCLC. Importantly, this approval includes an indication for patients who have platinum-resistant disease, representing an area of particular unmet need.