Safety and efficacy data from CheckMate 568 and CheckMate 227 supported the approval of the CheckMate 9LA regimen. Progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review (BICR) were also hierarchically-tested as secondary endpoints. The primary efficacy outcome measure was overall survival (OS). Patients on the control arm with non-squamous histology could receive optional maintenance therapy with pemetrexed 500 mg/m 2 IV every 3 weeks until disease progression or unacceptable toxicity. Patients with squamous histology received carboplatin IV AUC 6 plus paclitaxel IV 200 mg/m 2 every 3 weeks and patients with non-squamous histology received pemetrexed 500 mg/m 2 plus investigator’s choice of carboplatin AUC 5 or 6 or cisplatin 75 mg/m 2 every 3 weeks. The approval of nivolumab with ipilimumab in combination with platinum-doublet chemotherapy (nivo/ipi/chemo) was primarily based on CheckMate 9LA, an open-label trial in patients with metastatic or recurrent NSCLC without prior therapy for metastatic disease randomized 1:1 to nivolumab 360 mg IV every 3 weeks with ipilimumab 1 mg/kg IV every 6 weeks plus two cycles of histology-based platinum-doublet chemotherapy or four cycles of histology-based platinum-doublet chemotherapy. This review was conducted under Project Orbis, a global collaborative review program launched by FDA’s Oncology Center of Excellence (OCE) to facilitate concurrent submission, review, and regulatory action for high-impact clinically significant marketing applications across multiple participating countries ( 14). Herein, we provide a summary of FDA’s review of the marketing application that led to the approval of nivolumab, ipilimumab, and chemotherapy for first-line treatment of advanced NSCLC. Importantly, the regimen includes only two cycles of chemotherapy compared to existing combinations of immune checkpoint inhibitors with four cycles of chemotherapy. The approval of nivolumab, ipilimumab, and two cycles of platinum-doublet chemotherapy marked the first treatment regimen combining two immune checkpoint inhibitors for patients with advanced NSCLC, regardless of PD-L1 status. There are also several frontline chemotherapy sparing options for PD-L1-selected populations ( 8– 13). In patients with metastatic NSCLC without targetable genomic tumor aberrations in EGFR, ALK, ROS1, or BRAF, standard-of-care first-line treatment options include immune checkpoint inhibitors administered in combination with four cycles of histology-based platinum-doublet chemotherapy ( 4– 7). Metastatic NSCLC accounts for significant mortality globally, and effective and durable treatment options represent a significant unmet medical need. Most patients present with metastatic disease and long-term survival is poor ( 3). In the U.S., approximately 229,000 adults will be diagnosed with lung cancer in 2020, of which approximately 80–84% of cases will be NSCLC ( 3). Lung cancer remains the leading cause of cancer deaths worldwide, despite recent reports of decreased mortality with advances in treatment ( 1, 2). The benefit-risk analysis supports FDA’s approval of nivolumab with ipilimumab and chemotherapy. This was the first NSCLC application reviewed under FDA’s Project Orbis, in collaboration with Singapore’s Health Sciences Authority (HSA), Australia’s Therapeutic Goods Administration (TGA), and Health Canada (HC). Progression-free survival (PFS) and overall response rate (ORR) per blinded independent central review (BICR) were also statistically significant. Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.1 months (95% CI: 13.2, 16.2) compared to 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). 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). Food and Drug Administration (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 epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.
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