![]() ![]() Conversely, patients on the chemotherapy arm had higher rates of anemia. As expected, compared with chemotherapy alone, the nivo/ipi/chemo regimen had higher rates of diarrhea, rash, pruritus, and endocrinopathies that are known ARs associated with immune checkpoint inhibitors. For patients treated with nivo/ipi/chemo, 56% experienced dose delays or dose reductions. Permanent discontinuation due to ARs occurred in 24% of patients and serious ARs (SARs) occurred in 57% of patients receiving nivo/ipi/chemo. ![]() In CheckMate 9LA, fatal adverse reactions (ARs) occurred in seven (2.0%) patients treated with nivo/ipi/chemo and included hepatic toxicity ( n = 2), acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia ( 16). The safety review primarily focused on studies CheckMate 9LA and CheckMate 568, with additional relevant supportive data from CheckMate 227 and studies of nivolumab in combination with ipilimumab for other cancer types. Finally, approvals of nivolumab plus ipilimumab in other tumor types, specifically melanoma, renal cell carcinoma, hepatocellular carcinoma, and microsatellite instable-high or mismatch repair–deficient colorectal cancer, were considered supportive evidence of the clinical benefit of the nivo/ipi combination. In cross-trial comparisons, the magnitude of OS benefit over chemotherapy of the CheckMate 9LA regimen (nivo/ipi/chemo) was greater than that seen with either the nivo/ipi or nivo/chemo regimens in CheckMate 227. In part 2 of CheckMate 227, although there was not a statistically significant improvement in OS, there was a positive trend favoring the combination of nivolumab with chemotherapy (nivo/chemo) over chemotherapy alone. Part 1 of CheckMate 227 demonstrated improved efficacy of the combination of nivo/ipi versus nivolumab monotherapy for the same patient population enrolled in CheckMate 9LA. The FDA evaluated data from the randomized, controlled study CheckMate 227 using both within trial comparisons and nonformal cross-trial comparisons ( Table 2). 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). every 3 weeks until disease progression or unacceptable toxicity. Patients on the control arm with nonsquamous histology could receive optional maintenance therapy with pemetrexed 500 mg/m 2 i.v. plus investigator's choice of carboplatin AUC 5 or 6 i.v. every 3 weeks and patients with nonsquamous histology received pemetrexed 500 mg/m 2 i.v. Patients with squamous histology received carboplatin i.v. every 6 weeks plus two cycles of histology-based platinum-doublet chemotherapy or four cycles of histology-based platinum-doublet chemotherapy. 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 intravenously (i.v.) every 3 weeks with ipilimumab 1 mg/kg i.v. 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, Australia's Therapeutic Goods Administration, and Health Canada. Progression-free survival and overall response rate per blinded independent central review 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 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). 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). 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. ![]()
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