On May 15, 2020, the FDA approved a new indication for the first immunotherapy combination with the PD-1 inhibitor nivolumab (Opdivo; BMS) and the CTLA-4 inhibitor ipilimumab (Yervoy; BMS) for the first-line treatment of adults with metastatic non–small-cell lung cancer (NSCLC) and PD-L1 expression of ≥1%, as determined by an FDA-approved test, but without EGFR or ALK genomic translocations. The new approval was based on the results from the CheckMate-227 phase 3 clinical trial.
The combination of nivolumab and ipilimumab was previously approved for several indications, including metastatic NSCLC that is progressing during or after platinum-based chemotherapy, and in patients with EGFR mutations or ALK genomic translocations, when the disease is progressing while using a treatment approved for these aberrations; for unresectable or metastatic melanoma; for treatment-naïve patients with intermediate- or poor-risk advanced renal-cell carcinoma; for patients aged ≥12 years with MSI-H or dMMR metastatic colorectal cancer that has progressed after a chemotherapy regimen; and for hepatocellular carcinoma in patients who had received sorafenib.
“Patients with metastatic lung cancer remain in need of new treatment options that may provide durable responses,” said Matthew D. Hellmann, MD, CheckMate-227 study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. “The results from the CheckMate-227 trial show that a dual immunotherapy approach offers a chance at long-term survival for appropriate patients with metastatic NSCLC.”
The FDA approved this new indication based on the results from part 1a of the phase 3 CheckMate-227 clinical trial, a randomized, open-label, multicenter study in treatment-naïve patients with metastatic or recurrent NSCLC across nonsquamous and squamous tumor histologies. All patients enrolled in part 1a had tumors with PD-L1 expression of ≥1%; patients with known EGFR mutations or ALK genomic translocations were excluded.
The study compared the overall survival (OS) of 396 patients who received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg and 397 patients who received chemotherapy. The checkpoint inhibitor combination demonstrated superior OS versus chemotherapy (hazard ratio, 0.79; 95% confidence interval [CI], 0.67-0.94; P = .0066), regardless of tumor histology, and a minimum follow-up of 29.3 months.
The median OS was 17.1 months (95% CI, 15.0-20.1) with nivolumab plus ipilimumab versus 14.9 months (95% CI, 12.7-16.7) with chemotherapy. At 1 year, the OS rate was 63% with the immunotherapy combination versus 56% with chemotherapy; at 2 years, the OS was 40% and 33%, respectively; and at 3 years, at a median of 43.1 months, the OS was 33% versus 22%, respectively, indicating an 11% OS advantage with the use of nivolumab plus ipilimumab.
Based on a blinded independent central review, at a minimum of 28.3 months of follow-up, the overall response rate was 36% (95% CI, 31-41) with the combination (including 5.8% complete responses) versus 30% (95% CI, 26-35) with chemotherapy (including 1.8% complete responses). The median duration of response was 23.2 months (95% CI, 15.2-32.2) among the patients who received the immunotherapy combination versus 6.2 months (95% CI, 5.6-7.4) in the patients who received chemotherapy.
This immunotherapy combination can result in immune-mediated adverse reactions, which can be severe and potentially fatal. Serious adverse events occurred in 58% of the patients, and the combination was discontinued because of adverse reactions in 24% of patients; 53% of the patients had ≥1 doses withheld. The most common (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis.
Fatal adverse events occurred in 1.7% of patients, including pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multisystem organ failure, and renal failure. The most common (≥20%) side effects were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus.
