On May 26, 2020, the FDA approved a new indication for the combination of the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb) and the CTLA-4 inhibitor ipilimumab (Yervoy; Bristol Myers Squibb) plus 2 chemotherapy cycles for the first-line treatment of patients with recurrent or metastatic non–small-cell lung cancer (NSCLC), including patients with squamous or nonsquamous NSCLC, regardless of PD-L1 expression, and no EGFR or ALK genomic aberrations. Nivolumab plus ipilimumab may offer a synergistic mechanism of action of 2 types of immune checkpoint inhibitors—PD-1 and CTLA-4 inhibitors.
This new approval comes on the heels of the May 15, 2020, approval of nivolumab plus ipilimumab for the first-line treatment of patients with metastatic NSCLC whose tumors express PD-L1 ≥1% and have no EGFR or ALK genomic aberrations. The new approval represents the sixth indication for the combination of nivolumab plus ipilimumab across 5 types of cancer.
“We have come a long way in understanding the role of dual immunotherapy-based approaches in cancer and the potential impact on patients’ long-term outcomes,” said David P. Carbone, MD, PhD, study investigator and Director of the James Thoracic Oncology Center, Ohio State University. “The positive findings from CheckMate-9LA demonstrate the benefit of combining dual immunotherapy with limited chemotherapy for NSCLC patients regardless of PD-L1 status.”
“Receiving a diagnosis of advanced lung cancer is devastating,” said Andrea Ferris, President and Chief Executive Officer of LUNGevity. “Today’s announcement is welcome news as it provides a new dual immunotherapy-based option for previously untreated patients searching for a treatment that may help extend their lives.”
The FDA approved this new indication for nivolumab plus ipilimumab and limited chemotherapy based on the results of the CheckMate-9LA phase 3 clinical trial, a randomized, open-label, multicenter study. The study included patients with metastatic or recurrent NSCLC regardless of PD-L1 expression who received either nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy (N = 361) or 4 cycles of platinum-doublet chemotherapy followed by optional pemetrexed maintenance therapy if eligible (N = 358), for up to 2 years, or until disease progression or unacceptable toxicity.
The primary end point was overall survival (OS). The secondary efficacy outcomes included progression-free survival, overall response rate (ORR), and duration of response, as assessed by blinded independent central review.
The approval of 360 mg of nivolumab plus 1 mg/kg of ipilimumab with limited chemotherapy for this indication was based on the results of the prespecified interim analysis from the CheckMate-9LA study, which showed that nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy had superior OS versus chemotherapy (P = .0006), regardless of PD-L1 expression or tumor histology. The median OS was 14.1 months (95% confidence interval [CI], 13.2-16.2) versus 10.7 months (95% CI, 9.5-12.5), respectively.
The ORR was 38% (95% CI, 33-43) with nivolumab plus ipilimumab and limited chemotherapy versus 25% (95% CI, 21-30) with chemotherapy alone. At 12.7 months, the median OS was 15.6 months (95% CI, 13.9-20.0) versus 10.9 months (95% CI, 9.5-12.5), respectively. Furthermore, at 1 year, 63% of patients who received the combination therapy plus limited chemotherapy versus 47% of those who received chemotherapy alone were still alive.
As with all immunotherapies, nivolumab and ipilimumab are associated with immune-mediated adverse events. The most common (>2%) serious adverse events with nivolumab and ipilimumab in combination with platinum-doublet chemotherapy were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure.
Serious adverse reactions were reported in 57% of the patients who received the immunotherapy combination with limited chemotherapy; 24% of patients discontinued treatment because of adverse events, and 56% of patients had at least 1 treatment withheld because of side effects. Fatal adverse reactions occurred in 7 (2%) patients.