FDA Approves Nivolumab/Ipilimumab Plus Chemo for Frontline NSCLC

The FDA has approved nivolumab (Opdivo) plus ipilimumab (Yervoy) and 2 cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent non—small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations.

The approval, which is not contingent on tumor PD-L1 status, is based on findings from the phase 3 CheckMate-9LA trial, in which patients with advanced non—small cell lung cancer (NSCLC) who received nivolumab plus low-dose ipilimumab given concomitantly with 2 cycles of chemotherapy had superior overall survival (OS) compared with patients who received up to 4 cycles of chemotherapy alone followed by optional maintenance treatment for eligible patients with nonsquamous disease.

The median overall survival (OS) at the prespecified interim analysis was 14.1 months in the nivolumab/ipilimumab arm compared with 10.7 months in the platinum-doublet chemotherapy arm (HR, 0.69; 96.71% CI, 0.55-0.87; P = .0006). The median progression-free survival (PFS) per blinded independent central review (BICR) was 6.8 months versus 5 months, respectively (HR, 0.70; 95% CI, 0.57-0.86; P = .0001). The overall response rate (ORR) per BICR was 38% versus 25%, and the median duration of response per BICR was 10 months versus 5.1 months, respectively.

Following an additional 4.6 months of follow-up, the median OS was 15.6 months in the nivolumab/ipilimumab arm versus 10.9 months in the chemotherapy-alone arm, with a new hazard ratio for OS of 0.66 (95% CI, 0.55-0.80).

“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,” CheckMate-9LA investigator David P. Carbone, MD, PhD, director of the James Thoracic Oncology Center at The Ohio State University, stated in a press release. “The positive findings from CheckMate-9LA demonstrate the benefit of combining dual immunotherapy with limited chemotherapy for NSCLC patients regardless of PD-L1 status. With today’s approval, more patients now have access to an Opdivo plus Yervoy-based option and a chance at a longer life.”

The open-label, multicenter, randomized, phase 3 CheckMate-9LA trial evaluated nivolumab at 360 mg every 3 weeks plus ipilimumab at 1 mg/kg every 6 weeks plus 2 cycles of chemotherapy versus chemotherapy alone for up to 4 cycles followed by optional maintenance pemetrexed in the first-line setting for patients with advanced NSCLC, regardless of PD-L1 expression and histology.

To be eligible for enrollment, patients had to have histologically confirmed stage IV or recurrent NSCLC with squamous or nonsquamous histology, could not have received prior therapy, have an ECOG performance status of ≤1, measurable disease by RECIST v1.1 criteria, and be tested for PD-L1 expression via immunohistochemistry. Those with EGFR or ALK mutations that were sensitive to available targeted therapy or untreated central nervous system metastases were excluded from the trial.

The immunotherapy plus chemotherapy arm included 361 patients and the chemotherapy-alone arm included 358 patients. The median patient age was 65 years (range, 26-86). Over half (51%) of patients were aged ≥65 years and 10% of patients were aged ≥75 years. Over two-thirds (70%) of patients were male, 89% were white, 31% had a baseline ECOG performance status of 0, and 68% had a baseline ECOG performance status of 1.

Regarding tumor histology, 32% of patients had squamous disease and 68% of patients had nonsquamous disease. Tumor PD-L1 expression was ≥1% in 57% of patients and <1% in 37% of patients. Additionally, 86% of patients were former or current smokers, and 17% of patients had CNS metastases.

The primary end point of the trial was OS in the intent-to-treat population; secondary endpoints included PFS, ORR, and efficacy measures according to biomarkers.

Adverse event (AE)-related discontinuation from the study occurred in 24% of patients in the nivolumab/ipilimumab arm, and 56% of patients in the immunotherapy arm required the withholding of ≥1 treatment due to an AE. Also in this cohort, serious AEs occurred in 57% of patients, with the most common (>2%) being pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis and respiratory failure.

Overall, the most frequently reported (>20%) AEs across all grades in the nivolumab/ipilimumab arm were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%). and pruritus (21%).

Earlier this month, the FDA has approved nivolumab plus ipilimumab for the first-line treatment of patients with metastatic NSCLC that does not have EGFR or ALK genomic tumor aberrations, and whose tumors express a PD-L1 level ≥1%, as determined by an FDA-approved test.

U.S. Food and Drug Administration Approves Opdivo® (nivolumab) + Yervoy® (ipilimumab) Combined with Limited Chemotherapy as First-Line Treatment of Metastatic or Recurrent Non-Small Cell Lung Cancer. Published May 26, 2020. https://bit.ly/2yxso7U. Accessed May 26, 2020.

Overall, 719 patients were enrolled in the study. Those who were enrolled on the experimental arm were treated for ≤2 years or until disease progression or unacceptable toxicity, while patients in the control arm were treated with ≤4 cycles of chemotherapy and optional pemetrexed maintenance, if eligible, until disease progression or toxicity.