Promising Results for Patients with Advanced NSCLC Treated with Flat-Dose Nivolumab plus Weight-Based Ipilimumab

First-line immunotherapy targeting PD-1 and PD-L1 alone or in combination with chemotherapy and/or immune checkpoint therapies has improved the survival outcomes of patients with metastatic non–small-cell lung cancer (NSCLC). Nivolumab is a PD-1 inhibitor that restores antitumor T-cell function. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 inhibitor that induces antitumor T-cell responses. When combined, they have complementary mechanisms of action. This combination has gained approval in the United States for the first-line treatment of adults with metastatic NSCLC expressing PD-L1 ≥1% without EGFR or ALK mutations. The National Comprehensive Cancer Network and the European Society for Medical Oncology guidelines both recommend nivolumab plus ipilimumab as first-line treatment regardless of PD-L1 expression.

The phase 3 CheckMate 227 study evaluated first-line nivolumab plus ipilimumab versus chemotherapy in patients with metastatic NSCLC with PD-L1 tumor expression <1% or ≥1%. The 4-year overall survival rate in patients treated with nivolumab plus ipilimumab was 29% with PD-L1 tumor expression ≥1% and 24% with PD-L1 tumor expression <1%. The CheckMate 012 phase 1 clinical trial was designed to assess the optimal dose and schedule of nivolumab plus ipilimumab for patients with metastatic NSCLC. A dosage rate of nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks had acceptable patient tolerance along with clinical benefit. The CheckMate 817 phase 3b study assessed the clinical safety of flat-dose nivolumab at 240 mg every 2 weeks along with 1 mg/kg ipilimumab every 6 weeks.

An article in the Journal for ImmunoTherapy of Cancer reported the safety and efficacy data on the CheckMate 817 treatment regimen in patients with metastatic NSCLC in 2 cohorts: patients with ECOG performance status (PS) 0-1 (cohort A) and patients with ECOG PS 0-1 and untreated brain metastases, positive HIV status, renal or hepatic impairment, or with ECOG PS 2 (cohort A1). The primary end point for cohort A was treatment-related adverse events (AEs) and grade 3-4 and grade 5 immune-mediated adverse events (IMAEs). Secondary end points for cohort A were progression-free survival, objective response rate, and duration of response. In cohort A1, efficacy and safety were exploratory.

A total of 391 patients were in cohort A. Cohort A1 included 198 patients, with 139 patients having a ECOG PS 2 and 68 patients with EGOG PS 0-1. In this last group, 49 patients had untreated brain metastases, 9 had renal impairment, 7 had hepatic impairment, and 4 had a positive HIV status. Pneumonitis, diarrhea/colitis, and hepatitis were the most common grade 3-4 IMAEs in cohort A, whereas diarrhea/colitis, hepatitis, and rash were most common in cohort A1. The most common grade 3-4 treatment-related AEs were hepatic, gastrointestinal, and pulmonary events in cohort A and gastrointestinal, skin, and endocrine events in cohort A1. No grade 5 IMAEs or treatment-related select AEs were reported. In cohort A, there were 4 treatment-related deaths, and the 3-year overall survival rate was 33.7%. For cohort A1, 3 treatment-related deaths occurred, and the 3-year overall survival rate was 20.5%.

Source: Ready NE, Audigier-Valette C, Goldman JW, et al. First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817. J Immunother Cancer. 2023;11(2):e006127.