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Nivolumab (Opdivo) plus ipilimumab (Yervoy) combined with chemotherapy for the first-line treatment of non-small cell lung cancer (NSCLC) did not improve overall survival (OS) and led to more adverse events when compared with pembrolizumab (Keytruda) plus chemotherapy, a randomized phase III study from Japan showed.

Among 295 patients, the median OS reached 23.7 months in the nivolumab-ipilimumab group versus 20.5 months in the pembrolizumab group (HR 0.98, 90% CI 0.72-1.34, P=0.46), reported Isamu Okamoto, MD, of Kyushu University in Fukuoka, and colleagues.

More patients in the nivolumab-ipilimumab group than the pembrolizumab group experienced grade 3 or higher non-hematological adverse events (60% vs 41%), and the dual immunotherapy group had more treatment-related deaths (7% vs 2%), resulting in the trial being stopped early, the researchers detailed in .

"Although an updated analysis will be needed to draw a definitive conclusion from our study, the safety and efficacy data are suggestive of an unfavorable benefit-risk profile for platinum-based chemotherapy combined with nivolumab plus ipilimumab, versus platinum-based chemotherapy combined with pembrolizumab, as a first-line treatment for patients with advanced NSCLC," the authors wrote.

In explaining the rationale behind the study, Okamoto and colleagues noted that multiple trials have established that the addition of anti-PD-L1 therapy to chemotherapy improves outcomes in advanced NSCLC. The randomized phase III CheckMate 9LA and POSEIDON trials demonstrated an OS benefit with the addition of dual PD-L1 and CTLA-4 blockade to chemotherapy compared with chemotherapy alone.

However, neither of these trials included PD-L1 blockade in the control group; thus, "the question of whether CTLA-4 inhibitors should be added to chemotherapy plus PD-1 or PD-L1 inhibitors has remained unanswered, given that no head-to-head trials have been conducted," the authors pointed out.

In a , Molly Li, MBBS, of the Chinese University of Hong Kong, and colleagues called the high incidence of treatment-related deaths in the nivolumab-ipilimumab arm "alarming," but also noted that the majority of these deaths appeared to be immune related.

They also observed that in the CheckMate 9LA trial, the incidence of treatment-related deaths was similar between the nivolumab-ipilimumab plus chemotherapy and chemotherapy-alone groups (2% vs 2%), and pointed out that subgroup analyses of and showed that treatment-related adverse events with nivolumab-ipilimumab were more frequent among Japanese patients compared with the general population.

This suggests Japanese patients might be more susceptible to developing immune-related adverse events, they wrote, adding that the safety findings in this study might not be applicable to non-Japanese patients.

Furthermore, while the OS results showed similar survival between the two arms, Li and colleagues said this "should be interpreted with caution" given the short follow-up.

This open-label study was conducted at 48 sites in Japan among patients with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with known driver oncogenes were excluded.

Participants (median age 68 years, about 80% men) were randomly assigned to receive four cycles of platinum-based chemotherapy plus pembrolizumab or two cycles of platinum-based chemotherapy plus nivolumab-ipilimumab.

Between the start of patient accrual in April 2021 and trial discontinuation in March 2023, 11 of the 148 patients in the nivolumab-ipilimumab group had a treatment-related death -- four with pneumonitis, three with cytokine release syndrome, two with myocarditis (one confirmed by myocardial biopsy and one suspected case), one with sepsis, and one with hemophagocytic syndrome.

Treatment-related death occurred in three of the 147 patients in the pembrolizumab group, including two with lung infection and one with upper gastrointestinal bleeding.

Due to the high number of treatment-related deaths in the nivolumab-ipilimumab group, the study was terminated early. Consequently, the overall survival analysis was conducted based on 117 deaths, instead of the planned 329 deaths.

In addition to OS results, the authors also reported that median progression-free survival was 7.4 months in the pembrolizumab group versus 6 months in the nivolumab-ipilimumab group (HR 0.95, 95% CI 0.73-1.25).

Patients in the pembrolizumab group also tended to have better quality of life based on a symptom score calculated from the seven items of the Lung Cancer Subscale of the Functional Assessment of Cancer Therapy-Lung questionnaire, they added.

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