CheckMate 9LA Confirms Chemo Benefit With Nivolumab Plus Ipilimumab

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: Use of nivolumab plus ipilimumab alongside chemotherapy significantly improved overall survival (OS) for treatment-naïve, stage IV or recurrent non-small-cell lung cancer (NSCLC) patients in the CheckMate 9LA trial compared with chemotherapy alone. 

When combined with the combination’s “favourable risk–benefit profile”, the investigators say their “data support this regimen as a new first-line treatment option for patients with advanced NSCLC.” 

Following positive phase II study results, the researchers further investigated the hypothesis that use of chemotherapy could “provide rapid disease control” while the benefits of immunotherapy can take hold.  

At the prespecified interim analysis, after a median follow-up of 9.7 months, the primary endpoint of OS was a median 14.1 months for the 361 patients who were randomly assigned to receive nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks, combined with two cycles of a histology-driven regimen of platinum-based doublet chemotherapy. 

This compared with the median OS of 10.7 months achieved by the 358 patients who instead received four cycles of chemotherapy, giving a significant hazard ratio (HR) for death of 0.69 in favour of immunotherapy use. 

After a further 3.5 months of median follow-up, median OS continued to be significantly better with immunotherapy plus chemotherapy than chemotherapy alone, at 15.6 versus 10.9 months and a HR of 0.66. 

Forest plot analysis of OS favoured the immunotherapy regimen across the prespecified subgroups, including by PD–L1 expression, with the exceptions of patients aged at least 75 years and never smokers. 

“Notably, a survival benefit was observed across various patient subgroups, including populations with a high unmet medical need, such as those with CNS metastases”, report Luis Paz-Ares, from Hospital Universitario 12 de Octubre in Madrid, Spain, and co-workers in The Lancet Oncology. 

Safety analysis showed grade 3–4 treatment-related adverse events (TRAEs) in 47% of the immunotherapy plus chemotherapy arm versus 38% of the chemotherapy only arm, most commonly neutropenia (7 vs 9%), anaemia (6 vs 14%), diarrhoea (4 vs 1%), elevated liapse (6 vs 1%) and asthenia (1 vs 2%).  

Prespecified analysis gave an incidence of TRAEs per 100 patient–years of 785.1 for immunotherapy plus chemotherapy versus 951.8 with chemotherapy alone, the researchers say. 

Serious TRAEs occurred in a corresponding 30% and 18% of patients, including at grade 3–4 in 25% and 15%, respectively. The latter resulted in discontinuation in 16% and 5% of the arms, respectively. 

In addition, potentially immune-related grade 3–4 TRAEs with immunotherapy plus chemotherapy included gastrointestinal, skin and hepatic side effects in 6%, 4% and 4% of patients, respectively, “most of which resolved”, the investigators say. 

The primary cause of death in both the immunotherapy plus chemotherapy and chemotherapy alone arms was disease progression (52 vs 43%), with treatment-related deaths reported in seven and six patients, respectively. 

The authors of a linked comment highlight that unlike the CheckMate 227 trial, which showed a delay in OS advantage for immunotherapy resulting in crossing survival curves, the CheckMate 9LA trial has showed “early separation” of the survival curves, “reflecting the presence of a patient subgroup deriving a clear advantage with the addition of the short course of platinum chemotherapy.” 

However, Antonio Passaro and co-authors, from the European Institute of Oncology in Milan, Italy, note that the control arm of CheckMate 9LA does “not represent the current standard of care in patients with all levels of PD-L1 expression, which has been identified as the combination of chemotherapy plus pembrolizumab in the KEYNOTE-189 and KEYNOTE-407 trials.” 

Acknowledging that “we do not yet have sufficiently robust data to identify the optimal treatment of the various approved immune-based combinations for the first-line treatment of patients with metastatic NSCLC”, the commentators conclude that “the debate about which treatment regimen is optimal to improve 2-year or 3-year overall survival highlights how much patients with NSCLC are benefiting from these major advances in the treatment of lung cancer.”

References  

Paz-Ares L, Ciuleanu T-E, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol; Advance online publication 18 January 2021. https://doi.org/10.1016/S1470-2045(20)30641-0

Passaro A, Attili I, de Marinis F. CheckMate 9LA: broadening treatment options for patients with non-small-cell lung cancer. Lancet Oncol; Advance online publication 18 January 2021. https://doi.org/10.1016/S1470-2045(20)30701-4