Research in context
Evidence before this study
We searched for articles in PubMed and abstracts from major oncology congresses for studies relevant to non-small-cell lung cancer (NSCLC) and cancer immunotherapy regimens with a focus primarily on phase 3 trials. Search terms were “non-small cell lung cancer”, “anti-PD-L1”, “anti-PD-1”, “anti-CTLA-4”, “chemotherapy”, “pembrolizumab”, “atezolizumab”, and “nivolumab” (full names and abbreviations), and relevant articles published from database inception to July 22, 2020, were identified. At the time of the design of CheckMate 9LA (2017), checkpoint inhibition had shown efficacy in patients with NSCLC expressing high levels of PD-L1; however, chemotherapy was the first-line standard of care for many patients with advanced or metastatic NSCLC and no actionable mutations, and was associated with poor survival outcomes. Since then, several clinical trials in patients with NSCLC have assessed first-line immunotherapy regimens versus chemotherapy; regimens included checkpoint inhibitors as monotherapies, in combination with chemotherapy, or alongside other immunotherapy. During the conduct of CheckMate 9LA, checkpoint inhibition in other studies was shown to improve the outcomes in patients with NSCLC regardless of PD-L1 expression, when administered in combination with chemotherapy. Additionally, data showing the clinical benefit of nivolumab plus ipilimumab in patients with NSCLC emerged in CheckMate 227. Improved disease control is needed during the initial phase of immunotherapy treatment to enhance clinical benefit. Because chemotherapy might provide rapid disease control, CheckMate 9LA was designed to investigate the efficacy and safety of nivolumab plus ipilimumab with a limited course (two cycles) of chemotherapy versus a full course (four cycles) of chemotherapy alone. A single-arm phase 2 study assessing nivolumab plus ipilimumab with a limited course (two cycles) of chemotherapy showed that this regimen was tolerable and had encouraging clinical activity.
Added value of this study
We provide results from the randomised CheckMate 9LA study, which to our knowledge is the first phase 3 study to show a significant overall survival benefit, regardless of PD-L1 expression or histology, with dual PD-1 and CTLA-4 inhibition combined with two cycles of chemotherapy versus a standard course (four cycles) of chemotherapy as first-line treatment in patients with advanced NSCLC. Results presented here build upon those previously reported in the single-arm, phase 2 study and confirm the clinical activity and tolerability of this regimen. Benefit improved with longer follow-up and was consistent across all efficacy endpoints. Notably, a survival benefit was observed across various patient subgroups, including populations with a high unmet medical need, such as those with CNS metastases. Furthermore, the safety profile of this combination therapy was consistent with the profiles of the components of the regimen in first-line treatment for patients with NSCLC, and no new safety signals were reported.
Implications of all the available evidence
Overall, efficacy and safety data from CheckMate 9LA support a favourable risk–benefit profile for nivolumab plus ipilimumab combined with two cycles of chemotherapy as first-line treatment for patients with advanced NSCLC. Nivolumab plus ipilimumab with two cycles of chemotherapy is now approved and indicated in the USA, Singapore, Australia, Canada, and other countries for first-line treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumour aberrations.