Dr. Alan P. Lyss
Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.
Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).
A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).
In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
Details of CheckMate 9LA
CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.
The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.
If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.
Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.
The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
Results prompt FDA approval
Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).
With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).
Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.
One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.
Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.
Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.
Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.