The phase 3 CheckMate-816 trial establishes a new standard of care for resectable non–small-cell lung cancer (NSCLC): neoadjuvant nivolumab (Opdivo) plus chemotherapy. Event-free survival (EFS) was significantly improved in patients with resectable NSCLC (stage IB-IIIA) treated with the combination versus chemotherapy alone (P = .005), and the benefit of neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone was observed across most subgroups. Moreover, at this early time point, survival trended in favor of the combination. These results were presented at the 2022 American Association for Cancer Research (AACR) annual meeting and published online in the New England Journal of Medicine simultaneously (N Engl J Med. 2022;386:1973-1985.).
The combination of nivolumab plus platinum-doublet chemotherapy is now approved by the FDA as neoadjuvant therapy for adults with resectable NSCLC.
“[EFS] was improved in patients with pathologic complete response compared with those without, suggesting pathologic complete response is an early indicator of therapeutic benefit with nivolumab and chemotherapy,” said lead investigator Nicolas Girard, MD, PhD, Head, Curie-Montsouris Thorax Institute, Curie Institute, Paris, France. “These results support neoadjuvant nivolumab plus chemotherapy as a standard of care for resectable NSCLC.”
Invited discussant David Paul Carbone, MD, PhD, Director, James Thoracic Center, Ohio State University, Columbus, agreed: “CheckMate-816 is a clearly positive study….Combining neoadjuvant therapy with surgery is a new standard of care for the first time in decades. It will almost certainly improve survival in early-stage disease.”
Study Details
The phase 2 CheckMate-816 trial included 358 patients with newly diagnosed, resectable (stage IB-IIIA) NSCLC and no known sensitizing EGFR mutations or ALK alterations. Patients were randomized in a 1:1 ratio to receive either nivolumab plus chemotherapy for 3 cycles or chemotherapy for 3 cycles. Surgery was performed within 6 weeks posttreatment. Patients were stratified for stage (IB vs IIIA), PD-L1 status (<1% vs ≥1%), and sex.
Baseline demographic and disease factors were well-balanced between the 2 arms. Two-thirds of patients were stage IIIA, and approximately 50% were PD-L1–positive. Histology was evenly divided between squamous and nonsquamous cancers. Almost 90% of patients in both arms were current or former smokers. Definitive surgery was performed in 83% in the combination arm and 75% in the control arm. Twenty percent in the combination arm and 32% in the chemotherapy arm received adjuvant therapy.
At AACR, Dr Girard presented the first prespecified interim analysis of EFS from randomization to any progression of disease and key secondary end points including overall survival.
“At a minimum follow-up of 21 months and a median follow-up of 29 months, the study met its primary end point,” Dr Girard told attendees.
Median EFS was 31.6 months for nivolumab plus chemotherapy versus 20.8 months for chemotherapy alone, for an absolute improvement of 1 year (P = .0052). One-year EFS was 76% versus 63%, respectively; 2-year EFS was 64% versus 45%, respectively.
EFS was improved by use of the neoadjuvant combination therapy across most subgroups, including stage, PD-1 expression, baseline stage of disease, and histology. Median progression-free survival was not reached in earlier stage disease (stage IB-II).
Treatment with nivolumab plus chemotherapy improved progression-free survival at all levels of PD-L1 expression, even in patients whose tumors had no PD-L1 expression.
The rate of pathologic complete response was 24.0% and 2.2%, respectively, for the combination versus chemotherapy alone (P <.001). In an exploratory analysis, achieving pathologic complete response was associated with an 84% improvement for treatment with nivolumab and chemotherapy versus chemotherapy alone.
Survival data are not yet mature, but the numbers seem to favor the combination. The 2-year overall survival was 83% for nivolumab plus chemotherapy versus 71% for chemotherapy alone—an absolute improvement of 12%.
Safety Profile
Neoadjuvant nivolumab plus chemotherapy appeared to be safe and did not compromise patients’ ability to undergo surgery versus chemotherapy alone. No increase in surgical complications was observed for those treated with the combination compared with chemotherapy alone. The rate of grade 3 or 4 treatment-related adverse events was similar in both groups.
Two grade 5 surgery-related events were reported in the nivolumab-containing arm, both judged to be unrelated to treatment.
