The combination of neoadjuvant nivolu­mab plus chemotherapy achieved statistically significant and clinically meaningful improvement in event-free survival vs chemotherapy alone (P = .005) in patients with resectable non–small cell lung cancer (NSCLC, stage IB–IIIA), according to the results of the open-label phase III CheckMate 816 trial, reported at the American Association for Cancer Research (AACR) Annual Meeting 2022.¹ The benefit was seen across most subgroups. Although survival data are not yet mature, the trend was toward improved survival with nivolumab plus chemotherapy compared with chemotherapy alone. The results of CheckMate 816 were published online in The New England Journal of Medicine to coincide with Dr. Girard’s presentation.²

“Event-free survival was improved more 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 author ­Nicolas ­Girard, MD, PhD, of the Curie Institute, Paris. “These results support neoadjuvant nivolu­mab plus chemotherapy as a standard of care for resectable ­NSCLC.” Dr. Girard presented the first prespecified interim analysis of event-free survival from randomization to any progression of disease and key secondary endpoints including overall survival.

Nicolas ­Girard, MD, PhD

Study Details

CheckMate 816 enrolled 358 patients with newly diagnosed, resectable (stage IB–IIIA) NSCLC and no known sensitizing EGFR mutations or ALK alterations. Patients were randomly assigned 1:1 to receive either nivolumab plus chemotherapy for three cycles or chemotherapy alone for three cycles.

After radiologic staging, surgery was performed within 6 weeks post treatment. Stratification factors were disease stage (IB and II vs IIIA), PD-L1 status (< 1% vs ≥ 1%), and sex.

At baseline, two-thirds of patients had stage IIIA disease, and about 50% had PD-L1–positive disease. 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% of the combination arm and 75% of the control arm. About 20% of the combination arm and 32% of the chemotherapy arm received adjuvant therapy.

Key Findings

“At a minimum follow-up of 21 months and a median follow-up of 29 months, the study met its primary endpoint,” Dr. Girard told listeners. Median event-free survival was 31.6 months for nivolumab plus chemotherapy vs 20.8 months for chemotherapy alone, for an absolute improvement of 1 year (P = .0052). The 1-year event-free survival was 76% vs 63%, respectively; the 2-year event-free survival was 64% vs 45%, ­respectively.

According to a subgroup analysis, event-free survival was consistently improved across most subgroups, including disease stage, PD-1 expression, and histology. However, at this time point, median progression-free survival was not reached in earlier-stage disease (stage IB–II). 

The combination improved progression-free survival at all levels of PD-L1 expression, and there was a signal of improvement in those with no PD-L1 expression.

The percentage of patients with a pathologic complete response was 24.0% and 2.2%, respectively (P < .001). An exploratory analysis of event-free survival found that achieving pathologic complete response was associated with improved event-free survival. 

At the first prespecified interim analysis for overall survival, the hazard ratio for death was 0.57 and did not meet the criterion for significance; neither arm crossed the prespecified line for statistical significance. The 2-year overall survival rate was 83% with nivolumab plus chemotherapy vs 71% with chemotherapy alone—for an absolute improvement of 12%.

Safety Profile

Nivolumab plus chemotherapy appeared to be safe in the neoadjuvant setting. Neoadjuvant nivolumab plus chemotherapy did not impact the feasibility of surgery vs chemotherapy alone. There was no increase in surgical complications compared with chemotherapy alone. Grade 3 or 4 treatment-related adverse events occurred in 34% of the patients in the nivolumab-plus-chemotherapy group and in 37% of those in the chemotherapy-alone group.

There were two grade 5 surgery-related events in the nivolu­mab-containing arm, but they were deemed unrelated to treatment. 

DISCLOSURE: CheckMate 816 was funded by Bristol Myers Squibb. Dr. Girard reported financial relationships with Bristol Myers Squibb, MSD, Roche, Novartis, AstraZeneca, Janssen, Pfizer, Sanofi, Lilly, and Amgen.

REFERENCES

1. Girard N, Spicer J, Provencio M, et al: Nivolumab plus platinum-doublet chemotherapy vs chemo as neoadjuvant treatment for resectable (IB-IIIA) non-small cell lung cancer: Event-free survival results from the phase 3 CheckMate 816 trial. AACR Annual Meeting 2022. Abstract CT012. Presented April 11, 2022.

2. Forde PM, Spicer J, Lu S, et al: Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. April 11, 2022 (early release online).