In the preplanned final analysis of the phase III CheckMate 816 trial, an overall survival benefit has been shown for neoadjuvant nivolumab plus chemotherapy in patients with resectable non–small cell lung cancer (NSCLC).1 Patients treated with the combination experienced an approximate 10% absolute improvement in survival from approximately 55% to 65% at 5 years. This survival benefit with neoadjuvant chemoimmunotherapy joins the other statistically significant improvements previously reported—increases in pathologic complete response rates and event-free survival.2 CheckMate 816 investigators reported these survival results at the 2025 ASCO Annual Meeting, which were concurrently published in The New England Journal of Medicine.3
“CheckMate 816 is the only phase III trial of neoadjuvant-only chemoimmunotherapy to demonstrate a statistically significant overall survival benefit across any resectable solid tumor. This affirms a paradigm shift in the treatment of resectable non–small cell lung cancer without actionable genomic alterations,” said Patrick M. Forde, MBBCh, PhD, Professor and Chair of Immuno-Oncology at Trinity St. James’s Cancer Institute at Trinity College in Dublin and Adjunct Professor of Oncology at Johns Hopkins University, Baltimore.
Patrick M. Forde, MBBCh, PhD
In the open-label, phase III trial, patients with stage IB to IIIA resectable NSCLC were randomly assigned to receive either nivolumab plus platinum-based chemotherapy or chemotherapy alone for three cycles, followed by surgery. Adjuvant chemotherapy with or without radiotherapy was optional.
The primary endpoints were pathologic complete response and event-free survival, which were previously reported.2 In that first report of the findings, a trend favoring overall survival was observed with the combination, but the 2-year rate of 83% compared with 71% for chemotherapy alone was not significantly different.
However, in the final analysis reported at the ASCO meeting by Dr. Forde, there was a statistically significant improvement in survival; at a median follow-up of 68.4 months, median overall survival was not reached in the nivolumab-plus-chemotherapy arm and was 73.7 months in the chemotherapy-alone arm; the 5-year overall survival rates were 65% and 55%, respectively (hazard ratio [HR] = 0.72; P = .0485). Some 20% more patients in the chemotherapy-alone arm received subsequent systemic therapy (78% vs 58%), and more than twice as many patients received subsequent immunotherapy (51% vs 25%).
Nivolumab plus chemotherapy is the sole neoadjuvant-only chemoimmunotherapy regimen approved in the United States, the European Union, and several other countries.
Other Key Findings
At 5 years, median event-free survival was 59.6 months with nivolumab plus chemotherapy and 21.1 months with chemotherapy alone (HR = 0.68; 95% confidence interval [CI] = 0.51–0.91); the 5-year rate was 49% vs 34%, respectively. The outcome remained consistent with the previously reported initial hazard ratio of 0.63 (P < .005).
In addition, lung cancer–specific survival was improved with the combination, with the 5-year overall survival rate of 75%, as compared with 65% with chemotherapy alone (HR = 0.65; 95% CI = 0.44–0.96). Medians were not reached in either arm in this comparison.
In an exploratory analysis of patients who achieved a pathologic complete response (which was 24% of the nivolumab-plus-chemotherapy arm and 2.2% of the chemotherapy-alone arm), 95% of patients receiving nivolumab plus chemotherapy were alive at 5 years vs 56% of those not achieving this ideal response (HR = 0.11; 95% CI = 0.04–0.36). Of note, in the former subset, three patients died, none as a result of their cancer, according to the investigators; in the latter group, 44 patients died as a result of their disease. A similar pattern was seen with regard to pathologic complete response status and event-free survival.
KEY POINTS
- The final preplanned overall survival analysis for CheckMate 816 showed a significant benefit for neoadjuvant nivolumab plus chemotherapy over chemotherapy alone in resectable non–small cell lung cancer.
- Patients treated preoperatively with chemoimmunotherapy had a 28% reduction in the risk of death.
- Pathologic complete response and preoperative circulating tumor DNA clearance were significantly associated with improved overall survival.
Presurgical clearance of circulating tumor DNA (ctDNA) was also associated with improved overall survival, regardless of treatment. In all, ctDNA clearance was observed in 24 of 43 patients (56%) given nivolumab plus chemotherapy and in 15 of 43 patients (35%) given chemotherapy alone. For patients with ctDNA clearance, median overall survival was not reached with either treatment. For patients without ctDNA clearance, median overall survival was 61.5 months with nivolumab plus chemotherapy (HR = 0.38) and 69.2 months with chemotherapy alone (HR = 0.39).
By subgroups, comparable benefit was seen for those with stage IB to II disease and stage III disease, with hazard ratios of 0.77 and 0.70, respectively, favoring the combination. With nivolumab plus chemotherapy, the 5-year overall survival rate was 65% for both those with stage IB to II and those with stage III disease.
Benefit was seen across PD-L1 strata as well, though it was enhanced for PD-L1–positive tumors, with a hazard ratio of 0.51 for those with PD-L1 expression ≥ 1%, as compared with 0.89 for those with PD-L1 expression < 1%. For patients with PD-L1–positive disease, the 5-year overall survival rates were 78% with the combination and 58% with chemotherapy alone.
Safety outcomes were similar to those reported in the first study analysis, with no new treatment-related deaths observed since then.
DISCLOSURE: Dr. Forde has served as a consultant or advisor to Ascendis Pharma, AstraZeneca/MedImmune, BioNTech SE, Bristol Myers Squibb, CureVac, Daiichi Sankyo/UCB Japan, F-Star Biotechnology, Fosun Pharma, G1 Therapeutics, Genelux, Gilead Sciences, iTeos Therapeutics, Janssen, Merck, Novartis, Novocure, Regeneron, Sanofi, Synthekine, Tavotek Biotherapeutics, and Teva Pharmaceuticals; and has received institutional research funding from AstraZeneca/MedImmune, BioNTech SE, Bristol Myers Squibb, Novartis, and Regeneron. For full disclosures of the other study authors, visit coi.asco.org.
REFERENCES
1. Forde PM, Spicer JD, Provencio M, et al: Overall survival with neoadjuvant nivolumab + chemotherapy in patients with resectable NSCLC in CheckMate 816. 2025 ASCO Annual Meeting. Abstract LBA8000. Presented June 2, 2025.
2. Forde PM, Spicer J, Lu S, et al: Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 386:1973-1985, 2022.
3. Forde PM, Spicer JD, Provencio M, et al: Overall survival with neoadjuvant nivolumab plus chemotherapy in lung cancer. N Engl J Med. June 2, 2025 (early release online).
EXPERT POINT OF VIEW
Invited discussant of CheckMate 816, Lizza E. Hendriks, MD, PhD, a pulmonologist at Maastricht University Medical Center and Associate Professor at GROW Research Institute for Oncology and Reproduction, of Maastricht University in the Netherlands, shared these comments: “CheckMate 816 is the first phase III neoadjuvant-only chemoimmunotherapy trial showing a sustained overall survival benefit compared with neoadjuvant chemotherapy-only treatment…. My key takeaway is this: Only three cycles of neoadjuvant chemoimmunotherapy resulted in a 10% absolute 5-year overall survival benefit compared with chemotherapy alone. However, I think we need trials to evaluate where to escalate—or even de-escalate—treatment.”
Lizza E. Hendriks, MD, PhD
Dr. Hendriks noted that among 43 patients who achieved a pathologic complete response, just 3 relapsed. “We clearly saw that pathologic complete response was associated with very good overall survival, confirming early-phase data. We also saw that preoperative circulating tumor DNA [ctDNA] clearance rates were higher with chemoimmunotherapy and were associated with good overall survival, confirming the AEGEAN1 and CheckMate 77T2 data.” She pointed out that ctDNA appears, however, to have a weaker “signal” than pathologic complete response, but this could be related to the technology. “Maybe we should explore this further,” she suggested.
Questions Remain
Moving forward, Dr. Hendriks maintained that the “big debate” still centers around the optimal strategy—neoadjuvant or perioperative immunotherapy—with these questions still to be settled:
- Can patients who are likely, or unlikely, to obtain a pathologic complete response be identified ahead of treatment to escalate, or de-escalate, treatment accordingly?
- What is the best way to de-escalate treatment?
- Is an adjuvant component of therapy still needed for all patients?
- Who needs intensified treatment? Could it be patients without a pathologic complete response, or specifically who have a major pathologic response; those with PD-L1–negative tumors; or those with no ctDNA clearance?
- What is the best way to increase pathologic complete response rates?
Even beyond exploring these and other key questions, Dr. Hendriks said, there is the question of how to further improve overall survival in patients with non–small cell lung cancer. To this end, there are novel drugs and strategies now in clinical trials.
DISCLOSURE: Dr. Hendriks reported personal financial relationships with Benecke, Medimix, MEDtalks, and VJOncology; has received institutional research funding from Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda Pharmaceuticals, Merck, Pfizer, Novartis, and Gilead Sciences; has served as a speaker (all institutional payments) for AstraZeneca, Bayer, Lilly, MSD, High5 Oncology, Takeda Pharmaceuticals, Janssen, GSK, Sanofi, and Pfizer; and has served as an advisor (all institutional payments) to AbbVie, Amgen, AnHeart Therapeutics, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, Gilead Sciences, GSK, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Summit Therapeutics, and Takeda Pharmaceuticals; and served as a paid member of the Dutch guidelines committee on NSCLC, brain metastases, and leptomeningeal metastases; and served as a local principal investigator of clinical trials (all institutional payments) for AstraZeneca, GSK, Novartis, Merck, Roche, Takeda Pharmaceuticals, Blueprint Medicines, Mirati Therapeutics, AbbVie, Gilead Sciences, MSD, Amgen, Boehringer Ingelheim, Pfizer, Daiichi Sankyo, Amgen, and BMS.
REFERENCES
1. Heymach JV, Harpole D, Mitsudomi T, et al: Perioperative durvalumab for resectable non–small-cell lung cancer. N Engl J Med 389:1672-1684, 2023.
2. Cascone T, Awad MM, Spicer JD, et al: Perioperative nivolumab in resectable lung cancer. N Engl J Med 390:1756-1769, 2024.
