Clinical trialPhase 3Lung cancer

Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer

N Engl J Med · 2025358 patients (concurrent allocation to the two main groups)

Forde PM, Spicer JD, Provencio M, Mitsudomi T, Awad MM, Wang C, et al. N Engl J Med. 2025. 393:741-752

Study type: Clinical trial
Study name: CheckMate 816
Phase: Phase 3
Design: Randomised, open-label trial (1:1)
Sample size: 358 patients (concurrent allocation to the two main groups)
Source: N Engl J Med · 2025
Trial registration: NCT02998528

In plain words

In this study, patients with lung cancer that could be removed by surgery received three cycles of chemotherapy before the operation; half of them also received the immunotherapy drug nivolumab. Adding nivolumab meant that in about a quarter of patients no living cancer cells were left at the time of surgery, and after 5 years 65% versus 55% of patients were alive. This treatment did not delay surgery or make it more difficult.

Key results

HR 0.72

Overall survival (final analysis)

95% CI 0.523–0.998; P=0.048

65.4% vs 55.0%

5-year overall survival

Median follow-up 68.4 months

95.3%

5-year survival in patients with pCR (exploratory)

Versus 55.7% without pCR (nivolumab group)

75.0% vs 52.6%

5-year survival with ctDNA clearance before surgery (exploratory)

31.6 vs 20.8 months

Median event-free survival (2022 analysis)

HR 0.63; 97.38% CI 0.43–0.91; P=0.005 — Forde PM et al., N Engl J Med 2022; DOI: 10.1056/NEJMoa2202170

24.0% vs 2.2%

Pathological complete response (2022 analysis)

Odds ratio 13.94; P<0.001

Drugs in this study:Carboplatin (Paraplatin)Cisplatin (Platinol)Docetaxel (Taxotere)Gemcitabine (Gemzar)Nivolumab (Opdivo)Paclitaxel (Taxol)Vinorelbine (Navelbine)

Dose and schedule cards

Nivolumab + platinum doublet chemotherapy before surgery (CheckMate 816)

Resectable NSCLC, stage IB (tumour ≥4 cm) to IIIA (AJCC 7th edition), without an EGFR mutation or ALK rearrangement; ECOG 0–1Cycle length: Every 21 daysOn the page “Lung cancer” · Resectable NSCLC: treatment before or after surgery

Resectable NSCLC, stage IB (tumour ≥4 cm) to IIIA (AJCC 7th edition), without an EGFR mutation or ALK rearrangement; ECOG 0–1

Drug	Dose	Route	Schedule
Nivolumab	360 mg	IV (30 min)	Day 1, before chemotherapy
Accompanying chemotherapy (one of the options)
Paclitaxel + carboplatin	175 or 200 mg/m² + AUC 5 or 6	IV	Day 1 (any histology)
Pemetrexed + cisplatin	500 + 75 mg/m²	IV	Day 1 (non-squamous only)
Gemcitabine + cisplatin	1000 or 1250 + 75 mg/m²	IV	Gemcitabine days 1 and 8, cisplatin day 1 (squamous only)

Cycle length: Every 21 days
Duration: 3 cycles, then surgery

Dose source: FDA label for nivolumab (description of the CheckMate 816 trial) and the trial publication; days 1 and 8 for gemcitabine from the trial protocol.

On the page “Lung cancer” · Resectable NSCLC: treatment before or after surgery

Resectable NSCLC, neoadjuvant (CheckMate 816)

Tumour of 4 cm or larger or N+Cycle length: 21 daysOn the page “Nivolumab (Opdivo)” · Combination regimens with chemotherapy or cabozantinib (FDA label, revised 05/2026)

Tumour of 4 cm or larger or N+

Drug	Dose	Route	Schedule
3 cycles
Nivolumab	360 mg	IV, 30-minute infusion	Day 1 every 3 weeks
Platinum doublet chemotherapy	As per those drugs' labels	IV	Same day, after nivolumab

Cycle length: 21 days
Duration: 3 cycles before surgery

On the page “Nivolumab (Opdivo)” · Combination regimens with chemotherapy or cabozantinib (FDA label, revised 05/2026)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Nivolumab + platinum chemotherapy

Nivolumab 360 mg IV (30-minute infusion) with platinum-doublet chemotherapy, day 1 every 3 weeks for up to 3 cycles, followed by definitive surgery within 6 weeks of completing neoadjuvant treatment (179 patients). Chemotherapy by histology:

Any histology: paclitaxel 175 or 200 mg/m² + carboplatin AUC 5 or 6
Non-squamous: pemetrexed 500 mg/m² + cisplatin 75 mg/m²
Squamous: gemcitabine 1000 or 1250 mg/m² + cisplatin 75 mg/m²

After surgery, up to 4 cycles of adjuvant chemotherapy and/or radiotherapy were allowed; adjuvant nivolumab was not given in this trial.

2Platinum chemotherapy alone

IV platinum-doublet chemotherapy every 3 weeks for up to 3 cycles, then surgery (179 patients); the same options as above, plus two additional options only in this group: vinorelbine 25 or 30 mg/m² + cisplatin 75 mg/m², or docetaxel 60 or 75 mg/m² + cisplatin 75 mg/m² (any histology). After surgery, up to 4 cycles of adjuvant chemotherapy and/or radiotherapy were allowed.

Source of the regimen details: FDA label for Opdivo (DailyMed, section 14.3, August 2026 version) for chemotherapy doses; full text of the primary N Engl J Med 2022 report of the same trial (PMC9844511) for nivolumab 360 mg, timing of surgery and permitted adjuvant therapy

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with resectable stage IB (tumour ≥4 cm) to IIIA NSCLC (AJCC 7th edition), ECOG 0 or 1, no previous anticancer treatment, with measurable disease (RECIST 1.1) and tumour tissue for PD-L1 testing; patients with known EGFR mutations or ALK rearrangements, grade ≥2 peripheral neuropathy, active autoimmune disease or a need for systemic immunosuppression were excluded. Stratification by PD-L1 (≥1% versus <1%), stage (IB/II versus IIIA) and sex.

Endpoints

Primary endpoints: event-free survival (EFS) and pathological complete response (pCR; 0% viable tumour in the lung and lymph nodes), both by blinded independent review. Key secondary: overall survival (this paper is the final overall survival analysis).

Safety and side effects

In the primary analysis (2022): grade 3 or 4 treatment-related adverse events in 33.5% of the nivolumab–chemotherapy group versus 36.9% of the chemotherapy group (most common: neutropenia 8.5% versus 11.9%); discontinuation because of a treatment-related adverse event 10.2% versus 9.7%. Immune-mediated adverse events were mostly grade 1 or 2. Adding nivolumab did not reduce the feasibility of surgery (83.2% versus 75.4% underwent surgery). According to the FDA label, serious adverse events in 30% (pneumonia and vomiting) and no fatal adverse events in the nivolumab group. No new safety signal was seen in the overall survival analysis.

Clinical significance and place in guidelines

CheckMate 816 was the first phase 3 trial to show a benefit of neoadjuvant immunotherapy in NSCLC and led to FDA approval of nivolumab with platinum chemotherapy before surgery (March 2022). With an overall survival benefit proven, the three-cycle neoadjuvant approach is one of the standards for resectable stage II–IIIA (and high-risk IB) NSCLC without EGFR/ALK alterations; perioperative approaches (KEYNOTE-671, CheckMate 77T, AEGEAN) are other options.

Limitations

The design was open-label; staging was based on the 7th edition; there was no adjuvant immunotherapy, so the contribution of the adjuvant phase in perioperative approaches cannot be assessed; the overall survival P value was close to the threshold, and the pCR and ctDNA analyses are exploratory.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.