Clinical trialPhase 3Lung cancer

Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial

Lancet · 2024797 patients

Spicer JD, Garassino MC, Wakelee H, Liberman M, Kato T, Tsuboi M, et al. Lancet. 2024. 404:1240-1252

A newer report of this study has been published: Five-Year Outcomes of Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer From the Randomized KEYNOTE-671 Study (2026)

Study type: Clinical trial
Study name: KEYNOTE-671
Phase: Phase 3
Design: Global randomised, double-blind, placebo-controlled trial (1:1) at 189 centres
Sample size: 797 patients
Source: Lancet · 2024
Trial registration: NCT03425643

In plain words

In this study, patients with lung cancer that could be operated on (stage II to IIIB) received 4 cycles of chemotherapy before surgery together with pembrolizumab or a placebo, and after surgery pembrolizumab or placebo continued for up to about a year. Adding pembrolizumab made the time without the cancer coming back about 2.5 times longer, and after 3 years 71% versus 64% of patients were alive. Serious side effects were slightly more common.

Key results

71% vs 64%

36-month overall survival

HR 0.72; 95% CI 0.56–0.93; one-sided p 0.0052 (threshold 0.0054)

47.2 vs 18.3 months

Median event-free survival

HR 0.59; 95% CI 0.48–0.72

18.1% vs 4.0%

Pathological complete response (2023 analysis)

Major pathological response 30.2% vs 11.0% — Wakelee H et al., N Engl J Med 2023; DOI: 10.1056/NEJMoa2302983

Drugs in this study:Cisplatin (Platinol)Gemcitabine (Gemzar)Pembrolizumab (Keytruda)

Dose and schedule cards

Perioperative pembrolizumab (KEYNOTE-671)

Resectable NSCLC, stage II, IIIA or IIIB (N2) (AJCC 8th edition; tumour ≥4 cm or node-positive), regardless of PD-L1Cycle length: Every 21 daysOn the page “Lung cancer” · Resectable NSCLC: treatment before or after surgery

Resectable NSCLC, stage II, IIIA or IIIB (N2) (AJCC 8th edition; tumour ≥4 cm or node-positive), regardless of PD-L1

Drug	Dose	Route	Schedule
Neoadjuvant: up to 4 cycles of 21 days
Pembrolizumab	200 mg	IV (30 min)	Day 1, before chemotherapy
Cisplatin	75 mg/m²	IV	Day 1
Pemetrexed (non-squamous) or gemcitabine (squamous)	500 mg/m² or 1000 mg/m²	IV	Pemetrexed day 1; gemcitabine days 1 and 8
Adjuvant, after surgery
Pembrolizumab	200 mg every 3 weeks (or 400 mg every 6 weeks)	IV	Start 4 to 12 weeks after surgery

Cycle length: Every 21 days
Duration: 12 weeks before surgery, then 39 weeks (up to 13 cycles) after surgery

Dose source: FDA label for pembrolizumab (description of the KEYNOTE-671 trial) and the trial publication; surgery no later than 20 weeks after the first dose; pembrolizumab dose reduction is not permitted (only interruption or discontinuation); 5-year results.

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

Resectable NSCLC, before and after surgery (KEYNOTE-671)

Resectable stage II, IIIA or IIIB (N2)Cycle length: Every 21 daysOn the page “Pembrolizumab (Keytruda)” · Early stages: before and after surgery or with chemoradiotherapy (FDA label)

Resectable stage II, IIIA or IIIB (N2)

Drug	Dose	Route	Schedule
Before surgery, 4 cycles
Pembrolizumab	200 mg	IV infusion over 30 minutes	Day 1
Cisplatin + pemetrexed or gemcitabine	75 mg/m² + 500 mg/m² (day 1) or 1000 mg/m² (days 1 and 8)	IV	Every 21 days
After surgery
Pembrolizumab	200 mg every 3 weeks or 400 mg every 6 weeks	IV infusion over 30 minutes	Day 1

Cycle length: Every 21 days
Duration: 12 weeks before surgery, then 39 weeks as a single agent after surgery (up to 13 cycles in the trial)

On the page “Pembrolizumab (Keytruda)” · Early stages: before and after surgery or with chemoradiotherapy (FDA label)

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

1Perioperative pembrolizumab

Neoadjuvant (4 cycles of 21 days): pembrolizumab 200 mg IV day 1 + cisplatin 75 mg/m² IV day 1 + one of: gemcitabine 1000 mg/m² IV days 1 and 8 (squamous histology) or pemetrexed 500 mg/m² IV day 1 (non-squamous).

Surgery (lobectomy, bilobectomy, pneumonectomy or sleeve resection) no later than 20 weeks after the first neoadjuvant dose.

Adjuvant: starting 4 to 12 weeks after surgery; pembrolizumab 200 mg IV every 3 weeks for up to 13 cycles. Pembrolizumab dose reductions were not allowed (only interruption or discontinuation).

2Placebo

The same neoadjuvant chemotherapy (cisplatin 75 mg/m² day 1 + gemcitabine 1000 mg/m² days 1 and 8 or pemetrexed 500 mg/m² day 1, every 21 days, 4 cycles) with placebo (normal saline IV day 1), then surgery and adjuvant placebo every 3 weeks for up to 13 cycles.

Source of the regimen details: Full text of the Lancet 2024 paper (PMC11512588, Procedures section) and ClinicalTrials.gov NCT03425643

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 (≥18 years) with pathologically confirmed, previously untreated stage II, IIIA or IIIB (N2) NSCLC per the AJCC 8th edition, judged resectable after surgical consultation; ECOG 0 or 1 (within 10 days before randomisation) and a tumour sample for PD-L1 testing. Stratified by stage, PD-L1 (TPS ≥50% versus <50%), histology and geographic region. Patients with EGFR mutations or ALK rearrangements were also included in the population.

Endpoints

Dual primary endpoints: overall survival and event-free survival (EFS) in the intention-to-treat population. Secondary: major pathological response, pathological complete response, safety and quality of life. This paper is the second interim analysis (overall survival).

Safety and side effects

Across all treatment phases (treated population): treatment-related grade ≥3 adverse events in 179 of 396 (45%) in the pembrolizumab group versus 151 of 399 (38%) in the placebo group; serious treatment-related adverse events 18% versus 15%. Most common grade ≥3 events: decreased neutrophil count 21% versus 20%, anaemia 7% versus 6%, decreased platelet count 5% versus 6%. Discontinuation of all treatment due to a treatment-related adverse event 14% versus 5%. Immune-mediated adverse events and infusion reactions 26% versus 9% (grade ≥3: 7% versus 2%). Deaths from treatment-related adverse events: 4 patients (1%; including one case of immune pneumonitis) versus 3 patients (1%).

Clinical significance and place in guidelines

KEYNOTE-671 was the first trial to show a significant overall survival benefit with a perioperative immunotherapy approach in NSCLC and led to the FDA approval of perioperative pembrolizumab (October 2023). The perioperative approach (neoadjuvant + adjuvant), alongside the neoadjuvant-only approach (CheckMate 816), is now among the standard options for resectable NSCLC without EGFR/ALK alterations.

Limitations

The separate contribution of the adjuvant phase cannot be isolated; only cisplatin-based regimens were allowed; few patients had multistation N2 disease; some placebo-group patients did not receive immunotherapy after recurrence, which may affect interpretation of overall survival.

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.