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Cited by 1,180Lung Cancer Diagnosis and TreatmentCancer Immunotherapy and BiomarkersLung Cancer Research Studies

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer

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Wakelee, Heather, Liberman, Moishe, Kato, Terufumi, Tsuboi, Masahiro, Lee, Se-Hoon, Gao, Shugeng, Chen, Ke-Neng, Dooms, Christophe +11 more·2023·New England Journal of Medicine
DOI 10.1056/nejmoa2302983PMC PMC11074923
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Abstract

BACKGROUND: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone. METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety. RESULTS: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events. CONCLUSIONS: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.).

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  • In perioperative HCC, no surrogate endpoint has been validated, unlike pathological complete response in NSCLC and breast cancer.

    “Given the lack of successful trials in the perioperative space in HCC, no surrogate end point has been validated yet, as is the case for pCR in patients with NSCLC20,120 and breast cancer8.”

    From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [120]

    The Methods (Assessments and Endpoints; page not provided) identify pathological complete response as a secondary endpoint in the NSCLC trial, and the Results (Efficacy; page not provided) report that pembrolizumab improved it. Neither passage establishes that pathological complete response is a validated surrogate endpoint in NSCLC. The HCC and breast-cancer portions of the sentence are not attributed to this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Many patients still fail to achieve clinically meaningful responses to ICI treatment.

    “Although ICI-treatment is approved for the treatment of NSCLC patients in the localized and metastatic setting regardless of PD-L1 status2–4, many patients still fail to achieve clinically meaningful responses.”

    From Predicting the tumor microenvironment composition and immunotherapy response in non-small cell lung cancer from digital histopathology images (2024) · cites this paper as [2]

    The Results (Efficacy) report major pathological response in only 30.2% of participants receiving perioperative pembrolizumab plus chemotherapy, supporting the point that many did not achieve that response. But the study concerns resectable NSCLC and also reports event-free survival benefit among participants without a major pathological response; it does not establish that those patients lacked any clinically meaningful benefit from ICI treatment generally. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Neoadjuvant immune checkpoint inhibitor efficacy and safety are firmly established in multiple tumour types, with FDA approvals for NSCLC and triple-negative breast cancer.

    “Since results from one of the first clinical trials of such a therapeutic approach in patients with NSCLC were reported in 2018 (ref. 19), the efficacy and safety of neoadjuvant ICIs have been firmly established in multiple tumour types, with FDA approvals for two indications (NSCLC20,120 and triple-negative breast cancer8).”

    From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [120]

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  1. [14]Brierly JD, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumors. Eighth Edition. Oxford, UK: John Wiley & Sons; 2016.

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Authors
Wakelee, H., Liberman, M., Kato, T., Tsuboi, M., Lee, S.-H., Gao, S., Chen, K.-N., Dooms, C., Majem, M., Eigendorff, E., Martinengo, G. L., Bylicki, O., Rodríguez-Abreu, D., Chaft, J. E., Novello, S., Yang, J., Keller, S. M., Samkari, A., & Spicer, J. D.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • From Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA (H.W.); Centre Hospitalier de l’Université de Montréal (M.L.) and McGill University Health Centre (J.D.S.) — both in Montreal; Kanagawa Cancer Center, Yokohama (T.K.), and National Cancer Center Hospital East, Kashiwa (M.T.) — both in Japan; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (S.-H.L.); the National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (S.G.), and Beijing Cancer Hospital, Peking University (K.-N.C.) — both in Beijing; University Hospitals Leuven, Leuven, Belgium (C.D.); Hospital de la Santa Creu i Sant Pau, Barcelona (M.M.), and Hospital Universitario Insular de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas (D.R.-A.) — both in Spain; Zentralklinik Bad Berka, Bad Berka, Germany (E.E.); Sanatorio Parque, Cordoba, Argentina (G.L.M.); Hôpital d’I...
  • Memorial Sloan Kettering Cancer Center (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2023-08-10
Volume
389
Issue
6
Pages
491-503
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa2302983
PMC
PMC11074923
OpenAlex
W4379209546
Cited by
1,180
References
18
Citations by year
2026: 324 · 2025: 388 · 2024: 368 · 2023: 100
FWCI
216.63
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Acceda (Universidad de Las Palmas de Gran Canaria) (submittedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
  • Lirias (KU Leuven) (submittedVersion)
Funders
  • Merck Sharp and Dohme LLC, a subsidiary of Merck & Co, Inc
  • National Cancer Institute (P30 CA008748)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
pembrolizumab, early-stage non-small cell lung cancer, perioperative immunotherapy, PD-1 inhibitors, cisplatin-based chemotherapy, event-free survival, overall survival, pathological response, pathological complete response, N2 disease, resectable lung cancer, treatment safety, immune-related adverse events
MeSH terms
Adjuvants, Immunologic, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Cisplatin, Combined Modality Therapy, Humans, Lung Neoplasms, Antibodies, Monoclonal, Humanized

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