Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater
Open accessAbstract
PURPOSE: In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab. PATIENTS AND METHODS: Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator's choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting. RESULTS: Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively). CONCLUSION: With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy.
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Combination therapy with ICIs plus other therapeutic approaches such as chemotherapy, radiotherapy, cancer vaccines, and CXCR4 blockade therapy can efficiently circumvent tumour resistance to ICI therapy.
“Accordingly, several studies have exhibited that combination therapy with ICIs plus other therapeutic approaches, such as chemotherapy [86], radiotherapy, cancer vaccines, and also CXCR4 blockade therapy [87] can efficiently circumvent tumour resistance to ICI therapy.”
From Immune Checkpoint Inhibitors in Cancer Therapy (2022) · cites this paper as [86]
Follow-up studies of the KEYNOTE-024 cohort revealed continuous survival benefit in patients treated with pembrolizumab as first-line monotherapy compared to those treated with chemotherapy.
“Follow-up studies of the KEYNOTE-024 cohort revealed continuous survival benefit in patients treated with pembrolizumab as first-line monotherapy compared to those treated with chemotherapy (96).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [96]
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- Authors
- Reck, M., Rodríguez–Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A., Gottfried, M., Peled, N., Tafreshi, A., Cuffe, S., O´Brien, M., Rao, S., Hotta, K., Vandormael, K., Riccio, A., Yang, J., Pietanza, M. C., & Brahmer, J. R.
- Affiliations
- LungenClinic Grosshansdorf (DE)
- Complejo Hospitalario Universitario Insular Materno–Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
- Kingston General Hospital (CA)
- The University of Sydney (AU)
- Jász-Nagykun-Szolnok County Hospital, Szolnok, Hungary
- Országos Korányi Tbc és Pulmonológiai Intézet (HU)
- Meir Medical Center (IL)
- Ben-Gurion University of the Negev (IL)
- University of Wollongong (AU)
- Cancer Trials Ireland (IE)
- The Royal Marsden Hospital, Sutton, Surrey, United Kingdom
- MedStar Franklin Square Medical Center (US)
- Okayama University Hospital (JP)
- MSD (Belgium) (BE)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Johns Hopkins University (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2019-03-01
- Volume
- 37
- Issue
- 7
- Pages
- 537-546
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2910245285
- Cited by
- 1,670
- References
- 22
- Citations by year
- 2026: 101 · 2025: 162 · 2024: 223 · 2023: 227 · 2022: 271 · 2021: 317 · 2020: 253 · 2019: 112 · 2018: 3 · 2013: 1
- FWCI
- 99.59
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Licence
- cc-by
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Acceda (Universidad de Las Palmas de Gran Canaria) (submittedVersion)
- Funders
- Health Research Board (ICORG-2016-1)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- pembrolizumab, platinum-based chemotherapy, advanced non-small cell lung cancer, PD-L1 tumor proportion score, overall survival, progression-free survival, crossover adjustment, treatment-related adverse events, immune checkpoint inhibitors, KEYNOTE-024, EGFR/ALK wild-type, inverse probability of censoring weighting, two-stage algorithm
- MeSH terms
- Antineoplastic Agents, Immunological, Progression-Free Survival, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Cisplatin, Female, Humans, Lung Neoplasms, Male, Middle Aged, Neoplasm Staging, Time Factors, Carboplatin, Disease Progression, Cross-Over Studies, B7-H1 Antigen, Antibodies, Monoclonal, Humanized
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