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Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer
Open accessAbstract
BACKGROUND: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).
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“Third, many of these studies utilized ICIs as monotherapy in a heavily pretreated population whereas current standard first-line therapy often includes a combination of ICIs or ICI with chemotherapy for multiple tumor types (35–40).”
From A Uniform Computational Approach Improved on Existing Pipelines to Reveal Microbiome Biomarkers of Nonresponse to Immune Checkpoint Inhibitors (2021) · cites this paper as [37]
In the citing paper
“KRAS mutation-positive patients derived benefit in both PFS and OS from the combination of pembrolizumab plus chemotherapy as opposed to platinum doublet therapy alone as first-line therapy for patients with metastatic NSCLC66.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [66]
In the citing paper
“Importantly, two remarkable phase III trials (KEYNOTE-189 and KEYNOTE-407) demonstrated that addition of pembrolizumab (Keytruda, anti-PD1) could significantly prolong the survival of NSCLC patients (45, 97).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [97]
In the citing paper
“The promising results from these studies have led to the approval of pembrolizumab in combination with chemotherapy (carboplatin-pemetrexed) for metastatic, non-squamous NSCLC, and the approval of pembrolizumab in combination with chemotherapy (carboplatin and Taxol) for patients with squamous lung carcinoma, excluding those carrying EGFR or ALK mutations.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [97]
In the citing paper
“Toward this end, combinations of ICTs with concurrent and/or sequential chemotherapy are under extensive investigation, with phase III clinical data demonstrating overall survival and/or progression-free survival benefi t in NSCLC ( 63-66 ), small cell lung cancer ( 51,52 ), triple-negative breast cancer ( 67 ), bladder cancer ( 53 ), and head and neck squamous cell carcinoma ( 68 ).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [63]
In the citing paper
“Later, in two phase 3 clinical studies (KEYNOTE-189 and KEYNOTE-407), pembrolizumab combined with standard chemotherapy led to a better overall survival (OS) and PFS in NSCLC patients, relative to chemotherapy monotherapy [53, 54].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [53]
In the citing paper
“Moreover, ORR, median PFS, and median DOR reported for the two treatment arms were consistent with those reported in the KEYNOTE-189 and KEYNOTE-407 trials of pembrolizumab i.v.þ chemotherapy for the treatment of mNSCLC.22,23”
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Metadata
- Authors
- Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., Domine, M., Clingan, P., Hochmair, M. J., Powell, S. F., Cheng, S. Y.-S., Bischoff, H. G., Peled, N., Grossi, F., Jennens, R. R., Reck, M., Hui, R., Garon, E. B., Boyer, M., Rubio-Viqueira, B., Novello, S., Kurata, T., Gray, J. E., Vida, J., Wei, Z., Yang, J., Raftopoulos, H., Pietanza, M. C., & Garassino, M. C.
- Affiliations
- Universidad de Las Palmas de Gran Canaria (ES)
- From NYU Perlmutter Cancer Center, New York (L.G.); Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria (D.R.-A.), Hospital Universitario Central de Asturias, Oviedo (E.E.), Vall d’Hebron University, Vall d’Hebron Institute of Oncology, Barcelona (E.F.), and Fundación Jiménez Díaz (M.D.) and Hospital Universitario Quirón Madrid (B.R.-V.), Madrid — all in Spain; Karmanos Cancer Institute, Detroit (S.G.);...
- ORCID
- Gandhi, Leena
- Gadgeel, Shirish
- Esteban, Emilio
- Felip, Enriqueta
- Clingan, Philip
- Hochmair, Maximilian J.
- Powell, Steven F.
- Bischoff, Helge G.
- Peled, Nir
- Grossi, Francesco
- Jennens, Ross R.
- Reck, Martin
- Hui, Rina
- Garon, Edward B.
- Boyer, Michael
- Novello, Silvia
- Kurata, Takayasu
- Gray, Jhanelle E.
- Wei, Ziwen
- Yang, Jing
- Pietanza, M. Catherine
- Garassino, Marina C.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-05-31
- Volume
- 378
- Issue
- 22
- Pages
- 2078-2092
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2796582438
- Cited by
- 6,607
- References
- 31
- Citations by year
- 2026: 484 · 2025: 646 · 2024: 777 · 2023: 824 · 2022: 901 · 2021: 1039 · 2020: 964 · 2019: 677 · 2018: 284
- FWCI
- 559.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Acceda (Universidad de Las Palmas de Gran Canaria) (submittedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- IrInSubria (University of Insubria) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Merck
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- pembrolizumab, metastatic non-small cell lung cancer, PD-L1, pemetrexed, platinum-based chemotherapy, immune checkpoint inhibitors, first-line therapy, overall survival, progression-free survival, PD-L1 expression, maintenance therapy, treatment safety, immune-related adverse events, pneumonitis, diarrhea, rash, hyperphosphatemia
- MeSH terms
- Antineoplastic Agents, Immunological, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Double-Blind Method, Female, Follow-Up Studies, Humans, Lung Neoplasms, Male, Middle Aged, Disease-Free Survival, Kaplan-Meier Estimate, Antibodies, Monoclonal, Humanized
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