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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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Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance
Reita, D., Pabst, L., Pencreach, E., Guérin, É., Dano, L., Rimelen, V., Voegeli, A., Vallat, L. D., Mascaux, C., & Beau‐Faller, M. (2022) · Cancers · doi:10.3390/cancers14051321 · Cited by 104
Clinical pattern of checkpoint inhibitor-induced liver injury in a multicentre cohort
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Expert consensus on neoadjuvant immunotherapy for non-small cell lung cancer
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“As described above, ICIs can bring long-term benefits to patients with driver mutation– negative NSCLC (11-13).”
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DNA repair defects and implications for immunotherapy
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“Several clinical trials are investigating DNAdamaging treatments in combination with CPI, and a recent study in NSCLC demonstrated a significant survival benefit with the addition of CPI to chemotherapy in the first line, in further support of this strategy (80).”
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“0%) and not all responding patients had long-term benefit (7,10,11), other biomarkers are needed that are better able to predict beneficial outcome of ICI treatment.”
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Dugage, M. R., Nassif, E. F., Italiano, A., & Bahleda, R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.775761 · Cited by 100
“For decades, the immuno-oncology concept was thereafter investigated (7, 8) and ICIs have eventually proven only recently to prolong survival in patients with melanoma (9, 10), lung cancer (11, 12), urothelial carcinoma (13) and renal cancer (14), amongst others.”
BackgroundCognitive adverse effects of chemotherapy and immunotherapy: are interventions within reach?
Schagen, S. B., Tsvetkov, A. S., Compter, A., & Wefel, J. S. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-021-00617-2 · Cited by 101
Alessi, J. V., Elkrief, A., Ricciuti, B., Wang, X., Cortellini, A., Vaz, V. R., Lamberti, G., Frias, R. L., Venkatraman, D., Fulgenzi, C. A. M., et al. (2023) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2023.01.091 · Cited by 97
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Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies
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Reck, M., Wehler, T., Orlandi, F., Nogami, N., Barone, C., Moro‐Sibilot, D., Shtivelband, M. I., González-Larriba, J. L., Rothenstein, J. M., Früh, M., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.19.03158 · Cited by 90
“of doses received (range) 10 (1-43) 12 (1-44) —”
Self-citationFOXA1 overexpression suppresses interferon signaling and immune response in cancer
He, Y., Wang, L., Wei, T., Xiao, Y., Sheng, H., Su, H., Hollern, D. P., Zhang, X., Ma, J., Wen, S., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci147025 · Cited by 96
“While a significant fraction of FOXA1 mutations in cancer are C-terminal truncation mutations (29, 30), we demonstrated that different from the SBR-deficient mutant FOXA1 (1-247), the two PCa-associated C-terminal truncation mutants FOXA1 (1-290) and FOXA1 (1-268) (29, 30) remained the ability to bind to STAT2 and sup…”
BackgroundResultMazières, J., Kowalski, D. M., Luft, A. V., Vicente, D., Tafreshi, A., Gümüş, M., Лактионов, К. К., Hermes, B., Çiçin, İ., Rodríguez‐Cid, J. R., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.19.01348 · Cited by 90
“gov identifier: NCT03950674), pembrolizumab plus pemetrexed-platinum improved OS and PFS and maintained HRQoL, with improved HRQoL over placebo plus pemetrexed-platinum after completion of platinum therapy among patients with metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations.(7)”
BackgroundSelf-citationPD-1/PD-L1 Based Combinational Cancer Therapy: Icing on the Cake
Zhang, J., Yan, Y., Li, J., Adhikari, R., & Fu, L. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00722 · Cited by 94
“…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 OS and PFS than chemotherapy alone (Clinical Trials: NCT02578680) (Gandhi et al., 2018).”
BackgroundMethodInfluentialPender, A., Titmuss, E., Pleasance, E., Fan, K. Y., Pearson, H., Brown, S. D., Grisdale, C. J., Topham, J. T., Shen, Y., Bonakdar, M., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-1163 · Cited by 87
“CD274 gene expression is poorly associated with response and survival Expression of measured by IHC, is used as a clinical biomarker to select patients that may benefit from ICIs (8), but there is evidence that PD-L1–low or –negative patients can also respond to therapy (44, 45).”
MethodImmunotherapy in nonsmall-cell lung cancer: current status and future prospects for liquid biopsy
Brozos-Vázquez, E., Díaz‐Peña, R., García, J., León‐Mateos, L., Mondelo‐Macía, P., Peña-Chilet, M., & López‐López, R. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02752-z · Cited by 93
Schüler, M., Cuppens, K., Plönes, T., Wiesweg, M., Pont, B. D., Hegedűs, B., Köster, J., Mairinger, F. D., Darwiche, K., Paschen, A., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-02965-0 · Cited by 91
Combination regimens with PD-1/PD-L1 immune checkpoint inhibitors for gastrointestinal malignancies
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The role of combination chemo-immunotherapy in advanced non-small cell lung cancer
Rocco, D., Gravara, L. D., Battiloro, C., & Gridelli, C. (2019) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2019.1631800 · Cited by 89
Immune checkpoint inhibitors‐induced neuromuscular toxicity: From pathogenesis to treatment
Psimaras, D., Velasco, R., Birzu, C., Tamburin, S., Lustberg, M. B., Bruna, J., & Argyriou, A. A. (2019) · Journal of the Peripheral Nervous System · doi:10.1111/jns.12339 · Cited by 90
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Advances in the Treatment of Non–Small Cell Lung Cancer
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PD-1/PD-L1 Blockers in NSCLC Brain Metastases: Challenging Paradigms and Clinical Practice
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Systematic Review of PD-1/PD-L1 Inhibitors in Oncology: From Personalized Medicine to Public Health
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“As a consequence of this lack of a good predictive biomarker, most patients with advanced-stage NSCLC are treated with a PD-L1 checkpoint inhibitor, with or without chemotherapy (2,5).”
BackgroundDisulfiram loaded calcium phosphate nanoparticles for enhanced cancer immunotherapy
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Immunotherapy-based combinations in metastatic NSCLC
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Tumour and microenvironment crosstalk in NSCLC progression and response to therapy
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The Resistance Mechanisms of Lung Cancer Immunotherapy
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“Multiple randomized phase III clinical trials have compared the combination of chemotherapy and ICIs with chemotherapy alone in treatment-naïve advanced lung cancer (4, 9, 293).”
MethodImmunotherapy resistance in non-small-cell lung cancer: From mechanism to clinical strategies
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Chemotherapy for Lung Cancer in the Era of Personalized Medicine
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Nanomedicine Combats Drug Resistance in Lung Cancer
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“Nevertheless, a consistent signature (if one exists) of dysbiosis associated with ICI resistance distinct from that of response (overall survival rate 50% for melanoma 61 and 40% for non-small cell lung cancer 62,63 (NSCLC)) remains undefined.”
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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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