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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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“This study was positive in terms of its two primary objectives (OS and PFS) and included a pre-planned analysis of the two previous objectives based on PD-L1 expression in the initial design [60].”
ResultCortellini, A., Ricciuti, B., Facchinetti, F., Alessi, J. V., Venkatraman, D., Dall’Olio, F. G., Cravero, P., Vaz, V. R., Ottaviani, D., Majem, M., et al. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.08.1744 · Cited by 69
Liu, J., Wei, L., Hu, N., Wang, D., Ni, J., Zhang, S., Liu, H., Lv, T., Yin, J., Ye, M., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005116 · Cited by 68
Mathematical modeling of cancer immunotherapy for personalized clinical translation
Butner, J. D., Dogra, P., Chung, C. D., Pasqualini, R., Arap, W., Lowengrub, J. S., Vittorio Cristini, C., & Wang, Z. (2022) · Nature Computational Science · doi:10.1038/s43588-022-00377-z · Cited by 71
Amoroso, V., Gallo, F., Alberti, A., Paloschi, D., Bravo, W. F., Esposito, A., Cosentini, D., Grisanti, S., Pedersini, R., Petrelli, F., et al. (2023) · ESMO Open · doi:10.1016/j.esmoop.2023.100787 · Cited by 70
“75) Gandhi et al.(55) NSCLC Pembrolizumab, pemetrexed, and platinum-based drug Pemetrexed and platinumbased drug 616 10.”
BackgroundFrom immune checkpoints to vaccines: The past, present and future of cancer immunotherapy
Osipov, A., Murphy, A. G., & Zheng, L. (2019) · Advances in cancer research · doi:10.1016/bs.acr.2019.03.002 · Cited by 69
Okamoto, I., Nokihara, H., Nomura, S., Niho, S., Sugawara, S., Horinouchi, H., Azuma, K., Yoneshima, Y., Murakami, H., Hosomi, Y., et al. (2020) · JAMA Oncology · doi:10.1001/jamaoncol.2019.6828 · Cited by 67
Kim, Y.-J., Keam, B., Ock, C.-Y., Song, S., Kim, M., Kim, S. H., Kim, K. H., Kim, J.-S., Kim, T. M., Kim, D., et al. (2019) · Lung Cancer · doi:10.1016/j.lungcan.2019.08.031 · Cited by 66
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“Our aim was to raise awareness on this issue, which might become even more significant as immunotherapy-chemotherapy combinations enter clinical practice in the near future [57,58].”
BackgroundSelf-citationBispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity
Kotanides, H., Li, Y. H., Malabunga, M., Carpenito, C., Eastman, S. W., Shen, Y., Wang, G., Inigo, I. V., Surguladze, D., Pennello, A. L., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0304 · Cited by 66
Low‐dose pembrolizumab in the treatment of advanced non‐small cell lung cancer
Low, J. L., Huang, Y., Sooi, K. W. X., Ang, Y. L. E., Chan, Z. Y., Spencer, K. L., Jeyasekharan, A. D. D., Sundar, R., Goh, B. C., Soo, R. A., et al. (2021) · International Journal of Cancer · doi:10.1002/ijc.33534 · Cited by 66
Amodio, V., Mauri, G., Reilly, N. M., Bianchi, A. S., Siena, S., Bardelli, A., & Germano, G. (2021) · Cancers · doi:10.3390/cancers13112638 · Cited by 67
Muto, S., Enta, A., Maruya, Y., Inomata, S., Yamaguchi, H., Mine, H., Takagi, H., Ozaki, Y., Watanabe, M., Inoue, T., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11010190 · Cited by 68
Bifidobacterium modulation of tumor immunotherapy and its mechanism
Pei, B., Peng, S., Huang, C., & Zhou, F. (2024) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-024-03665-x · Cited by 71
Response and Resistance to RAS Inhibition in Cancer
Ebright, R. Y., Dilly, J., Shaw, A. T., & Aguirre, A. J. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-25-0349 · Cited by 76
Rossi, G., Pezzuto, A., Sini, C., Tuzi, A., Citarella, F., McCusker, M. G., Nigro, O., Tanda, E. T., & Russo, A. (2019) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2019.07.005 · Cited by 66
Kato, S., Okamura, R., Kumaki, Y., Ikeda, S., Nikanjam, M., Eskander, R. N., Goodman, A. M., Lee, S., Glenn, S. T., Dressman, D. C., et al. (2020) · OncoImmunology · doi:10.1080/2162402x.2019.1708065 · Cited by 68
Mou, H., Yu, L., Liao, Q., Hou, X., Wu, Y., Cui, Q., Yan, N., Ma, R., Wang, L., Yao, M., et al. (2018) · BMC Cancer · doi:10.1186/s12885-018-5021-2 · Cited by 67
Kim, R., Keam, B., Hahn, S., Ock, C.-Y., Kim, M., Kim, T. M., Kim, D., & Heo, D. S. (2019) · Clinical Lung Cancer · doi:10.1016/j.cllc.2019.05.009 · Cited by 65
Kao, H., & Lou, P. (2019) · Head & Neck · doi:10.1002/hed.25930 · Cited by 66
Pembrolizumab microgravity crystallization experimentation
Reichert, P., Prosise, W. W., Fischmann, T. O., Scapin, G., Narasimhan, C. N., Spinale, A., Polniak, R., Yang, X., Walsh, E., Patel, D., et al. (2019) · npj Microgravity · doi:10.1038/s41526-019-0090-3 · Cited by 65
“Keytruda has been approved in the United States for several cancer indications, including non-small-cell lung cancer, melanoma, urothelial bladder cancer, head and neck squamous cell cancer, Hodgkin’s lymphoma, microsatellite instability cancer, and gastric cancer, and is under review in several additional countries.(…”
BackgroundChimeric Antigen Receptor T Cell Therapy Targeting ICAM-1 in Gastric Cancer
Jung, M., Yang, Y., McCloskey, J. E., Zaman, M., Vedvyas, Y., Zhang, X., Stefanova, D. I., Gray, K. D., Min, I. M., Zarnegar, R., et al. (2020) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2020.08.009 · Cited by 64
Frass, M., Lechleitner, P., Gründling, C., Pirker, C., Grasmuk‐Siegl, E., Domayer, J., Hochmair, M. J., Gaertner, K., Duscheck, C., Muchitsch, I., et al. (2020) · The Oncologist · doi:10.1002/onco.13548 · Cited by 66
Self-citationRetractedLiu, W., Ma, F., Sun, B., Liu, Y., Tang, H., Luo, J., Chen, H., & Luo, Z. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.756872 · Cited by 70
“The increased efficacy of combination therapy is accompanied by a rising incidence of irAEs, especially severe or life-threatening irAEs (8, 12, 13).”
BackgroundPal, S. K., Miller, M. J., Agarwal, N., Chang, S. M., Chávez‐MacGregor, M., Cohen, E. E. W., Cole, S., Dale, W., Diefenbach, C., Disis, M. L., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.02037 · Cited by 65
Jing, D., Wu, W., Chen, X., Xiao, H., Zhang, Z., Chen, F., Zhang, Z., Liu, J., Shao, Z., & Pu, F. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106287 · Cited by 67
Zhang, L., Zhou, C., Zhang, S., Chen, X., Liu, J., Xu, F., & Liang, W. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.939249 · Cited by 68
Polysaccharide‐Based Stimulus‐Responsive Nanomedicines for Combination Cancer Immunotherapy
Li, Q., Liu, X., Yan, C., Zhao, B., Zhao, Y., Yang, L., Shi, M., Yu, H., Li, X., & Luo, K. (2023) · Small · doi:10.1002/smll.202206211 · Cited by 68
Zhao, B., Wu, B. C., Feng, N., Zhang, X., Zhang, X., Wei, Y., & Zhang, W. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01426-4 · Cited by 68
Zhu, M., Kim, J., Deng, Q., Ricciuti, B., Alessi, J. V., Eglenen-Polat, B., Bender, M. E., Huang, H.-C., Kowash, R., Cuevas, I., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.09.006 · Cited by 66
Bourhis, J., Auperin, A., Borel, C., Lefebvre, G., Racadot, S., Geoffrois, L., Sun, X., Saâda-Bouzid, E., Cirauqui, B., Rutkowski, T., et al. (2025) · The Lancet · doi:10.1016/s0140-6736(25)01850-1 · Cited by 66
Yoda, S., Dagogo‐Jack, I., & Hata, A. N. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.08.007 · Cited by 68
Naidoo, J., Nishino, M., Patel, S. P., Shankar, B., Rekhtman, N., Illei, P. B., & Camus, P. (2020) · Clinical Lung Cancer · doi:10.1016/j.cllc.2020.02.025 · Cited by 67
Huemer, F., Lang, D., Westphal, T., Gampenrieder, S. P., Hutarew, G., Weiß, L., Hackl, H., Lamprecht, B., Rinnerthaler, G., & Greil, R. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8071014 · Cited by 68
“3 months from initiation of first-line therapy and will necessitate further systemic treatment [8,9].”
BackgroundParikh, R. B., Min, E. J., Wileyto, E. P., Riaz, F., Gross, C. P., Cohen, R. B., Hubbard, R. A., Long, Q., & Mamtani, R. (2021) · JAMA Oncology · doi:10.1001/jamaoncol.2021.4971 · Cited by 65
Naqash, A. R., McCallen, J., Mi, E., Iivanainen, S., Marie, M. A., Gramenitskaya, D., Clark, J., Koivunen, J. P., Macherla, S., Jonnalagadda, S., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007310 · Cited by 64
Immunotherapy for Urothelial Carcinoma: Current Evidence and Future Directions
Tripathi, A., & Plimack, E. R. (2018) · Current Urology Reports · doi:10.1007/s11934-018-0851-7 · Cited by 65
Criss, S. D., Mooradian, M. J., Sheehan, D. F., Zubiri, L., Lumish, M. A., Gainor, J. F., Reynolds, K. L., & Kong, C. Y. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2018.5449 · Cited by 64
Immunotherapy Associated Pulmonary Toxicity: Biology Behind Clinical and Radiological Features
Porcu, M., Silva, P. D., Solinas, C., Battaglia, A., Schena, M., Scartozzi, M., Bron, D., Suri, J. S., Willard-Gallo, K. E., Sangiolo, D., et al. (2019) · Cancers · doi:10.3390/cancers11030305 · Cited by 64
Hendriks, L. E. L., Bootsma, G. P., Mourlanette, J., Henon, C., Mezquita, L., Ferrara, R., Audigier-Valette, C., Mazières, J., Lefebvre, C., Duchemann, B., et al. (2019) · European Journal of Cancer · doi:10.1016/j.ejca.2019.05.019 · Cited by 64
“Because first-line ICI combined with chemotherapy proved superior to chemotherapy alone [15], it would be interesting to evaluate this combination in patients with LM.”
BackgroundPrognostic and clinical impact of PD-L2 and PD-L1 expression in a cohort of 437 oesophageal cancers
Okadome, K., Baba, Y., Nomoto, D., Yagi, T., Kalikawe, R., Harada, K., Hiyoshi, Y., Nagai, Y., Ishimoto, T., Iwatsuki, M., et al. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0811-0 · Cited by 65
de Vasconcellos, V. F., Marta, G. N., da Silva, E. M., de Góis, A. F. T., Castria, T. B. D., & Riera, R. (2020) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009256.pub3 · Cited by 64
Achievements and futures of immune checkpoint inhibitors in non-small cell lung cancer
Qiu, Z., Chen, Z., Zhang, C., & Zhong, W. (2019) · Experimental Hematology and Oncology · doi:10.1186/s40164-019-0143-z · Cited by 64
“However, recently single agent PD-1 inhibitor demonstrated better outcomes compared to platinum-based chemotherapy in ≥ 50% PD-L1 tumors [42], as well as in combination with platinum-based chemotherapy for nonsquamous population, regardless of PD-L1 expression [23, 43].”
ResultKhaddour, K., Jonna, S., Deneka, A. Y., Patel, J. D., Abazeed, M. E., Golemis, E. A., Borghaei, H., & Boumber, Y. (2021) · Cancers · doi:10.3390/cancers13133164 · Cited by 67
Neal, J. W., Pavlakis, N., Kim, S., Goto, Y., Lim, S. M., Mountzios, G., Fountzilas, E., Mochalova, A. S., Christoph, D. C., Bearz, A., et al. (2024) · Journal of Clinical Oncology · doi:10.1200/jco.23.02166 · Cited by 67
“6,7,32,33 However, in a more recent phase III trial studying cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC without previous exposure to cancer immunotherapy, OS favored the experimental arm in most subgroups, with women being among the few outliers (OS HR,…”
BackgroundKaderbhaï, C., Tharin, Z., & Ghiringhelli, F. (2019) · Cancers · doi:10.3390/cancers11020201 · Cited by 63
“For patients who have a PD-L1 tumor cell expression under 50%, the association of anti PD-1/PD-L1 monoclonal antibodies with chemotherapy has shown to be superior to chemotherapy alone [9,10].”
BackgroundRuíz-Patiño, A., Arrieta, O. G., Cardona, A. F., Martin, C. M., Raez, L. E., Zatarain-Barrón, Z. L., Barrón, F., Ricaurte, L., Bravo-Garzón, M. A., Mas, L. A., et al. (2019) · Thoracic Cancer · doi:10.1111/1759-7714.13272 · Cited by 64
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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