Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation
Open accessAbstract
Lessons Learned: This study evaluating first-line crizotinib plus pembrolizumab in patients with anaplastic lymphoma kinase (ALK)–positive advanced non-small cell lung cancer (NSCLC) was terminated early because increased availability of second-generation ALK inhibitors resulted in difficulty identifying and accruing eligible patients. In the small number of patients enrolled, elevated transaminases were the most common treatment-related toxicity. No other relevant toxicities were observed. Although no definitive conclusions could be drawn because of the small number of patients studied, the higher frequency of severe transaminase increases noted in this sample should be of concern if ALK inhibitor and PD-L1/PD-1 inhibitor combinations are tested in future studies. Background: Previous research suggests single-agent crizotinib is efficacious for the treatment of anaplastic lymphoma kinase (ALK)–rearranged advanced non-small cell lung cancer (NSCLC). Methods: This study evaluated the safety and preliminary antitumor activity of crizotinib plus pembrolizumab as first-line therapy in patients with ALK-rearranged NSCLC. Patients were initially treated at dose level 0 (DL0) with crizotinib 250 mg twice daily and pembrolizumab 200 mg every 3 weeks (cycle duration was 3 weeks). If a dose-limiting toxicity occurred, subsequent patients were enrolled at a lower dose level (dose level −1 [DL−1]: 3 weeks of crizotinib monotherapy 250 mg twice daily, followed by crizotinib 250 mg twice daily with the addition of pembrolizumab 200 mg every 3 weeks). The primary endpoint was dose-limiting toxicity. Antitumor activity was assessed. Results: Nine patients were enrolled: two at DL0, then seven at DL−1. Dose-limiting toxicities occurred in four patients (grade 3 increases in alanine aminotransferase [ALT] and aspartate aminotransferase [AST] and grade 3 fatigue at DL0; grade 3 increase in ALT and grade 3 increases in both ALT and AST at DL−1). Conclusion: The maximum tolerated dose was not determined because slow accrual resulted in early study termination.
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Pembrolizumab plus crizotinib showed intolerable hepatotoxicity in NSCLC.
“Moreover, pembrolizumab plus crizotinib also showed intolerable hepatotoxicity in NSCLC [204].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [204]
ALK-TKI combined with α-PD-1/PD-L1 might increase treatment-associated hepatotoxicity.
“It should be noted that ALK-TKI combined with α-PD-1/PD-L1 might increase treatment-associated hepatotoxicity.”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [204]
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Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer
Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Hui, R., Csőszi, T., Fülöp, A., Gottfried, M., Peled, N., Tafreshi, A., Cuffe, S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1606774 · Cited by 10,089 · see citing works
First-Line Crizotinib versus Chemotherapy in <i>ALK</i> -Positive Lung Cancer
Solomon, B. J., Mok, T., Kim, D.-W., Wu, Y.-L., Nakagawa, K., Mekhail, T., Felip, E., Cappuzzo, F., Paolini, J., Usari, T., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408440 · Cited by 3,190 · see citing works
Alectinib versus Crizotinib in Untreated <i>ALK</i> -Positive Non–Small-Cell Lung Cancer
Peters, S., Camidge, D. R., Shaw, A. T., Gadgeel, S., Ahn, J. S., Kim, D.-W., Ou, S.-H. I., Pérol, M., Dziadziuszko, R., Rosell, R., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1704795 · Cited by 2,527 · see citing works
Gainor, J. F., Shaw, A. T., Sequist, L. V. D., Fu, X., Azzoli, C. G., Piotrowska, Z., Huynh, T. G., Zhao, L., Fulton, L. E., Schultz, K. R., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-3101 · Cited by 1,256 · see citing works
PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients
D’Incecco, A., Andreozzi, M., Ludovini, V., Rossi, E., Capodanno, A., Landi, L. M., Tibaldi, C., Minuti, G., Salvini, J., Coppi, E., et al. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.555 · Cited by 594 · see citing works
Solomon, B., Kim, D., Wu, Y.-L. L. C., Nakagawa, K., Mekhail, T. M., Felip, E., Cappuzzo, F., Paolini, J., Usari, T., Tang, Y., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.77.4794 · Cited by 408 · see citing works
Lin, J. J., Chin, E., Yeap, B. Y., Ferris, L. A., Kamesan, V., Lennes, I. T., Sequist, L. V., Heist, R. S., Mino-Kenudson, M., Gainor, J. F., et al. (2019) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.09.001 · Cited by 140 · see citing works
Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC
Bassanelli, M., Sioletic, S., Martini, M., Giacinti, S., Viterbo, A., Staddon, A., Liberati, F., & Ceribelli, A. (2018) · Anticancer Research · doi:10.21873/anticanres.12662 · Cited by 84 · see citing works
ALK inhibitors and checkpoint blockade: a cautionary tale of mixing oil with water?
Patel, M. M., Jabbour, S. K., & Malhotra, J. D. (2018) · Journal of Thoracic Disease · doi:10.21037/jtd.2018.06.118 · Cited by 14 · see citing works
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Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01489-2 · Cited by 1,445 · see citing works
Targeting immunogenic cell stress and death for cancer therapy
Galluzzi, L., Guilbaud, E., Schmidt, D. R., Kroemer, G., & Marincola, F. M. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-00920-9 · Cited by 595 · see citing works
Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management
Cooper, A. J., Sequist, L. V. D., & Lin, J. J. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00639-9 · Cited by 525 · see citing works
Huang, M.-Y., Jiang, X.-M., Wang, B.-L., Sun, Y., & Lu, J.-J. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107694 · Cited by 136 · see citing works
Remón, J., Pignataro, D., Novello, S., & Passiglia, F. (2021) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2021.102178 · Cited by 76 · see citing works
Cognigni, V., Pecci, F., Lupi, A., Pinterpe, G., Filippis, C. D., Felicetti, C., Cantini, L., & Berardi, R. (2022) · Cancers · doi:10.3390/cancers14194765 · Cited by 43 · see citing works
Guaitoli, G., Tiseo, M., Maïo, M. D., Friboulet, L., & Facchinetti, F. (2021) · Translational Lung Cancer Research · doi:10.21037/tlcr-20-941 · Cited by 37 · see citing works
Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer
Gavralidis, A., & Gainor, J. F. (2020) · The Cancer Journal · doi:10.1097/ppo.0000000000000491 · Cited by 28 · see citing works
Fukui, T., TACHIHARA, M. Y., Nagano, T., & Kobayashi, K. (2022) · Cancers · doi:10.3390/cancers14051184 · Cited by 30 · see citing works
Kim, D., Gadgeel, S. M., Gettinger, S. N., Riely, G. J., Oxnard, G. R., Mekhail, T. M., Schmid, P., Dowlati, A., Heist, R. S., Wozniak, A. J., et al. (2022) · JTO Clinical and Research Reports · doi:10.1016/j.jtocrr.2022.100367 · Cited by 29 · see citing works
Kiełbowski, K., Żychowska, J., & Becht, R. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1285374 · Cited by 27 · see citing works
Starzer, A. M., Wolff, L., Popov, P., Kiesewetter, B., Preusser, M., & Berghoff, A. S. (2024) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2024.102718 · Cited by 27 · see citing works
Jiang, L., & Liu, J. (2022) · Oncology Letters · doi:10.3892/ol.2022.13285 · Cited by 16 · see citing works
Schenk, E. L. (2023) · Translational Lung Cancer Research · doi:10.21037/tlcr-22-883 · Cited by 16 · see citing works
Treatment of advanced ALK-rearranged NSCLC following second-generation ALK–TKI failure
Fukuda, A., & Yoshida, T. (2023) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2023.2265566 · Cited by 17 · see citing works
Solomon, B., Dagogo‐Jack, I., Lee, S.-H., Boyer, M. J., Ramalingam, S. S., Carcereny, E., Felip, E., Han, J., Hida, T., Hughes, B. G. M., et al. (2024) · JTO Clinical and Research Reports · doi:10.1016/j.jtocrr.2024.100685 · Cited by 14 · see citing works
Current status and challenges of immunotherapy in ALK rearranged NSCLC
Qi, R., Yu, Y., Shen, M., Lv, D., & He, S. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1016869 · Cited by 12 · see citing works
Désage, A.-L., Duruisseaux, M., Lafitte, C., Bayle-Bleuez, S., CHOUAID, C., Fournel, P., & Pierret, T. (2024) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2024.102805 · Cited by 11 · see citing works
Ramos-Ramírez, M., Caballé‐Perez, E., Lucio-Lozada, J., Romero-Núñez, E., Castillo-Ruiz, C., Dorantes-Sánchez, L., Flores‐Estrada, D., Recondo, G., Barrios‐Bernal, P., Cabrera-Miranda, L. A., et al. (2025) · Cancer and Metastasis Reviews · doi:10.1007/s10555-025-10245-7 · Cited by 11 · see citing works
Borowicz, S., Principe, D. R., Dorman, M. J., McHenry, A. J., Sondarva, G. V., Kumar, S., Ananthanarayanan, V., Simms, P. E., Hess, A., & Rana, A. (2021) · PLoS ONE · doi:10.1371/journal.pone.0252197 · Cited by 10 · see citing works
Bulutay, P., Akyürek, N., & Memış, L. (2020) · Turkish Journal of Pathology · doi:10.5146/tjpath.2020.01503 · Cited by 9 · see citing works
Anaplastic lymphoma kinase-special immunity and immunotherapy
Guo, Y., Guo, H., Zhang, Y., & Cui, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.908894 · Cited by 9 · see citing works
Co-delivery of F7 and crizotinib by thermosensitive liposome for breast cancer treatment
Li, M., Li, Y., Li, S., Jia, L., Du, C., Li, M., Li, S., Galons, H., Guo, N., & Yu, P. (2021) · Journal of Liposome Research · doi:10.1080/08982104.2021.2001499 · Cited by 8 · see citing works
Arai, K., Nishito, Y., Mizuno, H., Motoi, N., Hiraoka, N., Fuse, M., Arai, Y., Shibata, T., Sonobe, Y., Kayukawa, Y., et al. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-24-0532 · Cited by 7 · see citing works
Immune checkpoint inhibitors in driver mutation-positive nonsmall cell lung cancer: is there a role?
Lee, J., & Ahn, M. (2020) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000698 · Cited by 7 · see citing works
McMahon, D. J., McLaughlin, R. A., & Naidoo, J. (2024) · Cancers · doi:10.3390/cancers16030527 · Cited by 6 · see citing works
Leone, G., Passiglia, F., Bironzo, P., Bertaglia, V., & Novello, S. (2020) · Translational Lung Cancer Research · doi:10.21037/tlcr-20-710 · Cited by 4 · see citing works
Kim, T. H., Park, J.-H., Park, J., Son, D. M., Baek, J., Jang, H. J., Jung, W. K., Byun, Y., Kim, S. K., & Park, S. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174525 · Cited by 5 · see citing works
Emerging Biomarkers in Immune Oncology to Guide Lung Cancer Management
Safa, H., Rous, F. A., Belani, N., Borghaei, H., Gadgeel, S. M., & Halmos, B. (2022) · Targeted Oncology · doi:10.1007/s11523-022-00937-3 · Cited by 6 · see citing works
Accrual, Publication Bias, and the Coronavirus in 2020
Bates, S. E. (2020) · The Oncologist · doi:10.1634/theoncologist.2020-0455 · Cited by 4 · see citing works
Pulmonary toxicity in driver gene positive non-small cell lung cancer therapy
Zhao, Y., & Long, Y. (2022) · Current Medical Research and Opinion · doi:10.1080/03007995.2022.2085964 · Cited by 4 · see citing works
Liu, C., Zhu, S., Wu, J., Qiao, Y., Yang, N., & Chen, J. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102230 · Cited by 1 · see citing works
Sequential combined crizotinib and camrelizumab in MET-amplified hepatocellular carcinoma
Li, H., Gao, H., Chang, R., Xia, L., Chen, X., Zhang, B., Zhang, W.-G., & Ding, Z. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102141
Research Progress on Biomarkers for Immunotherapy of Non-Small Cell Lung Cancer
邹, 惠. (2026) · Advances in Clinical Medicine · doi:10.12677/acm.2026.1641320
- Authors
- Patel, S. P., Pakkala, S., Pennell, N. A., Reckamp, K. L., Lanzalone, S., Polli, A., Tarazi, J., & Robert-Vizcarrondo, F.
- Affiliations
- University of California San Diego (US)
- Winship Cancer Institute (US)
- Cleveland Clinic (US)
- City Of Hope National Medical Center (US)
- Pfizer (Italy) (IT)
- Pfizer (United States) (US)
- University of Alabama at Birmingham (US)
- Corresponding author
- Patel, Sandip Pravin
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-02-12
- Volume
- 25
- Issue
- 7
- Pages
- 562-e1012
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC7356710
- OpenAlex
- W3005583371
- Cited by
- 34
- References
- 9
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 10 · 2021: 5 · 2020: 6
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Oncologist (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- crizotinib, pembrolizumab, ALK-positive non-small cell lung cancer, ALK rearrangement, first-line therapy, combination immunotherapy, dose-limiting toxicity, transaminase elevation, maximum tolerated dose, second-generation ALK inhibitors
- MeSH terms
- Crizotinib, Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Gene Rearrangement, Receptor Protein-Tyrosine Kinases, Protein Kinase Inhibitors, Antibodies, Monoclonal, Humanized
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