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Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non–Small Cell Lung Cancer
Open accessAbstract
Introduction Immune checkpoint inhibitors (ICIs) are standard therapies in advanced NSCLC. Although genotype-directed tyrosine kinase inhibitors represent the standard of care for subsets of oncogene-driven NSCLC, patients may receive ICIs during their disease course. The impact of sequential ICI and tyrosine kinase inhibitor therapy on the risk of hepatotoxicity has not been described.Methods Patients with advanced ALK receptor tyrosine kinase (ALK)-driven, ROS1-driven, or MET proto-oncogene, receptor tyrosine kinase (MET)-driven NSCLC treated with crizotinib, with or without preceding ICI therapy, were identified. The cumulative incidences of crizotinib-associated grade 3 or higher increases in transaminase level (per the Common Terminology Criteria for Adverse Events, version 4.0) were compared.Results We identified 453 patients who had NSCLC with an oncogenic alteration in ALK receptor tyrosine kinase gene (ALK), ROS1, or MET proto-oncogene, receptor tyrosine kinase gene (MET) and were treated with crizotinib (11 with and 442 without prior ICI therapy). Among the 11 patients treated with an ICI followed by crizotinib, five (cumulative incidence 45.5% [95% confidence interval (CI): 14.9-72.2]) experienced development of a grade 3 or 4 increase in alanine transaminase level and four (cumulative incidence 36.4% [95% CI: 10.0-64.2]) experienced development of a grade 3 or 4 increase in aspartate transaminase level. In comparison, among the 442 patients who received crizotinib only, a grade 3 or 4 increase in alanine transaminase level occurred in 34 patients (cumulative incidence 8.1% [95% CI: 5.7-11.0, p < 0.0001]) and a grade 3 or 4 increase in aspartate transaminase level occurred in 14 (cumulative incidence 3.4% [95% CI: 1.9-5.5, p < 0.0001]). There were no grade 5 transaminitis events. All cases of hepatotoxicity after sequential ICI and crizotinib use were reversible and nonfatal, and no case met the Hy's law criteria.Conclusions Sequential ICI and crizotinib treatment is associated with a significantly increased risk of hepatotoxicity. Careful consideration and monitoring for hepatotoxicity may be warranted in patients treated with crizotinib after ICI therapy.
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“Additionally, the timing and sequence of combination therapy also influence treatment toxicity, which should be further validated in clinical studies [186, 207].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [207]
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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 · cited 2×
“Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 and its ligand programmed death ligand 1 (PD-L1) have entered the clinic across multiple solid tumors, including NSCLC.1 On the basis of KEYNOTE-189, pembrolizumab plus platinum-doublet chemotherapy is the standard first-line treatment for nonsquamo…”
Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer
Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., Domine, M., Clingan, P., Hochmair, M. J., Powell, S. F., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1801005 · Cited by 6,607
Crizotinib versus Chemotherapy in Advanced ALK -Positive Lung Cancer
Shaw, A. T., Kim, D.-W., Nakagawa, K., Seto, T., Crinó, L., Ahn, M.-J., De Pas, T., Besse, B., Solomon, B. J., Blackhall, F., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1214886 · Cited by 3,381
Self-citationCrizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer
Shaw, A. T., Ou, S.-H. I., Bang, Y.-J., Camidge, D. R., Solomon, B. J., Salgia, R., Riely, G. J., Varella-Garcia, M., Shapiro, G. I., Costa, D. B., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1406766 · Cited by 1,964
Self-citationCamidge, D. R., Bang, Y., Kwak, E. L., Iafrate, A. J., Varella‐Garcia, M., Fox, S. B., Riely, G. J., Solomon, B., Ou, S. I., Kim, D., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70344-3 · Cited by 1,267
Self-citationLisberg, A., Cummings, A., Goldman, J. W., Bornazyan, K., Reese, N., Wang, T., Coluzzi, P., Ledezma, B., Mendenhall, M., Hunt, J., et al. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.03.035 · Cited by 580
Oshima, Y., Tanimoto, T., Yuji, K., & Tojo, A. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2017.4526 · Cited by 313 · cited 1×
“In one observational study, the risk of EGFR TKI–associated pneumonitis was substantially higher with sequential or concurrent ICI and TKI therapy, although other toxicities were not investigated.(4) In a separate phase II study of pembrolizumab in TKI-naive EGFR-mutant NSCLC, two of seven patients subsequently treate…”
Spigel, D. R., Reynolds, C., Waterhouse, D., Garon, E. B., Chandler, J., Babu, S., Thurmes, P., Spira, A., Jotte, R., Zhu, J., et al. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.02.022 · Cited by 229 · cited 1×
“For example, a phase 1/2 study of nivolumab plus crizotinib in ALK-rearranged NSCLC was terminated early because of severe hepatotoxicity in five of 13 patients (38%).(6) Two patients died, highlighting the importance of diagnosing and intervening on potentially fatal hepatotoxicity.”
Gibbons, D. L., Chow, L. Q. M., Kim, D.-W., Kim, S., Yeh, T. C., Song, X., Jiang, H., Taylor, R., Karakunnel, J. J., & Creelan, B. (2016) · Journal of Thoracic Oncology · doi:10.1016/s1556-0864(16)30171-x · Cited by 112
Melosky, B. L., Chu, Q. S.-C., Juergens, R. A., Leighl, N. B., McLeod, D., & Hirsh, V. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.63.8049 · Cited by 81
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“Additionally, the timing and sequence of combination therapy also influence treatment toxicity, which should be further validated in clinical studies [186, 207].”
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Metadata
- Authors
- 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., & Shaw, A. T.
- Affiliations
- Massachusetts General Hospital (US)
- Corresponding author
- Shaw, Alice T.
- ORCID
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 14
- Issue
- 1
- Pages
- 135-140
- ISSN
- 1556-0864 (ISSN-L)
- PMC
- PMC6309637
- OpenAlex
- W2890230728
- Cited by
- 140
- References
- 15
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 24 · 2023: 24 · 2022: 16 · 2021: 15 · 2020: 24 · 2019: 5
- FWCI
- 8.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Massachusetts General Hospital
- National Cancer Institute (R01CA164273)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- immune checkpoint inhibitors, crizotinib, non-small cell lung cancer, anaplastic lymphoma kinase, ROS1, MET, tyrosine kinase inhibitors, sequential therapy, drug-drug interactions, transaminase elevation, liver injury, adverse drug reactions, immune-related adverse events, immune-related pneumonitis, immune-related colitis
- MeSH terms
- Crizotinib, Proto-Oncogene Mas, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Protein Kinase Inhibitors
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