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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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Immunotherapy in Non-Small-Cell Lung Cancer Patients with Driver Alterations: A New Strategy?
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BackgroundComedications Associated with Immune‐Related Adverse Events from Immune‐Checkpoint Inhibitors
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“In addition, it is now being recognized that immunotherapy drugs given sequentially before TKIs but not after are associated with a much higher rate of pneumonitis and other adverse events [3, 4].”
BackgroundCurrent 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
Sisi, M., Vitale, G., Fusaroli, M., Riefolo, M., Giunchi, V., D’Errico, A., Ardizzoni, A., Raschi, E., & Gelsomino, F. (2023) · JTO Clinical and Research Reports · doi:10.1016/j.jtocrr.2023.100563 · Cited by 12
O’Reilly, D., O'Leary, C., Reilly, A., Teo, M. Y., O'Kane, G. M., Hendriks, L. E. L., Bennett, K., & Naidoo, J. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1380453 · Cited by 13
“Similarly, this has been demonstrated with the combination of crizotinib plus PD(L)-1 inhibition (22).”
BackgroundImmune Checkpoint Blockade in Oncogene-Driven Non-Small-Cell Lung Cancer
Somasundaram, A., Socinski, M. A., & Villaruz, L. (2020) · Drugs · doi:10.1007/s40265-020-01320-0 · Cited by 12
“ICI before crizotinib (Clinical trial) [63] 11 NR NR NR 45.”
BackgroundShimoda, Y., Yoshida, T., Miyakoshi, J., Torasawa, M., Tateishi, A., Matsumoto, Y., Masuda, K., Shinno, Y., Okuma, Y., Goto, Y., et al. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03429-z · Cited by 11
“5%) patients treated with crizotinib after receiving previous treatment with an ICI developed grade 3 or 4 liver toxicity, leading to permanent discontinuation of crizotinib in four of five patients [15].”
BackgroundDésage, 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 15
Banyi, N., Alex, D., Hughesman, C. B., McNeil, K., Ionescu, D. N., Ma, C., Yip, S. S. F., & Melosky, B. L. (2022) · Current Oncology · doi:10.3390/curroncol29100624 · Cited by 11
“Immunotherapy in patients with EGFR-driven NSCLC is not effective and switching from immunotherapy to EGFR-TKI treatment can result in severe complications or death [12,13].”
BackgroundA Cautionary Analysis of Immunotherapy Prior to Targeted Therapy
McCoach, C. E. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.10.009 · Cited by 11
Chemotherapy after nivolumab for advanced gastric cancer (REVIVE): a prospective observational study
Narita, Y., Matsushima, T., Sakamoto, Y., Matsuoka, H., Tanioka, H., Kawakami, T., Shoji, H., Mizukami, T., Izawa, N., Nishina, T., et al. (2023) · ESMO Open · doi:10.1016/j.esmoop.2023.102071 · Cited by 10
“34,35 It has been suggested that the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors after nivolumab therapy increases the risk of interstitial pneumonitis in patients with EGFR mutation-positive lung cancer.”
Saw, S. P. L., Zhong, W., Fu, R., Li, M. S. C., Goto, Y., Fox, S. B., Yatabe, Y., Ong, B., Ng, C. S. H., Lee, D., et al. (2025) · Lung Cancer · doi:10.1016/j.lungcan.2024.108076 · Cited by 10
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 12
“Thus, these alterations are predictors of poor ICIs response as monotherapy [81] or in sequential combination with ALK inhibitors [128, 129], which also resulted in high liver toxicity rates [130], likely derived from the long-lasting half-life of tested ICIs [131] (Fig.”
Björnsson, H. K., & Bjornsson, E. S. (2023) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2023.2288260 · Cited by 10
“A study performed in Massachusetts General Hospital in Boston on patients with non-small cell lung cancer investigated the risk of liver injury in patients receiving sequential CPI and crizotinib treatment [29].”
BackgroundBorowicz, 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
“This approach is currently under early investigation, as Phase I trials are now evaluating crizotinib and the PD-1 inhibitor pembrolizumab in ALK, ROS1, and METdriven NSCLC [30, 31].”
Immune Checkpoint Inhibitors in “Special” NSCLC Populations: A Viable Approach?
Bronte, G., Cosi, D. M., Magri, C., Frassoldati, A., Crinò, L., & Calabrò, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612622 · Cited by 10
“She fully recovered after one month of supportive treatment [27].”
BackgroundKitahara, Y., Inoue, Y., Yasui, H., Karayama, M., Suzuki, Y., Hozumi, H., Furuhashi, K., Enomoto, N., Fujisawa, T., Funai, K., et al. (2024) · Respiratory Research · doi:10.1186/s12931-024-02683-8 · Cited by 9
Maloney, N. J., Rana, J., Yang, J. J., Zaba, L. C., & Kwong, B. Y. (2021) · Supportive Care in Cancer · doi:10.1007/s00520-021-06543-9 · Cited by 9
“In one series of non-small cell lung cancer patients treated with the tyrosine kinase inhibitor crizotinib, 5 of the 11 (45%) who had received prior ICI experienced grade 3 or 4 hepatotoxicity, whereas in the remaining cohort who only received crizotinib, this event only occurred in 8% of patients [28].”
Li, Z., Zhou, Z., Zhang, N., Tian, B., Chen, X., Zhao, H., & Wang, H. (2024) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-024-03858-4 · Cited by 13
RET‐rearranged non‐small‐cell lung cancer and therapeutic implications
Loh, Z., Mitchell, P., John, T., & Arulananda, S. (2019) · Internal Medicine Journal · doi:10.1111/imj.14654 · Cited by 8
Current treatment and novel insights regarding ROS1 ‐targeted therapy in malignant tumors
Li, S., Zhang, H., Chen, T., Zhang, X., & Shang, G. (2024) · Cancer Medicine · doi:10.1002/cam4.7201 · Cited by 8
Petrella, F., Cara, A., Cassina, E. M., Degiovanni, S., Libretti, L., Torto, S. L., Pirondini, E., Raveglia, F., Spinelli, F., Tuoro, A., et al. (2025) · Cancers · doi:10.3390/cancers17111844 · Cited by 7
“Similarly, combining immunotherapy with targeted therapy does not provide an additional advantage [65–67].”
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 6
“[53] reported that sequential treatment with ICB followed by crizotinib was also associated with increased hepatotoxicity, suggesting that the sequence of therapy is critical.”
BackgroundNogami, N., Nakamura, A., Shiraiwa, N., Kikkawa, H., Emir, B., Wiltshire, R., & Morise, M. (2023) · Future Oncology · doi:10.2217/fon-2023-0109 · Cited by 6
Myall, N. J., & Das, M. S. (2024) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2024.101133 · Cited by 6
Wang, S., Shi, Y., & Han, X. (2020) · PubMed Central · doi:10.3779/j.issn.1009-3419.2020.101.44 · Cited by 6
Severe hepatotoxicity during treatment with capmatinib
Soto, C. M. V., Callejo, V. M., Fernández-Cueto, A. G.-A., Palomares, M. V. V., Villanueva, S. B., Sufrategui, M. O., Piqueras, M. F. L.-B., & Domínguez, M. V. (2023) · Journal of Oncology Pharmacy Practice · doi:10.1177/10781552231173120 · Cited by 6
Cheung, J. M., Waliany, S., Yeap, B. Y., Peterson, J. L., Liu, A., Do, A., Liang, J., & Lin, J. J. (2025) · ESMO Open · doi:10.1016/j.esmoop.2025.105842 · Cited by 5
Self-citationSong, Z., Li, Z., Zhang, Y., Wang, P., Jiang, L., Zhao, Y., Zhou, J., Wang, X., Zhuang, W., Shi, J., et al. (2025) · European Journal of Cancer · doi:10.1016/j.ejca.2025.116153 · Cited by 5
Chung, C., & Umoru, G. (2024) · Journal of Oncology Pharmacy Practice · doi:10.1177/10781552241242684 · Cited by 5
“154 The ef fi cacy of ICIs with rare oncogenic drivers (e.g. BRAF , HER2 , and MET ) had been studied in a retrospective analysis in a cohort (n = 82) that harbored nonclassic EGFR / ALK gene alterations versus nonselected real-world cohort (n = 278) with ICIs.”
Catania, C., Filippi, A. R., Sangalli, C., Piperno, G., Russano, M., Greco, C., Scotti, V., Proto, C., Bennati, C., Paolo, M. D. P., et al. (2023) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2023.104108 · Cited by 6
Kemper, M., Elges, S., Kies, P., Wiebe, K., Lenz, G., Bleckmann, A., & Evers, G. (2024) · Translational Lung Cancer Research · doi:10.21037/tlcr-24-359 · Cited by 4
“In addition, the choice of neoadjuvant therapy may affect the side effects of subsequent lines of treatment, as sequential immunotherapy and targeted therapy are known to be associated with a significantly increased risk of severe immune-related adverse events, such as hepatotoxicity (22,72,73).”
Piper-Valillo, A. J., Sehgal, K., Costa, D. B., & Rangachari, D. (2019) · Translational Lung Cancer Research · doi:10.21037/tlcr.2019.05.12 · Cited by 4
“Perhaps of even greater concern, there is mounting evidence that use of ICIs sequentially or in combination with TKIs like crizotinib in ALK-, ROS-1-, and MET-altered NSCLC as well as osimertinib in EGFR-mutated NSCLC can be associated with high-grade TKI- and ICI-related AEs, in some cases requiring permanent discont…”
BackgroundChou, M.-Y., & Yang, M. (2025) · Translational Oncology · doi:10.1016/j.tranon.2025.102353 · Cited by 4
“Similarly, POPLAR found no OS benefit with atezolizumab vs. docetaxel in this subgroup (HR 0.99 vs. 0.70 in WT) [121,122].”
InfluentialPhase 1 Study of the Selective c-MET Inhibitor, HS-10241, in Patients With Advanced Solid Tumors
Dong, X., Li, X., Chen, J., Ma, S., Mu, D., Hu, J., & Lü, S. (2022) · JTO Clinical and Research Reports · doi:10.1016/j.jtocrr.2022.100449 · Cited by 4
“such as the recently approved savolitinib in the People’s Republic of China and a first-line drug crizotinib.(8,14,15) In addition, a case of tepotinib leading to intolerable peripheral edema in the patient was reported; however, MET inhibitor could be continued by switching to capmatinib.”
BackgroundThe safety profile of EGFR/ALK-TKIs administered immediately before or after ICIs in advanced NSCLC
Liao, D., Yu, L., Chen, S., Liu, G., Tang, J., & Yang, N. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.109787 · Cited by 5
The role of immunotherapy in fusion-driven lung cancer
Tan, A. C., Chan, J., & Khasraw, M. (2021) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2021.1899816 · Cited by 4
“Higher rates of hepatic toxicity for example, have been reported with sequential ALK TKI after immune checkpoint inhibitor therapy [38] and the combination of nivolumab and crizotinib [39].”
BackgroundRisk factors and prediction for DILI in clinical practice
Björnsson, H. K., & Bjornsson, E. S. (2025) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2025.2468200 · Cited by 3
“However, a study on patients treated with crizotinib, a tyrosine kinase inhibitor used against non-small cell lung cancer, indicated that prior CPI treatment was a risk factor for crizotinib-DILI [77].”
InfluentialTargeted Therapy for Non–Small Cell Lung Cancer
Brea, E. J., & Rotow, J. K. (2023) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2023.02.009 · Cited by 4
Desai, A. P., & Dimou, A. (2023) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2023.07.013 · Cited by 3
An update on Alectinib: a first line treatment for ALK-positive advanced lung cancer
Zhou, Y., Yin, Y., Xu, J., Xu, Z., Yang, B., He, Q., Luo, P., Yan, H., & Yang, X. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2221786 · Cited by 2
“[106] found that patients treated with ICI followed by crizotinib had a much higher rate of grade 3 or 4 elevations in ALT (45% vs 8%) or AST (36% vs 3%) levels than patients treated with crizotinib only.”
Background
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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