Abstract
Background: Cabozantinib, a tyrosine kinase inhibitor, is a standard-of-care therapy for previously treated advanced renal cell carcinoma, hepatocellular carcinoma, and radioiodine-refractory differentiated thyroid cancer. We evaluated the impact of cabozantinib-associated adverse events (AEs) on treatment outcomes in these populations. Here we report our findings and discuss AE management. Methods: In this post-hoc analysis of three cabozantinib monotherapy pivotal studies (METEOR, CELESTIAL, and COSMIC-311), we compared progression-free survival (PFS) and treatment duration between patients who experienced ≥ 1 any-cause grade ≥ 3 AE and the overall population in the cabozantinib arm of each study. We characterized the most common any-cause AEs leading to dose modification, and advanced practitioner authors provided AE management strategies. Results: Of 923 cabozantinib-treated patients across the studies, the most common grade 3/4 AEs occurring in ≥ 10% of patients in all three studies combined were hypertension (15%), palmar-plantar erythrodysesthesia syndrome (13%), diarrhea (10%), and fatigue (10%). In each trial, median PFS was similar in patients with a grade ≥ 3 AE vs. the respective overall study populations; treatment durations were also similar. Among the four most common any-grade AEs leading to dose modifications, discontinuation rates due to each event were low (< 3%). Advanced practitioner–led AE management strategies included prophylaxis, monitoring, supportive care, and dose modifications. Conclusions: Cabozantinib has a consistent safety profile across indications. With proactive management, patients experiencing grade ≥ 3 AEs had similar PFS outcomes and treatment durations as the overall study populations. Advanced practitioner–led proactive AE management can allow patients to remain on therapy and maximize clinical benefits.
References
Abou-Alfa, G. K., Meyer, T., Cheng, A.-L., El-Khoueiry, A. B., Rimassa, L., Ryoo, B.-Y., Cicin, I., Merle, P., Chen, Y., Park, J. W., Blanc, J. F., Bolondi, L., Klümpen, H. J., Chan, S. L., Zagonel, V., Pressiani, T., Ryu, M. H., Venook, A. P., Hessel, C.,…Kelley, R. K. (2018). Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. The New England Journal of Medicine, 379(1), 54–63. https://doi.org/10.1056/NEJMoa1717002
Albiges, L., Powles, T., Sharma, A., Venugopal, B., Bedke, J., Borkowetz, A., Gravis, G., Özdemir, B. C., Schnabel, M. S., Dutailly, P., Qvick, B., Perrot, V., & Grünwald, V. (2026). CaboPoint: A phase 2 study of second-line cabozantinib after checkpoint inhibitor-based combination therapy in patients with metastatic renal cell carcinoma. European Urology, 89(3), 210–219. https://doi.org/10.1016/j.eururo.2025.07.018
Basch, E., Deal, A. M., Kris, M. G., Scher, H. I., Hudis, C. A., Sabbatini, P., Rogak, L., Bennett, A. V., Dueck, A. C., Atkinson, T. M., Chou, J. F., Dulko, D., Sit, L., Barz, A., Novotny, P., Fruscione, M., Sloan, J. A., & Schrag, D. (2016). Symptom monitoring with patient-reported outcomes during routine cancer treatment: A randomized controlled trial. Journal of Clinical Oncology, 34(6), 557–565. https://doi.org/10.1200/JCO.2015.63.0830
Belum, V. R., Serna-Tamayo, C., Wu, S., & Lacouture, M. E. (2015). Incidence and risk of hand–foot skin reaction with cabozantinib, a novel multikinase inhibitor: A meta-analysis. Clinical and Experimental Dermatology, 41(1), 8–15. https://doi.org/10.1111/ced.12694
Bergerot, P., Lamb, P., Wang, E., & Pal, S. K. (2019). Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: Rationale and clinical evidence. Molecular Cancer Therapeutics, 18(12), 2185–2193. https://doi.org/10.1158/1535-7163.MCT-18-1399
Bower, J. E., Lacchetti, C., Alici, Y., Barton, D. L., Bruner, D., Canin, B. E., Escalante, C. P., Ganz, P. A., Garland, S. N., Gupta, S., Jim, H., Ligibel, J. A., Loh, K. P., Peppone, L., Tripathy, D., Yennu, S., Zick, S., & Mustian, K. (2024). Management of fatigue in adult survivors of cancer: ASCO–Society for Integrative Oncology guideline update. Journal of Clinical Oncology, 42(20), 2456–2487. https://doi.org/10.1200/JCO.24.00541
Brose, M. S., Robinson, B. G., Sherman, S. I., Jarzab, B., Lin, C., Vaisman, F., Hoff, A. O., Hitre, E., Bowles, D. W., Sen, S., Oliver, J. W., Banerjee, K., Keam, B., & Capdevila, J. (2022). Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: Updated results from the phase 3 COSMIC-311 trial. Cancer, 128(24), 4203–4212. https://doi.org/10.1002/cncr.34493
Brose, M. S., Robinson, B., Sherman, S. I., Krajewska, J., Lin, C. C., Vaisman, F., Hoff, A. O., Hitre, E., Bowles, D. W., Hernando, J., Faoro, L., Banerjee, K., Oliver, J. W., Keam, B., & Capdevila, J. (2021). Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): A randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology, 22(8), 1126–1138. https://doi.org/10.1016/S1470-2045(21)00332-6
Choueiri, T. K., Escudier, B., Powles, T., Mainwaring, P. N., Rini, B. I., Donskov, F., Hammers, H., Hutson, T. E., Lee, J. L., Peltola, K., Roth, B. J., Bjarnason, G. A., Géczi, L., Keam, B., Maroto, P., Heng, D. Y., Schmidinger, M., Kantoff, P. W., Borgman-Hagey, A.,…Motzer, R. J.; METEOR Investigators (2015). Cabozantinib versus everolimus in advanced renal-cell carcinoma. The New England Journal of Medicine, 373(19), 1814–1823. https://doi.org/10.1056/NEJMoa1510016
Choueiri, T. K., Escudier, B., Powles, T., Tannir, N. M., Mainwaring, P. N., Rini, B. I., Hammers, H. J., Donskov, F., Roth, B. J., Peltola, K., Lee, J. L., Heng, D. Y. C., Schmidinger, M., Agarwal, N., Sternberg, C. N., McDermott, D. F., Aftab, D. T., Hessel, C., Scheffold, C.,…Motzer, R. J.; METEOR investigators (2016). Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): Final results from a randomised, open-label, phase 3 trial. The Lancet Oncology, 17(7), 917–927. https://doi.org/10.1016/S1470-2045(16)30107-3
Colombo, C., De Leo, S., Trevisan, M., Giancola, N., Scaltrito, A., & Fugazzola, L. (2022). Daily management of patients on multikinase inhibitors’ treatment. Frontiers in Oncology, 12, 903532. https://doi.org/10.3389/fonc.2022.903532
De Leo, A., Di Simone, E., Spano, A., Puliani, G., & Petrone, F. (2021). Nursing management and adverse events in thyroid cancer treatments with tyrosine kinase inhibitors. A narrative review. Cancers, 13(23), 5961. https://doi.org/10.3390/cancers13235961
Exelixis, Inc. (2025). Cabometyx (cabozantinib) package insert. https://www.cabometyxhcp.com/sites/default/files/2021-03/prescribing-information.pdf
Gerendash, B. S., & Creel, P. A. (2017). Practical management of adverse events associated with cabozantinib treatment in patients with renal-cell carcinoma. OncoTargets and Therapy, 10, 5053–5064. https://doi.org/10.2147/OTT.S145295
Gordan, J. D., Kennedy, E. B., Abou-Alfa, G. K., Beal, E., Finn, R. S., Gade, T. P., Goff, L., Gupta, S., Guy, J., Hoang, H. T., Iyer, R., Jaiyesimi, I., Jhawer, M., Karippot, A., Kaseb, A. O., Kelley, R. K., Kortmansky, J., Leaf, A., Remak, W. M., Sohal, D. P. S.,…Rose, M. G. (2024). Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline update. Journal of Clinical Oncology, 42(15), 1830–1850. https://doi.org/10.1200/JCO.23.02745
Ipsen Pharma. (2025). Cabometyx [summary of product characteristics]. https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf
Jimenez, C., Habra, M. A., Campbell, M. T., Tamsen, G., Cruz-Goldberg, D., Long, J., Bassett, R., Dantzer, R., Balderrama-Brondani, V., Varghese, J., & Lu, Y. (2024). Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): A single-arm, phase 2 trial. The Lancet Oncology, 25(5), 658–667. https://doi.org/10.1016/S1470-2045(24)00133-5
Johnston, H., Deal, A. M., Morgan, K. P., Patel, B., Milowsky, M. I., & Rose, T. L. (2023). Dose intensity in real-world patients with metastatic renal cell carcinoma taking vascular endothelial growth factor receptor tyrosine kinase inhibitors. Clinical Genitourinary Cancer, 21(3), 357–365. https://doi.org/10.1016/j.clgc.2023.02.007
Jones, D. W., Ferdinand, K. C., Taler, S. J., Johnson, H. M., Shimbo, D., Abdalla, M., Altieri, M. M., Bansal, N., Bello, N. A., Bress, A. P., Carter, J., Cohen, J. B., Collins, K. J., Commodore-Mensah, Y., Davis, L. L., Egan, B., Khan, S. S., Lloyd-Jones, D. M., Melnyk, B. M., Mistry, E. A.,…Williamson, J. D. (2025). 2025 AHA/ACC/AANP/AAPA/ABC/ACCP/ACPM/AGS/AMA/ASPC/NMA/PCNA/SGIM guideline for the prevention, detection, evaluation and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Hypertension, 82(10), e212–e316. https://doi.org/10.1161/HYP.0000000000000249
Kang, Y.-E., Yoon, J.-H., Park, N., Ahn, Y.-C., Lee, E.-J., & Son, C.-G. (2023). Prevalence of cancer-related fatigue based on severity: a systematic review and meta-analysis. Scientific Reports, 13(1), 12815. https://doi.org/10.1038/s41598-023-39046-0
Kwakman, J. J. M., Elshot, Y. S., Punt, C. J. A., & Koopman, M. (2020). Management of cytotoxic chemotherapy-induced hand-foot syndrome. Oncology Reviews, 14(1), 442. https://doi.org/10.4081/oncol.2020.442
National Cancer Institute. (2017). Common terminology criteria for adverse events (CTCAE) version 5.0. U.S. Department of Health and Human Services. https://dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events/ctcae-v5-8x11.pdf
Pal, S. K., Albiges, L., Tomczak, P., Suárez, C., Voss, M. H., de Velasco, G., Chahoud, J., Mochalova, A., Procopio, G., Mahammedi, H., Zengerling, F., Kim, C., Osawa, T., Angel, M., Gupta, S., Khan, O., Bergthold, G., Liu, B., Kalaitzidou, M., Huseni, M., Scheffold, C., Powles, T., & Choueiri, T. K. (2023). Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): A multicentre, randomised, open-label, phase 3 trial. Lancet, 402(10397), 185–195. https://doi.org/10.1016/S0140-6736(23)00922-4
Pandey, S., Kalaria, A., Jhaveri, K. D., Herrmann, S. M., & Kim, A. S. (2023). Management of hypertension in patients with cancer: challenges and considerations. Clinical Kidney Journal, 16(12), 2336–2348. https://doi.org/10.1093/ckj/sfad195
Rathmell, W. K., Rumble, R. B., Van Veldhuizen, P. J., Al-Ahmadie, H., Emamekhoo, H., Hauke, R. J., Louie, A. V., Milowsky, M. I., Molina, A. M., Rose, T. L., Siva, S., Zaorsky, N. G., Zhang, T., Qamar, R., Kungel, T. M., Lewis, B., & Singer, E. A. (2022). Management of metastatic clear cell renal cell carcinoma: ASCO guideline. Journal of Clinical Oncology, 40(25), 2957–2995. https://doi.org/10.1200/JCO.22.00868
Rimassa, L., Danesi, R., Pressiani, T., & Merle, P. (2019). Management of adverse events associated with tyrosine kinase inhibitors: Improving outcomes for patients with hepatocellular carcinoma. Cancer Treatment Reviews, 77, 20–28. https://doi.org/10.1016/j.ctrv.2019.05.004
Ringel, M. D., Sosa, J. A., Baloch, Z., Bischoff, L., Bloom, G., Brent, G. A., Brock, P. L., Chou, R., Flavell, R. R., Goldner, W., Grubbs, E. G., Haymart, M., Larson, S. M., Leung, A. M., Osborne, J., Ridge, J. A., Robinson, B., Steward, D. L., Tufano, R. P., & Wirth, L. J. (2025). 2025 American Thyroid Association management guidelines for adult patients with differentiated thyroid cancer. Thyroid, 35(8), 841–985. https://doi.org/10.1177/10507256251363120
Schmidinger, M., & Danesi, R. (2018). Management of adverse events associated with cabozantinib therapy in renal cell carcinoma. The Oncologist, 23(3), 306–315. https://doi.org/10.1634/theoncologist.2017-0335
Schwartz, G., Darling, J. O., Mindo, M., & Damicis, L. (2020). Management of adverse events associated with cabozantinib treatment in patients with advanced hepatocellular carcinoma. Targeted Oncology, 15(4), 549–565. https://doi.org/10.1007/s11523-020-00736-8
Tahara, M. (2018). Management of recurrent or metastatic thyroid cancer. ESMO Open, 3(Suppl 1), e000359. https://doi.org/10.1136/esmoopen-2018-000359
Unger, T., Borghi, C., Charchar, F., Khan, N. A., Poulter, N. R., Prabhakaran, D., Ramirez, A., Schlaich, M., Stergiou, G. S., Tomaszewski, M., Wainford, R. D., Williams, B., & Schutte, A. E. (2020). 2020 International Society of Hypertension global hypertension practice guidelines. Journal of Hypertension, 38(6), 982–1004. https://doi.org/10.1097/HJH.0000000000002453
Yakes, F. M., Chen, J., Tan, J., Yamaguchi, K., Shi, Y., Yu, P., Qian, F., Chu, F., Bentzien, F., Cancilla, B., Orf, J., You, A., Laird, A. D., Engst, S., Lee, L., Lesch, J., Chou, Y. C., & Joly, A. H. (2011). Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Molecular Cancer Therapeutics, 10(12), 2298–2308. https://doi.org/10.1158/1535-7163.MCT-11-0264
