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Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review

Open AccessPublished:December 23, 2021DOI:https://doi.org/10.1016/j.ctrv.2021.102333

      Highlights

      • Cabozantinib + nivolumab is a first-line therapy for patients with advanced RCC.
      • Proper AE management improves safety, prolongs treatment, and may optimize efficacy.
      • Cabozantinib AEs are managed with prophylaxis, dose modification, and supportive care.
      • Immune-related AEs may require nivolumab dose holds and immunosuppressive therapy.
      • Providers should be aware of overlapping AEs and how to manage them.

      Abstract

      Tyrosine kinase inhibitors have been successfully developed in combination with immune checkpoint inhibitors to treat advanced renal cell carcinoma (RCC), further advancing treatment. While safety profiles are generally manageable with combination regimens, overlapping adverse events (AEs) and immune-related AEs can make treatment more complex. The CheckMate 9ER study evaluated the tyrosine kinase inhibitor cabozantinib in combination with the anti-programmed cell death protein-1 antibody nivolumab in patients with previously untreated advanced RCC. Cabozantinib + nivolumab demonstrated superiority over sunitinib for progression-free survival, overall survival, and objective response rate. These outcomes supported the approval of cabozantinib + nivolumab as a first-line therapy for advanced RCC. The safety profile was manageable with prophylaxis, supportive care, dose holds and reductions for cabozantinib, and dose holds and immunosuppressive therapy for nivolumab. This review discusses the safety results of CheckMate 9ER and provides guidance on managing some of the more clinically relevant AEs with a focus on overlapping AEs, including diarrhea, elevated amylase/lipase, hepatotoxicity, dermatologic reactions, fatigue, endocrine disorders, and nephrotoxicity. We discuss AE management strategies (prophylaxis, supportive care, dose modification, and immunosuppressive therapy), and provide recommendations for identifying the causative agent of overlapping AEs and for consulting specialists about organ-specific immune-related AEs. Optimizing AE management can maintain tolerability and should be a priority with cabozantinib + nivolumab treatment.

      Graphical abstract

      Keywords

      Introduction

      Treatment of advanced clear-cell renal cell carcinoma (RCC) has improved in recent years with the introduction of novel tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs [PD-L1, PD-1, and CTLA-4 inhibitors]) [
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      ]. Due to the angiogenic nature of RCC, TKIs targeting the vascular endothelial growth factor receptor (VEGFR) have been a cornerstone of therapy, providing improved disease control and survival with manageable safety profiles [
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      ]. RCC is also immunogenic [
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      ], which led to the development of ICIs in RCC as single-agents, in dual ICI combinations, and in combination with TKIs that have immunomodulatory activity that may enhance the immune response to ICIs [
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      ]. ICIs have demonstrated manageable safety profiles in RCC and other solid tumors, although they are associated with a spectrum of immune-related adverse events (irAEs), some serious but rarely fatal [
      • Motzer R.J.
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      • George S.
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      ]. Management of irAEs can be complex and may require immunosuppressive therapy (corticosteroids, mycophenolate mofetil, and others) [

      Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(4 suppl):iv264–iv6.

      ,

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ,
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      ]. First-line TKI-ICI combinations have shown superior outcomes versus sunitinib, a previous standard of care [
      • Motzer R.J.
      • Penkov K.
      • Haanen J.
      • Rini B.
      • Albiges L.
      • Campbell M.T.
      • et al.
      Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Motzer R.
      • Alekseev B.
      • Rha S.-Y.
      • Porta C.
      • Eto M.
      • Powles T.
      • et al.
      Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
      ]. Safety and tolerability with these combinations are manageable, although overlapping adverse events (AEs) between TKIs and ICIs can complicate AE management. TKI-ICI combinations approved for first-line advanced RCC include axitinib + avelumab, axitinib + pembrolizumab, lenvatinib + pembrolizumab, and cabozantinib + nivolumab [
      • Motzer R.J.
      • Penkov K.
      • Haanen J.
      • Rini B.
      • Albiges L.
      • Campbell M.T.
      • et al.
      Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Rini B.I.
      • Plimack E.R.
      • Stus V.
      • Gafanov R.
      • Hawkins R.
      • Nosov D.
      • et al.
      Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Motzer R.
      • Alekseev B.
      • Rha S.-Y.
      • Porta C.
      • Eto M.
      • Powles T.
      • et al.
      Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
      ,
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ].
      The TKI cabozantinib targets multiple tyrosine kinase receptors—VEGFR, MET, the TAM family of kinases (TYRO3, AXL, MER), TIE-2, RET, FLT-3, KIT, and ROS1. VEGFR, MET, and the TAM family of kinases are involved in tumor angiogenesis, cell survival, and metastasis [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,
      • Faoro L.
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      • El-Hashani E.
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      MET receptor tyrosine kinase.
      ,
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      Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies.
      ,
      • Smart S.
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      The emerging role of TYRO3 as a therapeutic target in cancer.
      ,
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      • Wei X.
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      ]. Cabozantinib also has immunomodulatory properties that may shift the tumor microenvironment from immunosuppressive to immunopermissive [
      • Apolo A.B.
      • Nadal R.
      • Tomita Y.
      • Davarpanah N.N.
      • Cordes L.M.
      • Steinberg S.M.
      • et al.
      Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.
      ,
      • Kwilas A.R.
      • Ardiani A.
      • Donahue R.N.
      • Aftab D.T.
      • Hodge J.W.
      Dual effects of a targeted small-molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a cancer vaccine.
      ]. The tablet formulation of cabozantinib was approved as a single-agent in advanced RCC after demonstrating a progression-free survival (PFS) and overall survival (OS) benefit in the second-line setting [
      • Choueiri T.K.
      • Halabi S.
      • Sanford B.L.
      • Hahn O.
      • Michaelson M.D.
      • Walsh M.K.
      • et al.
      Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial.
      ]. Guidelines also recommend cabozantinib as a preferred treatment option for patients with RCC with variant histology based on outcomes from the randomized Phase 2 SWOG 1500 trial showing improvement in PFS with cabozantinib over sunitinib in patients with papillary RCC [
      • Pal S.K.
      • Tangen C.
      • Thompson I.M.
      • Balzer-Haas N.
      • George D.J.
      • Heng D.Y.C.
      • et al.
      A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.
      ,

      Motzer RJ, Jonasch E, Agarwal N, Alva A, Baine M, Beckermann K, et al. NCCN Guidelines Version 3.2022 Kidney cancer. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Published November 2021. Accessed December 6, 2021.

      ]. Furthermore, recent data highlights the activity of cabozantinib + nivolumab in patients with papillary/translocation associated/unclassified RCC with objective response rate (ORR) approaching 50%, though there were no objective responses in patients with chromophobe RCC [

      Lee C-H, Voss MH, Carlo MI, Chen Y-B, Reznik E, Knezevic A, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial. J Clin Oncol 2021;39(15 suppl):Abstract 4509.

      ]. Nivolumab is a monoclonal antibody that binds to PD-1, blocking its interaction with PD-L1 and preventing deactivation of T-cells, leading to an improved anti-tumor immune response [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. Single-agent nivolumab was approved after demonstrating an OS benefit in the second-line advanced RCC setting [
      • Motzer R.J.
      • Escudier B.
      • McDermott D.F.
      • George S.
      • Hammers H.J.
      • Srinivas S.
      • et al.
      Nivolumab versus everolimus in advanced renal-cell carcinoma.
      ]. Approval of cabozantinib + nivolumab was based on the Phase 3 CheckMate 9ER study, which evaluated first-line cabozantinib + nivolumab versus sunitinib in patients with advanced RCC [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ].
      In this review we discuss CheckMate 9ER, focusing on the safety profile of cabozantinib + nivolumab. We review pharmacologic properties of these agents in relation to AEs and provide practical guidance on AE management, focusing on overlapping events.

      Methods

      We reviewed the available literature on AE management of TKIs and ICIs, including: guidelines from major oncology societies (eg, the American Society of Clinical Oncology); prescribing information and product monographs for nivolumab and cabozantinib; and online resources for supportive management of treatment-related toxicities (eg, American Cancer Society). We performed PubMed searches focused on AE management for TKI-ICI combinations, selecting primary and review articles from peer-reviewed journals. We also searched PubMed and major oncology conferences for relevant presentations on cabozantinib + nivolumab studies and available study protocols.

      Clinical development of cabozantinib plus nivolumab in RCC

      Phase 1

      Cabozantinib + nivolumab was initially assessed in a Phase 1 study of 54 patients with genitourinary tumors, including RCC [
      • Apolo A.B.
      • Nadal R.
      • Girardi D.M.
      • Niglio S.A.
      • Ley L.
      • Cordes L.M.
      • et al.
      Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors.
      ]. This study evaluated cabozantinib + nivolumab ± ipilimumab. For the dose-escalation stage, cabozantinib was assessed at 40 mg/day or 60 mg/day orally in the combination. Nivolumab was dosed at 1 or 3 mg/kg every 2 weeks (Q2W) intravenously (IV) for the first 21 cycles (28 days per cycle) of treatment, followed by a maintenance dose of 480 mg every 4 weeks (Q4W). While there were no dose-limiting toxicities with cabozantinib 60 mg/day, grade 1/2 AEs and dose modifications were frequent. The study supported advancement of cabozantinib 40 mg/day plus nivolumab 3 mg/kg Q2W. For the triplet, ipilimumab 1 mg/kg IV was added, with both nivolumab and ipilimumab given every 3 weeks for the first four cycles (21 days per cycle), followed by maintenance with cabozantinib + nivolumab. Both regimens demonstrated promising clinical activity and tolerable safety profiles with dose modification. The ORR was 39.1% for cabozantinib + nivolumab and 26.9% for the triplet. Grade 3/4 treatment-related AEs (TRAEs) occurred in 75% of patients with cabozantinib + nivolumab and 87% with the triplet. There were no grade 5 TRAEs. These results supported further development of cabozantinib + nivolumab and initiation of CheckMate 9ER and the ongoing COSMIC-313 study exploring the triplet versus nivolumab + ipilimumab (NCT03937219).

      CheckMate 9ER

      CheckMate 9ER was a global, randomized, open-label, Phase 3 trial assessing cabozantinib + nivolumab versus sunitinib in 651 patients with previously untreated advanced clear-cell RCC [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. Patients received cabozantinib 40 mg/day orally plus nivolumab 240 mg IV Q2W (n = 323) or sunitinib 50 mg/day orally for 4 weeks on and 2 weeks off (n = 328). Treatment was continued until unacceptable toxicity or disease progression (maximum 2 years on nivolumab) [

      Choueiri TK, Powles T, Burotto M, et al. Clinical protocol CA2099ER: A phase 3, randomized, open-label study of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib versus sunitinib in participants with previously untreated, advanced or metastatic renal cell carcinoma. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2026982/suppl_file/nejmoa2026982_protocol.pdf. Published March 2021. Accessed March 23, 2021.

      ]. Although the 3 mg/kg nivolumab dose was used in the Phase 1 study, pharmacokinetic and exposure–response analyses have demonstrated that the flat-dose regimen (240 mg Q2W or 480 mg Q4W) has a comparable benefit-risk profile to weight-based dosing and may be more convenient [
      • Bei D.i.
      • Osawa M.
      • Uemura S.
      • Ohno T.
      • Gobburu J.
      • Roy A.
      • et al.
      Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers.
      ,
      • Zhao X.
      • Suryawanshi S.
      • Hruska M.
      • Feng Y.
      • Wang X.
      • Shen J.
      • et al.
      Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors.
      ].
      At a median follow-up of 18.1 months, cabozantinib + nivolumab demonstrated superiority over sunitinib for the primary endpoint of PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent central review (BICR), with a doubling of the median at 16.6 versus 8.3 months (hazard ratio [HR], 0.51 [95% confidence interval {CI} 0.41–0.64], P < 0.001) [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. The combination also demonstrated superiority for OS, with a 12-month rate of 85.7% for cabozantinib + nivolumab and 75.6% for sunitinib (HR, 0.60 [98.89% CI, 0.40–0.89], P = 0.001). ORR by BICR was 55.7% for the combination versus 27.1% for sunitinib (P < 0.001), with complete response rates of 8% versus 5%.
      Dose delay and reduction were allowed with cabozantinib to manage grade ≥ 3 TRAEs and grade 2 TRAEs that persisted > 1 week or could not be managed with supportive care [

      Choueiri TK, Powles T, Burotto M, et al. Clinical protocol CA2099ER: A phase 3, randomized, open-label study of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib versus sunitinib in participants with previously untreated, advanced or metastatic renal cell carcinoma. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2026982/suppl_file/nejmoa2026982_protocol.pdf. Published March 2021. Accessed March 23, 2021.

      ]. Once the AE resolved to grade ≤ 1 with a dose hold, cabozantinib could be resumed at a lower dose (40 mg/day to 20 mg/day and then to 20 mg/every other day). Dose reduction was not required for grade 3 hypertension that improved with anti-hypertensives and grade 2/3 laboratory abnormalities that improved to grade ≤ 1 within 7 days using supportive care. Dose reduction was not allowed with nivolumab, but dose holding was recommended for certain grade ≥ 2 irAEs (eg, non-skin irAEs, grade 2 creatinine, aspartate/alanine aminotransferase [AST/ALT], or bilirubin abnormalities) and grade 3 skin AEs or other laboratory abnormalities until resolution to grade ≤ 1 or baseline and completion of immunosuppressive therapy if required.
      Nearly all patients (≥99%) in both arms experienced a treatment-emergent AE (TEAE) of any grade, with grade ≥ 3 rates of 75% for cabozantinib + nivolumab versus 71% for sunitinib [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. The most common TEAEs of any grade in the cabozantinib + nivolumab arm were diarrhea (64%), palmar-plantar erythrodysesthesia (PPE; 40%), hypertension (35%), hypothyroidism (34%), fatigue (32%), increased ALT (28%), decreased appetite (28%), and nausea (27%) (Fig. 1). The most common grade ≥ 3 TEAEs were hypertension (13%), hyponatremia (9%), PPE (8%), diarrhea (7%), increased lipase (6%), hypophosphatemia (6%), increased ALT (5%), asthenia (4%), increased AST (3%), fatigue (3%), and increased amylase (3%). The most common irAEs of any grade included hypothyroidism (25%), hyperthyroidism (9%), and rash (6%). Grade ≥ 3 irAEs were uncommon, the most frequent being hepatotoxicity (3%), increased ALT (2%), adrenal insufficiency (2%), and diarrhea (2%). In the cabozantinib + nivolumab arm, there were three deaths (0.9%) due to intestinal perforation [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. It is worth noting that the open-label design of CheckMate 9ER may have led to overestimation of some adverse events [
      • Trone J.C.
      • Ollier E.
      • Chapelle C.
      • Bertoletti L.
      • Cucherat M.
      • Mismetti P.
      • et al.
      Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events-a meta-analysis.
      ].
      Figure thumbnail gr1
      Fig. 1Summary of select treatment-emergent and immune-related adverse events (% any grade, % grade ≥ 3) in the cabozantinib + nivolumab arm of CheckMate 9ER
      [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]
      . *irAE; associated with cabozantinib only. ALT: alanine aminotransferase; AST: aspartate aminotransferase; irAE: immune-related adverse event; PPE: palmar-plantar erythrodysesthesia. Template reproduced from Powered Template (https://poweredtemplate.com/human-anatomy-%E2%80%93-infographic-54841/).
      Dose holds were required by 72% of patients for nivolumab and 68% for cabozantinib [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. Dose reductions of cabozantinib occurred for 56% of patients [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. First-level dose reductions due to AEs occurred for 50%; 8% required a second-level dose reduction to 20 mg every other day due to AEs [

      Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC). Presented at the ASCO virtual meeting, June 4-8, 2021. https://meetinglibrary.asco.org/record/197689/poster. Accessed June 21, 2021.

      ]; the median average daily dose was 29.4 mg [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ,

      Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC). Presented at the ASCO virtual meeting, June 4-8, 2021. https://meetinglibrary.asco.org/record/197689/poster. Accessed June 21, 2021.

      ]. Twenty percent of patients receiving cabozantinib + nivolumab discontinued at least one agent due to AEs, with 6% discontinuing both [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. Nineteen percent of patients experienced an irAE requiring corticosteroid treatment at ≥ 40 mg of prednisone daily or equivalent, with 10% and 4% of patients receiving continuous treatment for ≥ 14 days and ≥ 30 days, respectively.
      The change in health-related quality of life (QoL) from baseline was assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. QoL was maintained over time in the combination arm versus a consistent deterioration in the sunitinib arm. Disease related symptoms (DRS) were evaluated using FKSI-DRS and showed that DRS improved from baseline during treatment with the combination and declined with sunitinib. This is in contrast to other TKI-ICI combinations where QoL was comparable with sunitinib [

      Uro Today. EAU 2020: Health-related quality-of-life analysis from KEYNOTE-426: pembrolizumab plus axitinib vs sunitinib for advanced renal cell carcinoma. https://www.urotoday.com/conference-highlights/eau-2020/kidney-cancer/123218-eau-2020-health-related-quality-of-life-analysis-from-keynote-426-pembrolizumab-plus-axitinib-vs-sunitinib-for-advanced-renal-cell-carcinoma.html?pk_campaign=Bedke_SocialEAU20_123218. Published 2020. Accessed December 13, 2021.

      ,

      Motzer RJ, Porta C, Alekseev B, Rha SY, Choueiri TK, Mendez-Vidal MJ, et al. Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol;39(15 suppl):Abstract 4502.

      ].
      The safety profile of cabozantinib 40 mg in the combination was generally consistent with studies of single-agent cabozantinib 60 mg in RCC, with comparable rates for dose reduction and treatment discontinuation due to AEs [
      • Choueiri T.K.
      • Halabi S.
      • Sanford B.L.
      • Hahn O.
      • Michaelson M.D.
      • Walsh M.K.
      • et al.
      Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial.
      ,
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • Mainwaring P.N.
      • Rini B.I.
      • Donskov F.
      • et al.
      Cabozantinib versus everolimus in advanced renal-cell carcinoma.
      ,
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. The rates of some AEs appeared to differ among these studies (Supplementary Table 1), including fatigue (32% CheckMate 9ER vs 56% METEOR vs 64% CABOSUN), hypothyroidism (34% vs 20% vs 23%), and AST elevations (28% vs 16% vs 55%) [
      • Choueiri T.K.
      • Halabi S.
      • Sanford B.L.
      • Hahn O.
      • Michaelson M.D.
      • Walsh M.K.
      • et al.
      Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial.
      ,
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • Mainwaring P.N.
      • Rini B.I.
      • Donskov F.
      • et al.
      Cabozantinib versus everolimus in advanced renal-cell carcinoma.
      ,
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. Cabozantinib was also recently evaluated in patients with RCC at 40 mg and 60 mg in combination with the ICI atezolizumab in the Phase 1b COSMIC-021 study [
      • Pal S.K.
      • Tangen C.
      • Thompson I.M.
      • Balzer-Haas N.
      • George D.J.
      • Heng D.Y.C.
      • et al.
      A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.
      ]. Rates of TRAEs were similar between the 40 and 60 mg arms, with 71% and 67% of patients, respectively, experiencing a grade 3/4 TRAE; however, rates of any grade PPE (29% for 40 mg vs 56% for 60 mg), dysgeusia (35% vs 58%), decreased appetite (24% vs 53%), and proteinuria (6% vs 22%) were higher in the 60 mg arm. Rates of dose holds were similar (94% for 40 mg vs 92% for 60 mg), but the 60 mg arm had a higher rate of dose reductions (56% vs 86%) while the 40 mg arm had a higher rate of discontinuations (18% vs 8%). The safety results from COSMIC-021 are consistent with those reported in the Phase 1 study of cabozantinib + nivolumab [
      • Apolo A.B.
      • Nadal R.
      • Girardi D.M.
      • Niglio S.A.
      • Ley L.
      • Cordes L.M.
      • et al.
      Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors.
      ].

      Cabozantinib AEs

      VEGFR plays important roles in normal bodily processes; thus, non-tumor inhibition of VEGFR with cabozantinib is associated with multiple AEs, including PPE, hypertension, gastrointestinal AEs, and proteinuria [
      • Facemire C.S.
      • Nixon A.B.
      • Griffiths R.
      • Hurwitz H.
      • Coffman T.M.
      Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression.
      ,
      • Schmidinger M.
      • Danesi R.
      Management of adverse events associated with cabozantinib therapy in renal cell carcinoma.
      ,
      • Cappagli V.
      • Moriconi D.
      • Bonadio A.G.
      • Giannese D.
      • La Manna G.
      • Egidi M.F.
      • et al.
      Proteinuria is a late-onset adverse event in patients treated with cabozantinib.
      ,
      • Azad N.S.
      • Aragon-Ching J.B.
      • Dahut W.L.
      • Gutierrez M.
      • Figg W.D.
      • Jain L.
      • et al.
      Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy.
      ]. Other AEs associated with cabozantinib include fatigue, thyroid dysfunction, AST/ALT elevations, amylase/lipase elevations, and hypophosphatemia [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      European Medicines Agency. Cabometyx: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ].
      Cabozantinib has a half-life of approximately 99 h [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]; upon dose hold AEs generally begin to resolve within days. Cabozantinib is hepatically metabolized by the CYP3A4 enzyme [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]; therefore, adjustments are required for concomitant use with strong CYP3A4 modifiers to avoid altered exposure. Cabozantinib should be taken on an empty stomach, at least 1 h before or 2 h after eating, due to increased serum concentrations and drug exposure when administered with high-fat meals [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ].
      Generally, cabozantinib AEs occur within weeks of treatment initiation, although some infrequent but serious AEs (eg, fistulas) can occur months after initiation [

      European Medicines Agency. CHMP assessment report: cabometyx. https://www.ema.europa.eu/en/documents/assessment-report/cabometyx-epar-public-assessment-report_en.pdf. Updated July 2016. Accessed January 6, 2021.

      ,
      • Schwartz G.
      • Darling J.O.
      • Mindo M.
      • Damicis L.
      Management of adverse events associated with cabozantinib treatment in patients with advanced hepatocellular carcinoma.
      ,
      • Gerendash B.S.
      • Creel P.A.
      Practical management of adverse events associated with cabozantinib treatment in patients with renal-cell carcinoma.
      ]. High interpatient variability in the clearance of cabozantinib can lead to elevated cabozantinib concentrations in some patients, increasing the risk for AEs. In an exposure–response model of CheckMate 9ER, the predicted risk of dose modification increased with decreasing cabozantinib clearance, while the predicted risk of developing select AEs, including PPE and diarrhea, increased with higher cabozantinib exposure [

      Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC). Presented at the ASCO virtual meeting, June 4-8, 2021. https://meetinglibrary.asco.org/record/197689/poster. Accessed June 21, 2021.

      ]. The exposure–response analysis also predicted no difference in PFS for cabozantinib 40 mg/day versus 20 mg/day with the combination [

      Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC). Presented at the ASCO virtual meeting, June 4-8, 2021. https://meetinglibrary.asco.org/record/197689/poster. Accessed June 21, 2021.

      ]. Thus, dose modification is a common strategy for AE management. Given its half-life, median time of dose holds has ranged from 7─9 days for single-agent cabozantinib [

      Exelixis, Inc. Cabometyx dosing & management. https://www.cabometyxhcp.com/dosing-and-management. Accessed January 18, 2021.

      ]. During CheckMate 9ER, 29.4% of patients held cabozantinib for 1─3 days, 22.1% for 4─7 days, 31.8% for 8─14 days, and 14.3% for 15─42 days (data courtesy of Exelixis). Median time to first cabozantinib dose reduction during CheckMate 9ER was 98 days (range, 9–506) [

      Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC). Presented at the ASCO virtual meeting, June 4-8, 2021. https://meetinglibrary.asco.org/record/197689/poster. Accessed June 21, 2021.

      ].

      Nivolumab irAEs

      Nivolumab’s PD-1 inhibition enhances T-cell proliferation and tumor surveillance [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. It is hypothesized that upregulation of these immune responses can trigger recognition of autoantigens or worsening of underlying inflammation [
      • Postow M.A.
      • Sidlow R.
      • Hellmann M.D.
      Immune-related adverse events associated with immune checkpoint blockade.
      ,
      • Grover S.
      • Rahma O.E.
      • Hashemi N.
      • Lim R.M.
      Gastrointestinal and hepatic toxicities of checkpoint inhibitors: algorithms for management.
      ], resulting in irAEs such as endocrine disorders, hepatotoxicity, diarrhea/colitis, and amylase/lipase elevations [
      • Grover S.
      • Rahma O.E.
      • Hashemi N.
      • Lim R.M.
      Gastrointestinal and hepatic toxicities of checkpoint inhibitors: algorithms for management.
      ,
      • Osorio J.C.
      • Ni A.
      • Chaft J.E.
      • Pollina R.
      • Kasler M.K.
      • Stephens D.
      • et al.
      Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.
      ]. Infrequent but serious irAEs associated with nivolumab include pneumonitis, nephritis, myocarditis, and neurotoxicities; but the mechanisms of these are unknown [
      • Johnson D.B.
      • Balko J.M.
      • Compton M.L.
      • Chalkias S.
      • Gorham J.
      • Xu Y.
      • et al.
      Fulminant myocarditis with combination immune checkpoint blockade.
      ,
      • Naidoo J.
      • Wang X.
      • Woo K.M.
      • Iyriboz T.
      • Halpenny D.
      • Cunningham J.
      • et al.
      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      ,
      • Mamlouk O.
      • Selamet U.
      • Machado S.
      • Abdelrahim M.
      • Glass W.F.
      • Tchakarov A.
      • et al.
      Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience.
      ,
      • Mirabile A.
      • Brioschi E.
      • Ducceschi M.
      • Piva S.
      • Lazzari C.
      • Bulotta A.
      • et al.
      PD-1 inhibitors-related neurological toxicities in patients with non-small-cell lung cancer: a literature review.
      ].
      Presentation of nivolumab irAEs is highly variable, ranging from the early days of therapy to months after treatment discontinuation [
      • Weber J.S.
      • Hodi F.S.
      • Wolchok J.D.
      • Topalian S.L.
      • Schadendorf D.
      • Larkin J.
      • et al.
      Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma.
      ,

      Bristol-Myers Squibb Company. Immune-mediated adverse reactions management guide. https://www.opdivohcp.com/assets/commercial/us/opdivo-hcp-pan-tumor/en/pdf/Immune_Mediated_Adverse_Management_Guide.pdf. Published January 2021. Accessed January 27, 2021.

      ]; thus, for nivolumab AEs that overlap with those associated with cabozantinib, time-to-onset is not a reliable measure to determine the causative agent (Fig. 2). However, nivolumab has a half-life of approximately 25 days [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]; therefore, time to AE resolution after a dose hold is generally longer than that for cabozantinib. In a pooled analysis of nivolumab monotherapy, median time to resolution (range) was 2.1 weeks (0.1–124.4 + ) for colitis, 5.9 weeks (0.1–94.3 + ) for abnormal liver function tests, 12.1 weeks (0.3–79.1 + ) for nephritis or renal dysfunction, and 17.4 weeks (0.1–150.0 + ) for rash [

      European Medicines Agency. Opdivo: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ].
      Figure thumbnail gr2
      Fig. 2Time-to-onset of select adverse events with cabozantinib and nivolumab in combination and as monotherapy [

      European Medicines Agency. Cabometyx: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ,

      European Medicines Agency. Opdivo: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ,

      European Medicines Agency. Opdivo assessment report. https://www.ema.europa.eu/en/documents/variation-report/opdivo-h-c-3985-ii-0092-epar-assessment-report-variation_en.pdf. Published April 2021. Accessed May 18, 2021.

      ]. Data are median (range) for CheckMate 9ER and nivolumab pooled analysis; data are median (IQR) for METEOR. ALT: alanine aminotransferase; AST: aspartate aminotransferase; IQR: interquartile range; ir: immune-related; NR: not reported; PPE: palmar-plantar erythrodysesthesia; ULN: upper limit of normal.

      AE management

      Proper management of AEs may optimize efficacy. Aggressive AE management, including dose modification and patient education, has been shown to significantly improve clinical outcomes [
      • Ravaud A.
      Treatment-associated adverse event management in the advanced renal cell carcinoma patient treated with targeted therapies.
      ,
      • Rini B.I.
      • Melichar B.
      • Ueda T.
      • Grünwald V.
      • Fishman M.N.
      • Arranz J.A.
      • et al.
      Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial.
      ,
      • Ninomiya N.
      • Tamada S.
      • Kato M.
      • Yamasaki T.
      • Iguchi T.
      • Nakatani T.
      Prolonging survival in metastatic renal cell carcinoma patients treated with targeted anticancer agents: a single-center experience of treatment strategy modifications.
      ]. To manage AEs with cabozantinib and nivolumab, dose holds and reductions of cabozantinib are important, in addition to dose holds of nivolumab with or without immunosuppressive therapy. Other strategies include prophylaxis, supportive care, and referral to a specialist. Treatment discontinuation of one or both agents may need to be considered. In this review, AE management is based upon severity, as described in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (Supplementary Table 2) [

      National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Published November 27, 2017. Accessed January 9, 2021.

      ].
      It is essential to identify the causative agent (Fig. 3). For intolerable grade 2 or grade 3/4 cabozantinib AEs, a dose hold with supportive care until resolution to grade ≤ 1 is generally appropriate (Table 1) [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. Cabozantinib may then be restarted at a reduced dose—from 40 mg/day to 20 mg/day, and then to 20 mg every other day [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC). Presented at the ASCO virtual meeting, June 4-8, 2021. https://meetinglibrary.asco.org/record/197689/poster. Accessed June 21, 2021.

      ]. There may be reason to restart cabozantinib at the same dose depending on the nature and severity of the AE, whether it is recurrent, occurs due to cumulative dose or is triggered by other factors (eg, dietary changes associated with GI AEs). If previously receiving 20 mg every other day, cabozantinib may be restarted at the same dose. If the lowest dose is not tolerated, cabozantinib should be discontinued [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. For patients who develop osteonecrosis of the jaw, the risk/benefit of restarting cabozantinib must be carefully considered after complete resolution and should be based on patient-specific factors including severity.
      Figure thumbnail gr3
      Fig. 3Management of adverse events based on etiology [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      Choueiri TK, Powles T, Burotto M, et al. Clinical protocol CA2099ER: A phase 3, randomized, open-label study of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib versus sunitinib in participants with previously untreated, advanced or metastatic renal cell carcinoma. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2026982/suppl_file/nejmoa2026982_protocol.pdf. Published March 2021. Accessed March 23, 2021.

      ]. *Cabozantinib and nivolumab can be restarted for Gr ≤ 2 fatigue and cabozantinib can be restarted for Gr ≤ 2 HTN; AST/ALT increases > 3 × to 8 × ULN or total bilirubin increases to > 1.5 × to 3 × ULN; baseline AST/ALT is > 1 × to 3 × ULN and increases to > 5 × to 10 × ULN, or baseline AST/ALT is > 3 × to 5 × ULN and increases to > 8 × to 10 × ULN; §General IST is 0.5–1 mg/kg/day of prednisone equivalent for grade 2 and 1─2 mg/kg/day for grade ≥ 3; AST/ALT > 8 × ULN or total bilirubin increases to > 3 × ULN; #AST/ALT increases to > 10 × ULN or total bilirubin increases to > 3 × ULN. AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; DRESS: drug reaction with eosinophilia and systemic symptoms; Gr: grade; HTN, hypertension; irAE: immune-related AE; IST: immunosuppressive therapy; IV: intravenously; MI: myocardial infarction; ONJ: osteonecrosis of the jaw; PO: orally; Q2W: every 2 weeks; Q4W: every 4 weeks; QD: once daily; QOD: every other day; SJS: Stevens-Johnson syndrome; TE: thromboembolic event; TEN: toxic epidermal necrolysis; ULN: upper limit of normal.
      Table 1Prophylactic and supportive care measures for adverse events associated with cabozantinib.
      (

      American Cancer Society. Diarrhea. https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/stool-or-urine-changes/diarrhea.html. Revised February 1, 2020. Accessed January 6, 2021. [updated February 1, 2020.

      ,

      Cancer.Net. Dental and oral health. https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/managing-physical-side-effects/dental-and-oral-health. Published June 2019. Accessed June 9, 2021.

      ,
      • Gupta A.
      • West H.J.
      Mucositis (or stomatitis).
      ,
      • Peterson D.E.
      • Boers-Doets C.B.
      • Bensadoun R.J.
      • Herrstedt J.
      • Committee E.G.
      Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up.
      ,

      American Cancer Society. Mouth dryness or thick saliva. https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/mouth-problems/dry-mouth.html. Updated February 2020. Accessed March 26, 2021.

      ,

      Cancer.Net. Mouth sores or mucositis. https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/managing-physical-side-effects/mouth-sores-or-mucositis. Published January 2020. Accessed March 26, 2021.

      ,

      Cancer.Net. Taste changes. https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/managing-physical-side-effects/taste-changes. Published January, 2020. Accessed February 2, 2021.

      ,

      Cancer.Net. Hand-foot syndrome or palmar-plantar erythrodysesthesia. https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/managing-physical-side-effects/hand-foot-syndrome-or-palmar-plantar-erythrodysesthesia. Published September 17, 2019. Accessed January 7, 2021.

      ,
      • Kollmannsberger C.
      • Bjarnason G.
      • Burnett P.
      • Creel P.
      • Davis M.
      • Dawson N.
      • et al.
      Sunitinib in metastatic renal cell carcinoma: recommendations for management of noncardiovascular toxicities.
      ,
      • Lilly E.
      • Burke M.
      • Kluger H.
      • Choi J.
      Pregabalin for the treatment of painful hand-foot skin reaction associated with dabrafenib.
      ,
      • McLellan B.
      • Ciardiello F.
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      • Segaert S.
      • Van Cutsem E.
      Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management.
      ,
      • Agarwal M.
      • Thareja N.
      • Benjamin M.
      • Akhondi A.
      • Mitchell G.D.
      Tyrosine kinase inhibitor-induced hypertension.
      ,
      • Unger T.
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      • et al.
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      ,
      • Brose M.S.
      • Frenette C.T.
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      Management of sorafenib-related adverse events: a clinician's perspective.
      .)
      Abbreviations: ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; DHP-CCB: dihydropyridine calcium channel blocker; NSAID: non-steroidal anti-inflammatory drug; PPE: palmar-plantar erythrodysesthesia; SPF: sun protection factor.
      Because dose reductions are not permitted with nivolumab [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ], grade 3 irAEs (and some grade 2 irAEs) are generally managed with dose hold and immunosuppressive therapy (Table 2). There are various types of immunosuppressive therapies to manage irAEs; oral and IV corticosteroids such as prednisone or methylprednisolone, dosed 0.5─2 mg/kg/day or equivalent depending on irAE severity, are used most frequently with a taper of at least 4 weeks [

      Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(4 suppl):iv264–iv6.

      ,

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ,
      • Brahmer J.R.
      • Abu-Sbeih H.
      • Ascierto P.A.
      • Brufsky J.
      • Cappelli L.C.
      • Cortazar F.B.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events.
      ,
      • Schneider B.J.
      • Naidoo J.
      • Santomasso B.D.
      • Lacchetti C.
      • Adkins S.
      • Anadkat M.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update.
      ]. Mycophenolate mofetil, infliximab, vedolizumab, intravenous immunoglobulin, antithymocyte globulin, cyclophosphamide, and other immunosuppressive therapies may be used when the irAE is steroid-refractory [

      Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(4 suppl):iv264–iv6.

      ,

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ,
      • Brahmer J.R.
      • Abu-Sbeih H.
      • Ascierto P.A.
      • Brufsky J.
      • Cappelli L.C.
      • Cortazar F.B.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events.
      ,
      • Schneider B.J.
      • Naidoo J.
      • Santomasso B.D.
      • Lacchetti C.
      • Adkins S.
      • Anadkat M.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update.
      ]. Once the irAE resolves to grade ≤ 1 and immunosuppressive therapy is completed or prednisone is ≤ 10 mg/day, nivolumab can be restarted in most cases. However, nivolumab should be permanently discontinued for grade 4 irAEs (with exceptions such as endocrinopathies), recurrent grade 3 irAEs requiring systemic immunosuppressive therapy, grade ≥ 2 myocarditis, any grade Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS) or toxic epidermal necrosis (TEN), or an inability to reduce the corticosteroid dose to ≤ 10 mg/day of prednisone (or equivalent) within 12 weeks [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ].
      Table 2Nivolumab-directed management of overlapping AEs according to irAE guidelines and considerations from the Phase 1 study of cabozantinib + nivolumab and CheckMate 9ER

      Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(4 suppl):iv264–iv6.

      ,

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ,
      • Brahmer J.R.
      • Abu-Sbeih H.
      • Ascierto P.A.
      • Brufsky J.
      • Cappelli L.C.
      • Cortazar F.B.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events.
      ,
      • Schneider B.J.
      • Naidoo J.
      • Santomasso B.D.
      • Lacchetti C.
      • Adkins S.
      • Anadkat M.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update.
      ,

      Choueiri TK, Powles T, Burotto M, et al. Clinical protocol CA2099ER: A phase 3, randomized, open-label study of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib versus sunitinib in participants with previously untreated, advanced or metastatic renal cell carcinoma. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2026982/suppl_file/nejmoa2026982_protocol.pdf. Published March 2021. Accessed March 23, 2021.

      ,

      Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Clinical protocol JCO.20.01652: A phase 1 study of cabozantinib plus nivolumab (CaboNivo) alone or in combination with ipilimumab (CaboNivoIpi) in patients with advanced/metastatic urothelial carcinoma and other genitourinary tumors. https://ascopubs.org/doi/suppl/10.1200/JCO.20.01652/suppl_file/protocol_JCO.20.01652.pdf. Published September 2020. Accessed September 15, 2021.

      . Note: The following table is a compilation of clinical management recommendations for the respective AEs based on ASCO, ESMO, NCCN, SITC, Phase 1 study, and CheckMate 9ER study; it is important to review the most up-to-date guidelines for updates in irAE management.
      Grade 1Grade 2Grade 3Grade 4
      Diarrhea/ColitisASCO: continue NIVO; alternatively, hold NIVO and resume if toxicity does not exceed Gr1 or resolves; consider loperamide if infection ruled out in patients with diarrhea only and not colitis sym; monitor for dehydration; dietary changes

      ESMO: continue NIVO; SC with oral fluids, loperamide, avoid diet of high fiber and lactose; if persists > 14 days add PSLa or consider oral budesonide if no bloody diarrhea; refer to Gr3 if no improvement in 72 h or worsening

      NCCN: consider holding NIVO; initiate loperamide or diphenoxylate/atropine for 2─3 days; hydration; if persistent, progressive sym check lactoferrin/calprotectin—if positive, treat as Gr2, if negative continue Gr1 management and add mesalamine, cholestyramine
      ASCO: hold NIVO until resolution to Gr1; consider loperamide if infection ruled out in patients with diarrhea only and not colitis sym; consult GE; administer CSb unless diarrhea is transient; consider infliximab or vedolizumab for colitis that is CS-refractory, dependent, or with high-risk endoscopic features

      ESMO: hold NIVO; refer to grade 1 for SC; PSLa or oral budesonide if diarrhea persists > 3 days or worsens; refer to Gr3 if no improvement in 72 h or worsening

      NCCN: hold NIVO; administer CSc; if no response in 2─3 days, continue CS and consider adding infliximab or vedolizumab within 2 wk

      SITC: obtain sigmoidoscopy or colonoscopy with biopsy if persists ≥ 5 days; initiate CSb
      ASCO: hold NIVO; resume if patient can recover to ≤ Gr1; administer CSc, consider IV MP, especially if concern for concurrent upper GI inflammation; consider hospitalization or outpatient facility for dehydration or electrolyte imbalance; consider early introduction of infliximab or vedolizumab in addition to CS if high risk endoscopic features on initial endoscopy or inadequate CS response; if colitis sym, consider inpatient care

      ESMO: hold NIVO; hospitalize and administer IV CSc; isolate until infection excluded; consult GE; if no improvement in 72 h or worsening switch to infliximab or alternatively, MMF or tacrolimus

      NCCN: hold NIVO; consider inpatient care for SC; administer IV MPc; if no response in 1─2 days, strongly consider adding infliximab or vedolizumab

      SITC: hold NIVO and may resume once sym resolve to ≤ Gr1 on < 10 mg/day PRED; obtain sigmoidoscopy or colonoscopy with biopsy; initiate CSc
      ASCO: disc NIVO; inpatient care; administer MPc; consider early infliximab or vedolizumab if sym refractory to CS after 3 days; consider lower GI endoscopy if sym refractory despite treatment or concern for infection

      ESMO: refer to Gr3

      NCCN: disc NIVO; refer to Gr3 for treatment

      SITC: hold NIVO and resume once sym resolve to ≤ Gr1 on < 10 mg/day PRED; obtain sigmoidoscopy or colonoscopy with biopsy; initiate IV CSc
      Additional considerations for NIVO

      ASCO: consider GI endoscopy or colonoscopy with biopsy for patients who have positive stool inflammatory markers or colitis-related symptoms; repeat endoscopy for ≥ Gr2; CS tapered over 4─6 wk upon resolution to ≤ Gr1 and NIVO may be resumed after completion or on low-dose CS after evaluating risks/benefits; consider fecal microbiota transplant, tofacitinib, or ustekinumab in patients who are refractory to the previous immunosuppressants; disc NIVO if concomitant hepatitis and colitis and offer IST that works for both conditions

      ESMO: obtain sigmoidoscopy/colonoscopy, but do not wait to start CS treatment if required; CS should be tapered over 2─4 wk for moderate and 4─8 wk for severe diarrhea

      NCCN: obtain labs for infectious workup; consider GE consult for Gr2─Gr4 and obtain colonoscopy or sigmoidoscopy; taper CS over 4─6 wk upon resolution to ≤ Gr1; NIVO may be resumed after sym have resolved to ≤ Gr1 and after CS taper or once PRED is ≤ 10 mg/day if patient cannot completely taper off CS

      SITC: taper CS over 4 wk after improvement of sym to ≤ Gr1; if sym do not respond to CS within 3–5 days, if sym recur after CS taper, or if there is severe ulcerative presentation on colonoscopy, administer infliximab to reduce the risk of colitis recurrence; if persistent after 2 doses of infliximab, administer vedolizumab; if no improvement after IST in Gr3/4, repeat endoscopy with infectious workup; repeat endoscopy before resuming NIVO

      Phase 1: continue NIVO for Gr1; for Gr2, hold NIVO and treat symptomatically until resolution to Gr1 or baseline, but if worsening/no improvement in 4 weeks or colitis diagnosed by colonoscopy, initiate CS; for Gr3, treat as with Gr2 and obtain colonoscopy, CS should be initiated for colitis or at any time as clinically indicated; disc NIVO for Gr4

      CheckMate 9ER: for Gr1, continue NIVO and treat sym; Gr2, hold NIVO until Gr1/baseline and treat sym, initiate MPa or oral equivalent if persists > 5–7 days and taper over 1 mo once improvement to Gr1/baseline, if worsens or persists > 3–5 days with CS, see Gr3/4; Gr3/4, disc NIVO and initiate MPc and prophylactic antibiotics for opportunistic infections, consider lower endoscopy, taper CS over 1 mo when improved to Gr1, if persists > 3–5 days or recurrent initiate infliximab; infliximab should not be used in cases of perforation or sepsis

      Considerations for CABO

      Phase 1: initiate SC (Table 1); for Gr1/tolerable Gr2, continue CABO; intolerable Gr2, hold CABO or reduce dose; Gr3, hold CABO; may reinitiate CABO at a ↓ dose or at the same dose (if easily managed with resolution within 24 h) upon resolution to ≤ Gr1; Gr4, disc CABO

      CheckMate 9ER: administer antidiarrheal/antimotility agents and other SC; Gr1/2, continue or consider ↓ CABO dose, reassess in 24 h and ↓ antidiarrheals if resolving or continue if not resolving; intolerable Gr2, Gr2 > 48 h, ≥Gr3 hold CABO and rule out infection, reassess as with Gr1/2 and consider 2nd line antidiarrheal or referral to GE if not resolving
      AST/ALT elevationASCO: for Gr1 asymptomatic AST/ALT or bilirubin elevations continue NIVO and monitor; manage sym with SC; consider alternate etiologies; monitor labs 1─2×/wk

      ESMO: continue NIVO; repeat LFTs in 1 wk

      NCCN: consider holding NIVO for concerning lab value trend; assess transaminases and bilirubin with increased frequency

      SITC: monitor LFTs wkly
      ASCO: for Gr2 asymptomatic AST/ALT or bilirubin elevations hold NIVO and resume once improvement to ≤ Gr1 on CS ≤ 10 mg/day; monitor every 3 days; if no improvement for 3─5 days administer CSa and taper over ≥ 1 mo after resolution to ≤ Gr1; consider MMF if no improvement on CS after 3 days

      ESMO: hold NIVO; if AST/ALT rising, start PSL 1 mg/kg; check LFTs/INR/albumin every 3 days

      NCCN: hold NIVO; monitor LFTs every 3─5 days; consider CSa

      SITC: initiate CSa; monitor LFTs wkly
      ASCO: for symptomatic dysfunction, disc NIVO and consider disc if not symptomatic; start MPc with 4─6 wk taper after resolution to ≤ Gr1; consider MMF or azathioprine if no improvement after 3 days; monitor every 1─2 days

      ESMO: disc NIVO and administer PSL 1 mg/kg or IV MP 2 mg/kg depending on extent of elevation; monitor labs daily; perform Doppler ultrasound

      NCCN: hold NIVO; initiate CSc; add MMF if refractory after 3 days; consider inpatient care and monitor LFTs every 1─5 days; consult hepatology

      SITC: initiate MPc; monitor LFTs every 1─2 days
      ASCO: refer to Gr3 and administer MPd with 4─6 wk taper after resolution to ≤ Gr1

      ESMO: disc NIVO; administer IV MP 2 mg/kg; consult hepatology and consider liver biopsy

      NCCN: disc NIVO; initiate PRED or MPc; if steroid refractory after 3 days, consider adding MMF; monitor LFTs daily; consult hepatology; consider liver biopsy

      SITC: monitor LFTs every 1─2 days
      Additional considerations for NIVO

      ASCO: taper CS over 4─6 wk after improvement to Gr1, and NIVO may be resumed after completion or on CS ≤ 10 mg/day; infliximab might not be appropriate in patients with immune-related hepatitis due to risk of idiosyncratic liver failure; consult hepatology for ≥ Gr2; if CS refractory, consider liver biopsy to rule out other etiologies and consider adding azathioprine or MMF if infectious cause is ruled out

      ESMO: review medications, perform liver screen, consider imaging for metastases/clots; taper CS over 2 wk for Gr2 once resolved to Gr1, resume NIVO once PSL ≤ 10 mg/day; CS taper over 4 wk for Gr3/4 once improved to Gr2 and rechallenge only at consultant discretion; if worsening, change from oral CS to IV, to MMF, to MMF + tacrolimus

      NCCN: infliximab should not be used for hepatitis; for ≥ Gr1 transaminitis elevations with bilirubin 1─2 × ULN hold NIVO and treat with PRED or MPc, monitoring LFTs every 2─3 days; with bilirubin 3─4 × ULN refer to Gr4; taper CS over 4─6 wk upon resolution to ≤ Gr1; NIVO may be resumed after sym have resolved to baseline once PRED is tapered to ≤ 10 mg/day

      SITC: CS should be tapered over 4─6 wk after LFTs return to ≤ Gr1; If ALT or AST results do not improve to ≤ Gr1 within 10–14 days of CS initiation, or if liver toxicity recurs after taper, MMF, tacrolimus, or antithymocyte globulin may be given; if ALT or AST results do not improve to ≤ Gr1 within 10–14 days of MMF administration, consider liver biopsy and rule out CMV by PCR; do not use infliximab

      Phase 1: Gr1, continue NIVO; Gr2, if normal LFTs as baseline, hold NIVO until Gr1/baseline, if Gr1 LFTs at baseline and no sym, continue NIVO and monitor wkly; Gr3, hold NIVO and monitor 2×/wk until ≤ Gr2 (or < Gr3 if Gr2 at baseline), then resume NIVO and monitor wkly until ≤ Gr1, no improvement/worsening after 4 wks, initiate CS; Gr4, initiate off protocol therapy; when CABO is held for LFT elevation, NIVO should also be held; NIVO may be held and CS initiated at any time if clinically indicated

      CheckMate 9ER: Gr1, continue NIVO and monitor LFTs; Gr2, hold NIVO and increase monitoring to every 3 days, if persists > 5–7 days/ worsens, initiate MPa or oral equivalent and taper over 1 mo once Gr1/baseline, consider antibiotics for opportunistic infection, resume NIVO once Gr1/baseline; Gr3/4, disc NIVO (or hold if AST/ALT ≤ 8 × ULN or total bilirubin ≤ 5 × ULN), monitor every 1–2 days, initiate MPc (or MPd for Gr4 hepatitis) IV or equivalent, add prophylactic antibiotics, consult GE, taper over 1 mo once improvement to Gr2, if persists > 3–5 days/worsens/rebounds add MMF and if no improvement in 3–5 more days, consider IST per local guidelines; IV CS may be switched to oral equivalent dose at start of taper or if sustained clinical improvement

      Considerations for CABO

      Phase 1: for Gr1/2, continue CABO; Gr2, monitor LFTs wkly for 2 wk; Gr3, hold CABO and monitor LFTs 2×/wk until ≤ Gr2 and resume CABO at the same dose or a ↓ dose at provider discretion and continue wkly LFTs until ≤ Gr1; if resumed at same dose, reduce if ≥ Gr3 transaminase elevation occurs; Gr4, disc CABO or resume at ↓ dose if patient derived clinical benefit at discretion of provider and monitor LFTs 2─3×/wk

      CheckMate 9ER: hold CABO for Gr2 AST/ALT or total bilirubin that persists > 1 wk or worsens despite SC; disc CABO for concurrent AST/ALT > 3 × ULN and total bilirubin > 2 × ULN or AST/ALT > 8 × ULN
      Amylase/Lipase elevationNCCN: for isolated elevation of amylase/lipase ≤ 3 × ULN (mild) without evidence of pancreatitis, continue NIVO

      SITC: if no sym of acute pancreatitis, monitor patient and continue NIVO
      NCCN: for isolated elevation of amylase/lipase > 3─5 × ULN (moderate) without evidence of pancreatitis, consider continuing NIVO; evaluate for pancreatitis; if persistent moderate to severe elevations obtain abdominal CT with contrast or MRCPNCCN: for isolated elevation of amylase/lipase > 5 × ULN (severe) without evidence of pancreatitis, consider continuing NIVO; evaluate for pancreatitis; if persistent moderate to severe elevations obtain abdominal CT with contrast or MRCPNCCN: refer to Gr3
      Additional considerations for NIVO

      ASCO: in the absence of sym, routine monitoring of amylase/lipase is not recommended unless pancreatitis is suspected

      NCCN: consider other causes for elevations; if evidence of pancreatitis, refer to pancreatitis recommendations

      Phase 1: continue NIVO for Gr1/2 with increased monitoring; continue or interrupt NIVO for Gr3/4, with monitoring increased to 1–2×/wk and optional radiographic evaluation if new onset of symptomatic pancreatitis or diabetes

      CheckMate 9ER: NIVO may be continued for asymptomatic elevations without clinical manifestations

      Considerations for CABO

      Phase 1: Gr1/2, continue CABO and monitor more frequently; Gr3, hold CABO and monitor 1─2×/wk; if resolution to ≤ Gr2 within 6 wk, may restart CABO at the same or ↓ dose; Gr4, hold CABO and monitor 2×/wk; if resolution occurs within 4 days, CABO can be resumed at the same or ↓ dose, if > 4 days, CABO must be resumed at a ↓ dose; if Gr3/4 elevations recur, hold CABO and resume at a ↓ dose once resolved to ≤ Gr2

      CheckMate 9ER: asymptomatic Gr3 elevations without clinical manifestations of pancreatitis may ↓ CABO dose without prior hold; treatment-related Gr4 elevations or if sym/clinical manifestations develop hold CABO; resume CABO upon resolution to ≤ Gr2
      PancreatitisNot applicableNCCN: consider holding NIVO; refer to Amylase/Lipase Elevation

      SITC: hold NIVO until resolution of sym; initiate CSa, if no improvement in sym in 3─5 days with SC (IV fluids, analgesics); refer to GE specialist
      NCCN: hold NIVO; initiate PRED or MPa

      SITC: refer to Gr2
      NCCN: disc NIVO; initiate PRED or MPc

      SITC: refer to Gr2
      Additional considerations for NIVO

      ASCO: the role of CS is not clearly defined but could be considered in symptomatic disease when non-irAE etiologies are ruled out

      NCCN: GE referral; IV hydration; taper CS over 4─6 wk upon resolution to ≤ Gr1; consider resuming NIVO if no clinical/radiologic evidence of pancreatitis, with or without improvement in amylase/lipase; consider consulting pancreatic specialist regarding resumption

      SITC: if pancreatitis persists > 4 wk or there are recurrent sym, repeat abdominal CT with contrast to evaluate for consequences of acute pancreatitis, also evaluate for non-pancreatic etiologies of amylase/lipase elevation

      Phase 1: continue NIVO for Gr2 and increase monitoring; patients who develop symptomatic pancreatitis or diabetes mellitus should hold (Gr3) or disc (Gr4) NIVO

      CheckMate 9ER: disc NIVO for treatment-related Gr3 symptomatic pancreatitis lasting > 7 days and Gr4

      Considerations for CABO

      Phase 1: Gr2, continue CABO and increase frequency of amylase/lipase monitoring; Gr3, hold CABO and monitor 2×/wk; reinitiate CABO at a ↓ dose or the same dose upon resolution to ≤ Gr1 if resolution occurred within 6 wk; Gr4, disc CABO

      CheckMate 9ER: hold CABO for sym or clinical manifestations of pancreatitis and resume upon resolution to ≤ Gr2
      a0.5─1 mg/kg/day (or equivalent); b1 mg/kg/day; c1─2 mg/kg/day; d2 mg/kg/day.
      Abbreviations: ↓: reduced; AE: adverse event; ALT: alanine aminotransferase; ASCO: American Society of Clinical Oncology; AST: aspartate aminotransferase; CABO: cabozantinib; CMV: cytomegalovirus; CS: corticosteroid; CT: computerized tomography; disc: discontinue; ESMO: European Society for Medical Oncology; Gr: grade; GE: gastroenterology; GI: gastrointestinal; h: hour; INR: international normalized ratio; irAE: immune-related AE; IST: immunosuppressive therapy; IV: intravenous; LFT: liver function test; MMF: mycophenolate mofetil; mo: month; MP: methylprednisolone; MRCP: magnetic resonance cholangiopancreatography; NCCN: National Comprehensive Cancer Network; NIVO: nivolumab; PCR: polymerase chain reaction; PRED: prednisone; PSL: prednisolone; SC: supportive care; SITC: Society for Immunotherapy of Cancer; sym: symptoms; TNF: tumor necrosis factor; ULN: upper limit of normal; wk: week(s); wkly: weekly.

      Overlapping AEs

      There are multiple overlapping AEs between cabozantinib and nivolumab; however, how these AEs manifest differs depending on the agent. For intolerable grade 2 and grade 3/4 AEs of unknown etiology, it is appropriate to withhold both agents [

      Choueiri TK, Powles T, Burotto M, et al. Clinical protocol CA2099ER: A phase 3, randomized, open-label study of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib versus sunitinib in participants with previously untreated, advanced or metastatic renal cell carcinoma. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2026982/suppl_file/nejmoa2026982_protocol.pdf. Published March 2021. Accessed March 23, 2021.

      ]. If an irAE has not been ruled out, consider initiating immunosuppressive therapy for grade 3/4 AEs while holding both agents, particularly for those associated with serious risk (eg, hepatitis, myocarditis, pneumonitis, nephritis, neurotoxicity). If the AE begins to resolve within 1 to 14 days of holding both agents, cabozantinib is likely responsible. During CheckMate 9ER, the majority of dose holds for cabozantinib (86%) were ≤ 14 days. If the AE does not resolve in a few weeks or progresses despite dose hold, it is likely related to nivolumab and immunosuppressive therapy should be started or continued as indicated. Resolution and corticosteroid use data from CheckMate 9ER are presented in Table 3. Overlapping AEs include diarrhea, elevated amylase/lipase, liver enzyme elevation, dermatologic reactions, fatigue, endocrine disorders, and nephrotoxicity; these AEs require identification of the causative agent so that appropriate management strategies can be put in place.
      Table 3Corticosteroid use and resolution for select adverse events in patients treated with cabozantinib + nivolumab in CheckMate 9ER

      European Medicines Agency. Cabometyx: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ,

      European Medicines Agency. Opdivo: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ,

      European Medicines Agency. Opdivo assessment report. https://www.ema.europa.eu/en/documents/variation-report/opdivo-h-c-3985-ii-0092-epar-assessment-report-variation_en.pdf. Published April 2021. Accessed May 18, 2021.

      .
      Adverse eventHigh dose corticosteroid use*% ResolutionPatients with recurrence after rechallenge, % (n/N)
      %Median duration (range), weeks
      GastrointestinalNRNR69NR
       ir diarrhea/colitis761.4 (0.1─8.7)8233 (1/3)
      HepaticNRNR77NR
       AST/ALT > 3 × ULNNRNR89NR
       ir hepatitis882.0 (0.3─81.2)9759 (10/17)
      PulmonaryNRNR71NR
       ir pneumonitis802.1 (0.4─7.8)70NR
      RenalNRNR70NR
       ir nephritis/renal dysfunction402.0 (1.0─3.1)80NR
      SkinNRNR66NR
       ir rash341.9 (0.6─42.1)780 (0/2)
      *≥40 mg prednisone daily, or equivalent; Percentages are based on patients who were rechallenged with study therapy (data courtesy of Exelixis). Numerator (n) is the number of patients who had a recurrence (or a positive rechallenge), and the denominator (N) is the number of patients who were rechallenged. A positive rechallenge/recurrence is defined as any occurrence of new event(s) or worsening of any severity grade irAE on or after study therapy re-initiation.
      Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; ir: immune-related; NR: not reported; PPE: palmar-plantar erythrodysesthesia; ULN: upper limit of normal.

      Gastrointestinal

      Gastrointestinal-related AEs, prevalent in CheckMate 9ER, are likely related to cabozantinib’s inhibition of VEGFR, which is highly expressed in the intestines [
      • Schmidinger M.
      • Danesi R.
      Management of adverse events associated with cabozantinib therapy in renal cell carcinoma.
      ,
      • Wang D.
      • Lehman R.E.
      • Donner D.B.
      • Matli M.R.
      • Warren R.S.
      • Welton M.L.
      Expression and endocytosis of VEGF and its receptors in human colonic vascular endothelial cells.
      ]. There is potential for treatment-related diarrhea, nausea, lack of appetite, and mucosal inflammation [

      European Medicines Agency. Cabometyx: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ]. Cabozantinib may cause elevations in amylase/lipase and rarely symptoms of clinical pancreatitis [

      European Medicines Agency. Cabometyx: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ], although the mechanism is unknown. Nivolumab-related gastrointestinal AEs usually occur as an effect of bowel inflammation, which may cause diarrhea, nausea, and vomiting [
      • Grover S.
      • Rahma O.E.
      • Hashemi N.
      • Lim R.M.
      Gastrointestinal and hepatic toxicities of checkpoint inhibitors: algorithms for management.
      ]. The T-cell response facilitated by nivolumab increases cytokine levels, which may cause colitis [
      • Postow M.A.
      • Sidlow R.
      • Hellmann M.D.
      Immune-related adverse events associated with immune checkpoint blockade.
      ]. Elevations in amylase/lipase and pancreatitis can also occur with nivolumab; enzyme elevations may be a result of T-cell–mediated inflammation of organs that produce these enzymes [
      • Grover S.
      • Rahma O.E.
      • Hashemi N.
      • Lim R.M.
      Gastrointestinal and hepatic toxicities of checkpoint inhibitors: algorithms for management.
      ,

      Liu Y, Zhang H, Zhou L, Li W, Yang L, Li W, et al. Immunotherapy-associated pancreatic adverse events: current understanding of their mechanism, diagnosis, and management. Front Oncol 2021;11: doi: 10.3389/fonc.2021.627612.

      ].
      Diarrhea is highly prevalent with cabozantinib and is one of the more common AEs associated with nivolumab [
      • Choueiri T.K.
      • Halabi S.
      • Sanford B.L.
      • Hahn O.
      • Michaelson M.D.
      • Walsh M.K.
      • et al.
      Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial.
      ,
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • Mainwaring P.N.
      • Rini B.I.
      • Donskov F.
      • et al.
      Cabozantinib versus everolimus in advanced renal-cell carcinoma.
      ,
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. Cabozantinib-related diarrhea tends to occur within the first few weeks of initiation, starting as grade 1/2 and presenting with bloating, flatulence, and small, frequent stools associated with meals; symptoms generally resolve within 1 week with antidiarrheal agents. Nivolumab-related diarrhea often presents suddenly, with cramping, watery stools in large volumes, and may persist despite dose holding and use of antidiarrheal agents [
      • Apolo A.B.
      • Nadal R.
      • Girardi D.M.
      • Niglio S.A.
      • Ley L.
      • Cordes L.M.
      • et al.
      Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors.
      ]. Lifestyle modifications for prophylaxis should be implemented upon initiation of therapy, including eating small, frequent meals and avoiding alcohol, caffeine, and exacerbating foods. Patients should be educated on appropriate diet and fluid intake. Supportive care should be initiated for cabozantinib-related diarrhea (Table 1). If symptoms do not provide adequate information to identify the causative agent, both agents should be held for grade ≥ 2; then diarrhea should be managed appropriately once the causative agent is identified.
      Cabozantinib dose hold is recommended in patients with intolerable grade 2 or grade 3 diarrhea that cannot be managed using antidiarrheal agents, or grade 4 diarrhea. Cabozantinib may be restarted at a reduced dose after improvement to grade 1 [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. In CheckMate 9ER, cabozantinib dose reduction without prior dose hold was permitted for grade 1 diarrhea, at the discretion of the investigator [

      Choueiri TK, Powles T, Burotto M, et al. Clinical protocol CA2099ER: A phase 3, randomized, open-label study of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib versus sunitinib in participants with previously untreated, advanced or metastatic renal cell carcinoma. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2026982/suppl_file/nejmoa2026982_protocol.pdf. Published March 2021. Accessed March 23, 2021.

      ]. For patients who experience grade 2/3 diarrhea related to a dietary pattern (eg, change to a high fiber diet), cabozantinib may be resumed at the same dose with instructions to avoid diarrhea-inducing foods. In patients with persistent grade 2 or grade 3 diarrhea, work-up should include stool (culture, Clostridium difficile, parasite, cytomegalovirus or other viral etiology, ova, and parasite). If stool studies are negative, colonoscopy or flexible sigmoidoscopy with biopsy should be obtained to diagnose colitis. Evaluation should also include foodborne illness, ischemic bowel, diverticulitis, and inflammatory bowel disease; if available, a stool sample with lactoferrin/calprotectin testing may be considered to determine need for urgent colonoscopy [

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ]. If immunosuppressive therapy is started, calprotectin may be followed every 2 months for trend to guide immunosuppressive therapy discontinuation. To treat grade 2/3 colitis, both agents should be held with immunosuppressive therapy until resolution to grade ≤ 1; nivolumab should be discontinued for grade 4 (Fig. 3) [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ].
      Cabozantinib and nivolumab may cause elevations in pancreatic enzymes [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      European Medicines Agency. Cabometyx: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ]. Elevations are often benign and asymptomatic, but they could potentially indicate acute pancreatitis. Modest elevations in lipase or amylase and asymptomatic pancreatitis do not require dose modification [

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ]. In CheckMate 9ER, for grade 3 drug-related lipase/amylase elevations without symptoms or clinical manifestation of pancreatitis, the cabozantinib dose could be reduced by one level without dose delay; for grade 4 elevations, cabozantinib and nivolumab could be held until resolution to grade ≤ 2 [

      Choueiri TK, Powles T, Burotto M, et al. Clinical protocol CA2099ER: A phase 3, randomized, open-label study of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib versus sunitinib in participants with previously untreated, advanced or metastatic renal cell carcinoma. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2026982/suppl_file/nejmoa2026982_protocol.pdf. Published March 2021. Accessed March 23, 2021.

      ].
      For symptomatic acute, moderate pancreatitis, cabozantinib and nivolumab dosing should be held and corticosteroids initiated at 0.5─1 mg/kg/day prednisone equivalent with a 4─6-week taper [

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ]. Dosing may be resumed once there is no longer evidence of pancreatitis and upon completion of corticosteroid taper. For grade 3/4 pancreatitis, cabozantinib and nivolumab should be discontinued and 1─2 mg/kg/day of prednisone equivalent is indicated [

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ].

      Hepatic

      Incidence of liver enzyme elevations was relatively high in CheckMate 9ER and in other studies of cabozantinib and nivolumab [
      • Choueiri T.K.
      • Halabi S.
      • Sanford B.L.
      • Hahn O.
      • Michaelson M.D.
      • Walsh M.K.
      • et al.
      Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial.
      ,
      • Motzer R.J.
      • Escudier B.
      • McDermott D.F.
      • George S.
      • Hammers H.J.
      • Srinivas S.
      • et al.
      Nivolumab versus everolimus in advanced renal-cell carcinoma.
      ,
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ], but grade ≥ 3 elevations were infrequent in each trial (Supplementary Table 1). Although it is well-known that cabozantinib may induce AST/ALT elevations, the mechanism remains unknown [

      National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: clinical and research information on drug-induced liver injury. https://www.ncbi.nlm.nih.gov/books/NBK548279/. Revised January 4, 2017. Accessed April 12, 2021.

      ]. The enhanced immune response produced by nivolumab may lead to hepatotoxicity, including elevations in AST/ALT and hepatitis [
      • Grover S.
      • Rahma O.E.
      • Hashemi N.
      • Lim R.M.
      Gastrointestinal and hepatic toxicities of checkpoint inhibitors: algorithms for management.
      ]. Liver enzyme elevations have been reported with other TKI-ICI combinations in patients with RCC. Grade ≥ 3 AST/ALT elevations occurred in 3%/5% of patients treated with cabozantinib + nivolumab [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ], 7%/13% treated with the axitinib + pembrolizumab [
      • Rini B.I.
      • Plimack E.R.
      • Stus V.
      • Gafanov R.
      • Hawkins R.
      • Nosov D.
      • et al.
      Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ], and 3%/4% treated with lenvatinib + pembrolizumab [
      • Motzer R.
      • Alekseev B.
      • Rha S.-Y.
      • Porta C.
      • Eto M.
      • Powles T.
      • et al.
      Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
      ]. In CheckMate 9ER, cabozantinib + nivolumab was held in 9% of patients who developed hepatitis, and 88% of these patients with hepatitis required corticosteroids (Table 3) [

      Bristol-Myers Squibb Company. Immune-mediated adverse reactions management guide. https://www.opdivohcp.com/assets/commercial/us/opdivo-hcp-pan-tumor/en/pdf/Immune_Mediated_Adverse_Management_Guide.pdf. Published January 2021. Accessed January 27, 2021.

      ].
      AST, ALT, and bilirubin should be monitored throughout treatment. For AST/ALT > 3 × to ≤ 10 × the upper limit of normal (ULN) with bilirubin < 2 × ULN, cabozantinib and nivolumab should be held until resolution to grade ≤ 1 and corticosteroids may be considered [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. Upon holding of both agents, resolution of AST/ALT elevations without intervention indicates that cabozantinib is likely the responsible agent and treatment may be resumed at a reduced dose after improvement to grade ≤ 1. No improvement or worsening indicates nivolumab is the responsible agent and immunosuppressive therapy is necessary; treatment may be resumed after appropriate immunosuppressive therapy treatment and tapering. For AST/ALT > 10 × ULN or > 3 × ULN with bilirubin ≥ 2 × ULN, cabozantinib and nivolumab should be permanently discontinued and corticosteroids considered. If hepatitis develops, nivolumab should be held or permanently discontinued depending on the extent of AST/ALT elevation (Fig. 3).
      Management of cabozantinib + nivolumab was more conservative in CheckMate 9ER compared with the Phase 1 combination study [

      Choueiri TK, Powles T, Burotto M, et al. Clinical protocol CA2099ER: A phase 3, randomized, open-label study of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib versus sunitinib in participants with previously untreated, advanced or metastatic renal cell carcinoma. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2026982/suppl_file/nejmoa2026982_protocol.pdf. Published March 2021. Accessed March 23, 2021.

      ,

      Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Clinical protocol JCO.20.01652: A phase 1 study of cabozantinib plus nivolumab (CaboNivo) alone or in combination with ipilimumab (CaboNivoIpi) in patients with advanced/metastatic urothelial carcinoma and other genitourinary tumors. https://ascopubs.org/doi/suppl/10.1200/JCO.20.01652/suppl_file/protocol_JCO.20.01652.pdf. Published September 2020. Accessed September 15, 2021.

      ]. In CheckMate 9ER, grade 2 AST/ALT elevations required nivolumab hold with liver function test (LFT) monitoring every 3 days and cabozantinib could be held for grade ≥ 2 if elevations persisted > 1 week or worsened despite supportive care; if elevations persisted > 5─7 days, 0.5─1 mg/kg/day of methylprednisolone or oral equivalent was administered; once enzymes returned to grade ≤ 1 and steroid taper was complete, nivolumab could be resumed [

      Choueiri TK, Powles T, Burotto M, et al. Clinical protocol CA2099ER: A phase 3, randomized, open-label study of nivolumab combined with cabozantinib or nivolumab and ipilimumab combined with cabozantinib versus sunitinib in participants with previously untreated, advanced or metastatic renal cell carcinoma. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2026982/suppl_file/nejmoa2026982_protocol.pdf. Published March 2021. Accessed March 23, 2021.

      ]. For grade 3/4, nivolumab was discontinued, monitoring was increased to every 1─2 days, and 1─2 mg/kg/day of IV methylprednisolone or equivalent was administered; if no improvement in 3─5 days, mycophenolate mofetil could be administered. Cabozantinib was discontinued for concurrent AST/ALT > 3 × ULN and total bilirubin > 2 × ULN or AST/ALT > 8 × ULN.
      In the Phase 1 study, for grade 2 AST/ALT elevation, nivolumab was held but cabozantinib could be continued with at least weekly monitoring of LFTs for 2 weeks [

      Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Clinical protocol JCO.20.01652: A phase 1 study of cabozantinib plus nivolumab (CaboNivo) alone or in combination with ipilimumab (CaboNivoIpi) in patients with advanced/metastatic urothelial carcinoma and other genitourinary tumors. https://ascopubs.org/doi/suppl/10.1200/JCO.20.01652/suppl_file/protocol_JCO.20.01652.pdf. Published September 2020. Accessed September 15, 2021.

      ]. For grade 3, cabozantinib and nivolumab were held and LFTs were monitored at least twice weekly until reduction to grade ≤ 2. Nivolumab could be resumed at the same dose and cabozantinib could be resumed at the same dose or at one dose-level reduction, with LFT monitoring decreased to at least weekly until resolution to grade ≤ 1. If the patient continued at the same dose level of cabozantinib and a grade ≥ 3 transaminase elevation recurred, cabozantinib was dose reduced. If no improvement or worsening occurred by 4 weeks, immunosuppressive therapy could be initiated. The study did not allow rechallenge of nivolumab if immunosuppressive therapy was initiated, although guidelines are evolving as more data becomes available with these combinations. A retrospective query analysis of patients treated with pembrolizumab and axitinib who developed hepatic adverse events found that 100 patients were rechallenged with one or both agents; 45% had ALT ≥ 3 × ULN recurrence, and all 45 recovered to ALT < 3 × ULN following study treatment hold/discontinuation with no fatalities [
      • Rini B.I.
      • Atkins M.B.
      • Plimack E.R.
      • Soulières D.
      • McDermott R.S.
      • Bedke J.
      • et al.
      Characterization and management of treatment-emergent hepatic toxicity in patients with advanced renal cell carcinoma receiving first-line pembrolizumab plus axitinib. Results from the KEYNOTE-426 trial.
      ].

      Dermatologic

      Dermatologic AEs such as rash (commonly acneiform, located on the head, neck, chest, and back), erythema, alopecia, pruritus, xerosis, skin and hair discoloration, and most notably palmar-plantar erythrodysesthesia occur with VEGFR TKIs [
      • Zuo R.C.
      • Apolo A.B.
      • DiGiovanna J.J.
      • Parnes H.L.
      • Keen C.M.
      • Nanda S.
      • et al.
      Cutaneous adverse effects associated with the tyrosine-kinase inhibitor cabozantinib.
      ,
      • Lacouture M.E.
      • Ciccolini K.
      • Kloos R.T.
      • Agulnik M.
      Overview and management of dermatologic events associated with targeted therapies for medullary thyroid cancer.
      ,
      • Deutsch A.
      • Leboeuf N.R.
      • Lacouture M.E.
      • McLellan B.N.
      Dermatologic adverse events of systemic anticancer therapies: cytotoxic chemotherapy, targeted therapy, and immunotherapy.
      ]. Although non-life threatening, PPE can impact quality of life. It is characterized by callus-like hyperkeratosis, manifesting as redness, swelling, and tenderness primarily on the palmoplantar surfaces [
      • Zuo R.C.
      • Apolo A.B.
      • DiGiovanna J.J.
      • Parnes H.L.
      • Keen C.M.
      • Nanda S.
      • et al.
      Cutaneous adverse effects associated with the tyrosine-kinase inhibitor cabozantinib.
      ]. PPE may occur due to capillary microtrauma, prominent in areas of high friction or pressure [
      • Lacouture M.E.
      • Reilly L.M.
      • Gerami P.
      • Guitart J.
      Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib.
      ], which is enhanced with the antiangiogenic mechanisms of cabozantinib [
      • Azad N.S.
      • Aragon-Ching J.B.
      • Dahut W.L.
      • Gutierrez M.
      • Figg W.D.
      • Jain L.
      • et al.
      Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy.
      ]. PPE is the most common dermatologic AE associated with cabozantinib and can be managed using prophylactic and supportive care measures (Table 1). Treatment of intolerable PPE requires a cabozantinib dose hold until improvement to grade ≤ 1, then treatment can be resumed at a lower dose [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. For patients who were not implementing prophylactic measures prior to PPE onset, cabozantinib may be resumed at the same dose after resolution of PPE with education about prophylaxis.
      T-cell proliferation induced by nivolumab PD-1 blockade may increase detection of dermal antigens, resulting in cutaneous immune responses including rash (generally manifesting as erythematous macules, papules, and plaques localized to the trunk and extremities), pruritis, and vitiligo [

      Shen J, Chang J, Mendenhall M, Cherry G, Goldman JW, Kulkarni RP. Diverse cutaneous adverse eruptions caused by anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) immunotherapies: clinical features and management. Ther Adv Med Oncol 2018;10:doi: 10.1177/1758834017751634.

      ,
      • Shi V.J.
      • Rodic N.
      • Gettinger S.
      • Leventhal J.S.
      • Neckman J.P.
      • Girardi M.
      • et al.
      Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell death 1 and anti-programmed cell death ligand 1 immunotherapy.
      ,
      • Belum V.R.
      • Benhuri B.
      • Postow M.A.
      • Hellmann M.D.
      • Lesokhin A.M.
      • Segal N.H.
      • et al.
      Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.
      ].
      For immune-related rashes grade ≤ 3, topical corticosteroids are appropriate, but should be used in conjunction with systemic corticosteroids (0.5─1 mg/kg/day prednisone equivalent) for grade 3 or potentially for involvement of 10%─30% of the body [

      Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(4 suppl):iv264–iv6.

      ,

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ,
      • Brahmer J.R.
      • Abu-Sbeih H.
      • Ascierto P.A.
      • Brufsky J.
      • Cappelli L.C.
      • Cortazar F.B.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events.
      ,
      • Schneider B.J.
      • Naidoo J.
      • Santomasso B.D.
      • Lacchetti C.
      • Adkins S.
      • Anadkat M.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update.
      ]. If there is no improvement or worsening to grade 4, prednisone may be increased to 1─2 mg/kg/day. For pruritus, topical antihistamines and topical corticosteroids should be used for grade 1/2, with oral antihistamines added if pruritus remains uncontrolled; other systemic treatments may be necessary for intolerable grade 2 or grade 3 pruritus, including gamma-aminobutyric acid antagonists, natural killer-1 receptor antagonists, corticosteroids, or potentially omalizumab if high serum immunoglobulin E is present [
      • Wu J.
      • Lacouture M.E.
      Pruritus associated with targeted anticancer therapies and their management.
      ,
      • Phillips G.S.
      • Wu J.
      • Hellmann M.D.
      • Postow M.A.
      • Rizvi N.A.
      • Freites-Martinez A.
      • et al.
      Treatment outcomes of immune-related cutaneous adverse events.
      ]. Serious dermatologic toxicities, such as SJS, TEN, and DRESS, rarely occur with nivolumab but can be fatal [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      European Medicines Agency. Opdivo: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ]. If a serious dermatologic irAE is suspected, irrespective of the body surface area involved, nivolumab should be withheld and immunosuppressive therapy should be started [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      Bristol-Myers Squibb. Opdivo treatment modifications. https://www.opdivohcp.com/dosing/treatment-modifications. Updated December 2020. Accessed January 18, 2021.

      ]; if confirmed, nivolumab should be discontinued.

      Fatigue and endocrinopathies

      Fatigue is multifactorial and may develop as a result of RCC, TKI or ICI treatment and associated AEs (eg, diarrhea), or endocrinopathies [
      • Schmidinger M.
      • Danesi R.
      Management of adverse events associated with cabozantinib therapy in renal cell carcinoma.
      ,
      • Rimassa L.
      • Danesi R.
      • Pressiani T.
      • Merle P.
      Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma.
      ]. There are multiple proposed mechanisms for fatigue with cabozantinib, including an association with FLT-3, a target of cabozantinib [
      • Schmidinger M.
      • Danesi R.
      Management of adverse events associated with cabozantinib therapy in renal cell carcinoma.
      ]. Nivolumab-associated fatigue may occur due to increased levels of cytokines in addition to irAEs such as adrenal insufficiency or hypothyroidism [
      • Cortellini A.
      • Vitale M.G.
      • De Galitiis F.
      • Di Pietro F.R.
      • Berardi R.
      • Torniai M.
      • et al.
      Early fatigue in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: an insight from clinical practice.
      ,

      Berger AM, Mooney K, Aranha O, et al. NCCN Guidelines Version 1.2021 Cancer-related fatigue. https://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. Published December 2020. Accessed January 18, 2021.

      ]. Intolerable grade 2 or grade 3 fatigue not attributable to another cause or persists despite optimal management may require cabozantinib dose hold until improvement to grade ≤ 1 [

      Exelixis, Inc. Cabometyx treatment management guide. https://www.cabometyxhcp.com/sites/default/files/2021-03/CABOMETYX-TreatmentManagementGuide.pdf. Revised March 2021. Accessed June 22, 2021.

      ], and nivolumab may be held or potentially discontinued for grade 3 fatigue [

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ]. Prophylactic measures should be implemented for fatigue, and supportive care is recommended (Table 1).
      Patients with fatigue should be evaluated for endocrinopathies, as these can be managed with hormonal supplementation while maintaining dose density and intensity [

      Berger AM, Mooney K, Aranha O, et al. NCCN Guidelines Version 1.2021 Cancer-related fatigue. https://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. Published December 2020. Accessed January 18, 2021.

      ]. Cabozantinib is associated with hypothyroidism, hyperthyroidism, and rarely adrenal insufficiency [
      • Yavuz S.
      • Apolo A.B.
      • Kummar S.
      • del Rivero J.
      • Madan R.A.
      • Shawker T.
      • et al.
      Cabozantinib-induced thyroid dysfunction: a review of two ongoing trials for metastatic bladder cancer and sarcoma.
      ,
      • Lodish M.B.
      Clinical review: kinase inhibitors: adverse effects related to the endocrine system.
      ]. The pathophysiology of thyroid dysfunction with TKIs remains largely unknown. PD-1 inhibition with nivolumab may result in induction of humoral immunity, potentially causing thyroid disorders in patients who have antithyroid antibodies [
      • Osorio J.C.
      • Ni A.
      • Chaft J.E.
      • Pollina R.
      • Kasler M.K.
      • Stephens D.
      • et al.
      Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.
      ]. Endocrine disorders, including adrenal insufficiency, may also present due to increased inflammation disrupting feedback loops between endocrine organ systems [
      • Sznol M.
      • Postow M.A.
      • Davies M.J.
      • Pavlick A.C.
      • Plimack E.R.
      • Shaheen M.
      • et al.
      Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management.
      ].
      Endocrinopathies associated with therapy are irreversible, and thus, use of high-dose steroids is usually not required. Determining whether cabozantinib or nivolumab is responsible can be challenging, but regardless of the causative agent supportive therapy is critical. Although guidelines recommend holding one or both agents for symptomatic dysfunction [

      Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(4 suppl):iv264–iv6.

      ,
      • Brahmer J.R.
      • Abu-Sbeih H.
      • Ascierto P.A.
      • Brufsky J.
      • Cappelli L.C.
      • Cortazar F.B.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events.
      ,
      • Schneider B.J.
      • Naidoo J.
      • Santomasso B.D.
      • Lacchetti C.
      • Adkins S.
      • Anadkat M.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update.
      ,

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

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      ], actions may vary in clinical practice. We recommend continuing treatment and managing endocrine events with supportive therapy [
      • Jonklaas J.
      • Bianco A.C.
      • Bauer A.J.
      • Burman K.D.
      • Cappola A.R.
      • Celi F.S.
      • et al.
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      ,
      • Ross D.S.
      • Burch H.B.
      • Cooper D.S.
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      • Laurberg P.
      • Maia A.L.
      • et al.
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      ]. Thyroid-stimulating hormone (TSH) levels should be monitored prior to and during treatment and free thyroxine should be checked if TSH is abnormal. Synthetic thyroid hormone replacement (levothyroxine) can be initiated for patients diagnosed with hypothyroidism per established guidelines; levothyroxine should be dosed on a patient-by-patient basis as an initial full replacement or as partial replacement gradually up-titrated to meet the TSH goal [
      • Jonklaas J.
      • Bianco A.C.
      • Bauer A.J.
      • Burman K.D.
      • Cappola A.R.
      • Celi F.S.
      • et al.
      Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement.
      ]. Hyperthyroidism, usually transient and followed by hypothyroidism, can be managed with beta-blockers and rarely with anti-thyroid medications such as methimazole if symptomatic [
      • Ross D.S.
      • Burch H.B.
      • Cooper D.S.
      • Greenlee M.C.
      • Laurberg P.
      • Maia A.L.
      • et al.
      2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis.
      ]. More severe hyperthyroidism, such as Graves’ disease, may require more extensive workup and treatment [
      • Ross D.S.
      • Burch H.B.
      • Cooper D.S.
      • Greenlee M.C.
      • Laurberg P.
      • Maia A.L.
      • et al.
      2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis.
      ]. Primary or secondary adrenal insufficiency can also occur with both agents. For grade ≥ 2 adrenal insufficiency, symptoms should be treated, including hormone replacement therapy as indicated [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,
      • Postow M.A.
      • Sidlow R.
      • Hellmann M.D.
      Immune-related adverse events associated with immune checkpoint blockade.
      ,
      • Lodish M.B.
      Clinical review: kinase inhibitors: adverse effects related to the endocrine system.
      ].

      Renal

      Nephrotoxicity can occur with both cabozantinib and nivolumab, with proteinuria associated with cabozantinib and nephritis with nivolumab. Cabozantinib-related proteinuria may be associated with the role of VEGF in renal function [
      • Cappagli V.
      • Moriconi D.
      • Bonadio A.G.
      • Giannese D.
      • La Manna G.
      • Egidi M.F.
      • et al.
      Proteinuria is a late-onset adverse event in patients treated with cabozantinib.
      ]. Renal toxicity with nivolumab may occur due to T-cell mediated hypersensitivity reactions or haptenization leading to tubular damage, but the exact cause has not been established [
      • Herrmann S.M.
      • Perazella M.A.
      Immune checkpoint inhibitors and immune-related adverse renal events.
      ,

      Marco T, Anna P, Annalisa T, Francesco M, Stefania SL, Stella D, et al. The mechanisms of acute interstitial nephritis in the era of immune checkpoint inhibitors in melanoma. Ther Adv Med Oncol 2019;11; doi: 10.1177/1758835919875549.

      ]. Proteinuria can lead to nephrotic syndrome, characterized by swelling of the eyes and ankles, foamy urine, fatigue, and loss of appetite [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      Mayo Clinic. Nephrotic syndrome. https://www.mayoclinic.org/diseases-conditions/nephrotic-syndrome/symptoms-causes/syc-20375608. Updated January 30, 2020. Accessed February 8, 2021.

      ]. Nephritis is associated with decreased urine output, blood in urine, swollen ankles, and loss of appetite [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. Both proteinuria and nephritis can present with increased serum creatinine levels.
      With proteinuria, frothy urine is the main sign, and an elevated urinary protein- or albumin-to-creatinine test can be diagnostic [

      BMJ Best Practice. Evaluation of proteinuria. https://bestpractice.bmj.com/topics/en-us/875. Updated January 12, 2021. Accessed February 12, 2021.

      ]. Proteinuria should be monitored with at a minimum urinalysis every 1─2 months throughout treatment. Urinary protein-to-creatinine ratio (UPCR) should be assessed if proteinuria is suspected [
      • Cappagli V.
      • Moriconi D.
      • Bonadio A.G.
      • Giannese D.
      • La Manna G.
      • Egidi M.F.
      • et al.
      Proteinuria is a late-onset adverse event in patients treated with cabozantinib.
      ]. If UPCR is ≥ 3.5, cabozantinib should be held and UPCR should be repeated within 7 days with consideration of a 24-hour urine collection for definitive grading; if improvement to < 3.5, cabozantinib may be restarted at a reduced dose. If UPCR remains ≥ 3.5 without development of nephrotic syndrome, restarting cabozantinib can be considered if the patient has experienced clinical benefit. If nephrotic syndrome develops, cabozantinib should be discontinued [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Published November 27, 2017. Accessed January 9, 2021.

      ].
      With nephritis, hematuria, oliguria, and sediment in the urine may be present; a kidney biopsy may help to confirm nephritis [

      Mayo Clinic. Glomerulonephritis. https://www.mayoclinic.org/diseases-conditions/glomerulonephritis/diagnosis-treatment/drc-20355710#:∼:text=Glomerulonephritis%20often%20comes%20to%20light,possible%20damage%20to%20the%20glomeruli. Published February 6, 2020. Accessed February 12, 2021.

      ,

      Cleveland Clinic. Glomerulonephritis (GN). https://my.clevelandclinic.org/health/diseases/16167-glomerulonephritis-gn. Updated November 4, 2020. Accessed June 8, 2021.

      ]. Nivolumab should be held for grade 2/3 serum creatinine increases until resolution to grade ≤ 1, and discontinued for grade 4 [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ].
      There is no dose adjustment recommended for cabozantinib in patients with mild or moderate renal impairment, but cabozantinib should be avoided in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) and those on hemodialysis as clinical data are lacking in these populations [

      Exelixis, Inc. Cabometyx (cabozantinib) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ,

      European Medicines Agency. Cabometyx: EPAR - medicine overview. https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf. Revised May 2021. Accessed May 13, 2021.

      ,
      • Nguyen L.
      • Holland J.
      • Ramies D.
      • Mamelok R.
      • Benrimoh N.
      • Ciric S.
      • et al.
      Effect of renal and hepatic impairment on the pharmacokinetics of cabozantinib.
      ,
      • Klajer E.
      • Garnier L.
      • Goujon M.
      • Schlurmann-Constans F.
      • Mery B.
      • Nguyen Tan Hon T.
      • et al.
      Targeted and immune therapies among patients with metastatic renal carcinoma undergoing hemodialysis: A systemic review.
      ]. Although renal impairment has demonstrated no significant impact on the clearance of nivolumab in patients with an eGFR ≥ 15 mL/min/1.73 m2, patients with severe renal dysfunction and those on hemodialysis were not included in the analysis [

      Bristol-Myers Squibb Company. Opdivo (nivolumab) [package insert]. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s090lbl.pdf. Revised January 2021. Accessed January 27, 2021.

      ]. Case reports and the pharmacokinetic properties of nivolumab suggest renal impairment is unlikely to significantly alter plasma concentrations but additional studies are warranted [
      • Ansari J.
      • Ali M.
      • Farrag A.
      • Ali A.M.
      • Alhamad A.
      Efficacy of nivolumab in a patient with metastatic renal cell carcinoma and end-stage renal disease on dialysis: case report and literature review.
      ,
      • Bajaj G.
      • Wang X.
      • Agrawal S.
      • Gupta M.
      • Roy A.
      • Feng Y.
      Model-based population pharmacokinetic analysis of nivolumab in patients with solid tumors.
      ,
      • Carlo M.I.
      • Feldman D.R.
      Response to nivolumab in a patient with metastatic clear cell renal cell carcinoma and end-stage renal disease on dialysis.
      ].

      Other AEs of clinical relevance

      Providers should be aware of rare but serious AEs associated with cabozantinib (eg, gastrointestinal perforations and thrombotic events) and with nivolumab (eg, myocarditis, pneumonitis, and type 1 diabetes) that are noted in Supplementary Table 3. Grade 2 pneumonitis requires nivolumab dose hold and grade 3/4 requires discontinuation (Fig. 3). Nivolumab should be discontinued for grade ≥ 2 myocarditis. TKIs and ICIs are both associated with rare neurological AEs (posterior reversible encephalopathy syndrome [PRES] for TKIs and ICIs and encephalitis for ICIs), which may present with similar symptoms (headache, seizures, altered mental status) [
      • Kim D.
      Posterior reversible encephalopathy syndrome induced by nivolumab immunotherapy for non-small-cell lung cancer.
      ,
      • Patwari A.
      • Bhatlapenumarthi V.
      • Pascual S.K.
      Atypical posterior reversible encephalopathy syndrome due to oral tyrosine kinase inhibitor cabozantinib: first case report.
      ,
      • Stuby J.
      • Herren T.
      • Schwegler Naumburger G.
      • Papet C.
      • Rudiger A.
      Immune checkpoint inhibitor therapy-associated encephalitis: a case series and review of the literature.
      ]. If neurological toxicity is suspected, there should be a very low threshold to hold both agents and explore diagnostic workup. To differentiate between PRES and immune-related encephalitis, brain magnetic resonance imaging should be performed, and analysis of blood and cerebrospinal fluid can rule out infectious etiologies and identify autoimmune antibodies [
      • Stuby J.
      • Herren T.
      • Schwegler Naumburger G.
      • Papet C.
      • Rudiger A.
      Immune checkpoint inhibitor therapy-associated encephalitis: a case series and review of the literature.
      ]. Consultation with a neurologist is advised. If PRES is diagnosed, both agents should be discontinued and intravenous anti-hypertensive treatment should be initiated [
      • Kim D.
      Posterior reversible encephalopathy syndrome induced by nivolumab immunotherapy for non-small-cell lung cancer.
      ,
      • Patwari A.
      • Bhatlapenumarthi V.
      • Pascual S.K.
      Atypical posterior reversible encephalopathy syndrome due to oral tyrosine kinase inhibitor cabozantinib: first case report.
      ]; as PRES can resolve through hypertension control, corticosteroids may not be required [
      • Kim D.
      Posterior reversible encephalopathy syndrome induced by nivolumab immunotherapy for non-small-cell lung cancer.
      ]. If immune-mediated encephalitis is diagnosed, nivolumab should be held if mild and discontinued if moderate/severe and 1–2 mg/kg/day of methylprednisolone equivalent should be administered [

      Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines version 3.2021 management of immunotherapy-related toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published May 14, 2021. Accessed May 20, 2021.

      ].

      Clinical implementation

      In addition to the oncologist, a multidisciplinary team can address specific AEs/irAEs appropriately and may improve patient outcomes. This team should include the primary care provider and specialists who are familiar with ICI-related sequalae—dermatologists, cardiologists, endocrinologists, gastroenterologists, nephrologists, pulmonologists, hepatologists, neurologists, nursing professionals, and pharmacists [
      • Naidoo J.
      • Zhang J.
      • Lipson E.J.
      • Forde P.M.
      • Suresh K.
      • Moseley K.F.
      • et al.
      A multidisciplinary toxicity team for cancer immunotherapy-related adverse events.
      ,
      • Crespo A.
      • Tyszka M.
      Evaluating the patient-perceived impact of clinical pharmacy services and proactive follow-up care in an ambulatory chemotherapy unit.
      ].
      Patient education is essential in regard to prophylactic measures and self-monitoring for symptoms of AEs [
      • Lambourne T.
      • Minard L.V.
      • Deal H.
      • Pitman J.
      • Rolle M.
      • Saulnier D.
      • et al.
      Optimizing patient education of oncology medications: a patient perspective.
      ]. Patients should be aware that AEs associated with cabozantinib generally occur within the first 3–5 weeks of treatment, while irAEs can emerge early, during long-term treatment, or even after treatment discontinuation. Because symptoms can start subtly and progress rapidly, patients should seek early intervention from their provider. Additional resources regarding AE management for both providers and patients are provided in Supplementary Table 4.

      Future directions

      With multiple TKI-ICI combinations becoming available, there is a need for additional studies to differentiate the safety profiles of the various TKI-ICI combinations and to inform clinical decision-making. There is currently no clear management pathway for treatment rechallenge with ICIs, and limited data are available for rechallenge with cabozantinib + nivolumab (Table 3). Further studies are needed to determine when rechallenge is appropriate. To individualize treatment, there is interest in identifying patient-specific factors that may be associated with AE risk. A retrospective study by the International Metastatic Renal Cell Carcinoma Database Consortium identified age ≥ 60 years, GFR < 30 mL/min/1.73 m2, a single metastatic site, and sodium < 135 mmol/L as significant predictors for discontinuation of VEGF-targeted therapies [
      • Kaymakcalan M.D.
      • Xie W.
      • Albiges L.
      • North S.A.
      • Kollmannsberger C.K.
      • Smoragiewicz M.
      • et al.
      Risk factors and model for predicting toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy: results from the International Metastatic Renal Cell Carcinoma Database Consortium.
      ]. There is also interest in the relationship between AEs and clinical outcomes. Several RCC studies have reported associations between AE onset and improved clinical outcomes [
      • D'Aniello C.
      • Berretta M.
      • Cavaliere C.
      • Rossetti S.
      • Facchini B.A.
      • Iovane G.
      • et al.
      Biomarkers of prognosis and efficacy of anti-angiogenic therapy in metastatic clear cell renal cancer.
      ,
      • Martini D.J.
      • Goyal S.
      • Liu Y.
      • Evans S.T.
      • Olsen T.A.
      • Case K.
      • et al.
      Immune-related adverse events as clinical biomarkers in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors.
      ,
      • Vitale M.G.
      • Pipitone S.
      • Venturelli M.
      • Baldessari C.
      • Porta C.
      • Iannuzzi F.
      • et al.
      Correlation between immune-related adverse event (IRAE) occurrence and clinical outcome in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab: IRAENE trial, an Italian multi-institutional retrospective study.
      ]. Future studies are warranted to prospectively assess the predictive value of AEs in patients with RCC treated with TKI-ICI combinations.

      Conclusions

      CheckMate 9ER demonstrated that cabozantinib + nivolumab improved clinical outcomes compared with sunitinib and had a manageable safety profile [
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • Escudier B.
      • Bourlon M.T.
      • Zurawski B.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ]. To optimize treatment, proper management of AEs is essential. Identifying the responsible agent is key to managing AEs with the combination. Overlapping AEs can be challenging, but closely monitoring patients and utilizing management guidelines and other resources can help to keep patients on treatment. Cabozantinib AEs usually occur within the first few weeks of initiation, while nivolumab irAE timing is less predictable. Given their pharmacologic profiles, holding both agents and monitoring time-to-resolution can aid in identification of the causative agent. Upon identification, holding of the responsible agent can continue with supportive care and dose reduction for cabozantinib and immunosuppressive therapy for nivolumab as indicated. Prophylactic measures can reduce the incidence and severity of AEs associated with cabozantinib.
      Cabozantinib + nivolumab is being explored in a number of solid tumors [

      Yau T, Zagonel V, Santoro A, et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol 2020; 38(4 suppl):Abstract 478.

      ,

      ClinicalTrials.gov. NCT03635892. A study of nivolumab in combination with cabozantinib in patients with non-clear cell renal cell carcinoma. https://clinicaltrials.gov/ct2/show/NCT03635892. Updated May 4, 2021. Accessed June 24, 2021.

      ,

      ClinicalTrials.gov. NCT04091750. Nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma. https://clinicaltrials.gov/ct2/show/NCT04091750. Updated December 7, 2020. Accessed June 24, 2021.

      ], including in studies with and without ipilimumab. The Phase 2 ICONIC study (NCT03866382) is assessing cabozantinib + nivolumab + ipilimumab in patients with rare genitourinary tumors [

      ClinicalTrials.gov. NCT03866382. Testing the effectiveness of two immunotherapy drugs (nivolumab and ipilimumab) with one anti-cancer targeted drug (cabozantinib) for rare genitourinary tumors. https://clinicaltrials.gov/ct2/show/NCT03866382. Updated October 26, 2021. Accessed November 2, 2021.

      ]; the Phase 2 CAN-I study (NCT04413123) is assessing the triplet in patients with advanced RCC with variant histology [

      ClinicalTrials.gov. NCT04413123. Cabozantinib in combo with NIVO + IPI in advanced NCCRCC. https://clinicaltrials.gov/ct2/show/NCT04413123. Updated November 10, 2020. Accessed November 2, 2021.

      ]; and the Phase 3 COSMIC-313 study (NCT03937219) will assess the triplet versus nivolumab + ipilimumab in patients with untreated intermediate- or poor-risk advanced RCC [

      ClinicalTrials.gov. NCT03937219. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313). https://clinicaltrials.gov/ct2/show/NCT03937219. Updated April 1, 2021. Accessed November 2, 2021.

      ]. The Phase 3 PDIGREE trial (NCT03793166) will evaluate a response adapted strategy in patients with untreated advanced RCC who receive 12 weeks of induction therapy with nivolumab + ipilimumab; patients who have a partial response or stable disease by immune-related RECIST with induction therapy will be randomized to cabozantinib + nivolumab versus nivolumab [

      ClinicalTrials.gov. NCT03793166. Immunotherapy with nivolumab and ipilimumab followed by nivolumab or nivolumab with cabozantinib for patients with advanced kidney cancer, the PDIGREE study. https://clinicaltrials.gov/ct2/show/NCT03793166. Updated November 2, 2021. Accessed November 2, 2021.

      ].

      Funding

      Medical writing and editorial assistance were funded by Exelixis, Inc. (Alameda, CA, USA).

      Author contributions

      All authors contributed to manuscript conception, data interpretation, and drafting of the manuscript. All authors provided critical review and revisions and approved the final version of the manuscript.

      Declaration of Competing Interest

      BM has a consulting or advisory role with Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Dendreon, Eisai, EMD Serono, Exelixis, Genentech/Roche, Janssen Oncology, Merck, Nextar, Pfizer, and Seattle Genetics/Astellas. Institutional research funding from Bristol-Myers Squibb, Calithera Biosciences, Exelixis, Pfizer, and Seattle Genetics/Astellas. AM has a consulting or advisory role with Debiopharm Group, Pfizer, and Seattle Genetics. Institutional research funding from Acerta Pharma, Astellas Pharma, Bristol-Myers Squibb, Debiopharm Group, Genentech, Merck, Mirati Therapeutics, Novartis, Roche, and Seattle Genetics. The other authors declare no competing interests.

      Acknowledgements

      Medical writing and editorial assistance were provided by Alexus Rivas, PharmD and Michael Raffin of Fishawack Communications Inc. (Conshohocken, PA).

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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