Table 1: Phase 3 trials of new combination regimens versus sunitinib
N = number, ORR = objective response rate, mPFS = median progression-free survival, mOS = median overall survival, HR = hazard ratio, CI = confidence interval, OR = odds ratio, RR = relative risk
AE management for IO/TKI combination regimens can be particularly challenging. Due to overlapping toxicities, it may be unclear which agent is the culprit; hence, deciding on which agent to hold or dose reduce is not straightforward. Furthermore, decisions must be made on whether to initiate systemic corticosteroids or other immunosuppressive therapy, which may counteract the beneficial effects of the IO component.9
The recent review article by McGregor et al.9 is a much-needed analysis and summary of the adverse event (AE) data of CaboNivo in clinical trials and provides practical management principles for this IO/TKI combination. Here, we highlight some of the data presented in the article, especially the common overlapping toxicities between IO and TKI (Figure 1) and some features which may attribute them to one agent over the other, along with management principles. One of the valuable points in the review is to take a multidisciplinary approach to these AEs to ensure optimal AE management.
Figure 1: Adverse events of cabozantinib and nivolumab9
Diarrhea: Cabozantinib-associated diarrhea typically occurs early (within the first few weeks), has a gradual onset, and is associated with small, frequent stools, bloating, and flatulence. It generally resolves within a week with antidiarrheal agents and/or dose interruption.10,11 On the other hand, nivolumab can cause diarrhea and colitis. Colitis can present as a sudden onset of large-volume watery stools and is associated with abdominal cramping. It may persist despite antidiarrheal medications and holding the agent.12
If the history is unclear on which agent may be causative, and the diarrhea is grade ≥2, both agents should be held and a workup performed to rule out infectious causes such as Clostridium difficile and parasites. Gastroenterology should also be consulted to perform an endoscopic workup for colitis. If diarrhea rapidly improves after withholding both agents (within a week), cabozantinib is likely the offending agent; however, if it persists, nivolumab is the more likely culprit.9
Rash: Both agents are commonly associated with dermatologic toxicity, which, although rarely life-threatening can be very distressing. Cabozantinib can cause palmar-plantar erythrodysesthesia (PPE) which usually requires supportive management but will occasionally require dose interruptions and/or reductions.13,14 Cabozantinib may also cause a number of other rashes, most of which can be managed supportively. Nivolumab can cause immune-related rashes, pruritus, and vitiligo. Grade 1 and 2 rashes can be treated with topical corticosteroids, whereas grade ≥ 3 rashes will require systemic corticosteroids.15-17 Rare and serious skin toxicities such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms would require systemic immunosuppressive therapy and permanent discontinuation of nivolumab.9,18,19
Hepatic: Both agents can induce AST and ALT elevations via different mechanisms.20,21 For grade ≥ 2 elevations in AST or ALT, both agents should be withheld until improvement to grade ≤ 1, and corticosteroids may be considered depending on the duration of the AE.14,18 If upon withholding both agents, the AST and ALT elevations improve without specific intervention, the likely culprit is cabozantinib, and it should be restarted at a lower dose. However, if the AST/ALT elevations persist beyond 2 weeks of holding both agents, the AE is likely related to nivolumab, and it should either be withheld or discontinued, depending on severity, and immunosuppressive therapy initiated. For severe hepatic dysfunction (ALT/AST ≥ 10x ULN or ≥ 3x ULN with bilirubin ≥ 2x ULN), both cabozantinib and nivolumab should be permanently discontinued.9
Renal: Although both agents can cause nephrotoxicity, there are differences in the clinical manifestation. Cabozantinib can cause proteinuria through VEGF inhibition.22 Hence, urine protein should be monitored every 1-2 months during treatment with a urine protein: creatinine ratio (UPCR). UPCR ≥ 3.5 requires withholding cabozantinib until it goes below 3.5, at which point cabozantinib may be restarted at a lower dose. If despite withholding cabozantinib, the UPCR remains ≥ 3.5 and there is no nephrotic syndrome, cabozantinib can be restarted at a lower dose based on the assessment of risks vs benefits. However, in the presence of nephrotic syndrome, cabozantinib should not be restarted.9 Nivolumab can cause an immune-related nephrotic syndrome, typically characterized by hematuria, oliguria, raised creatinine, and urine sediments. This may require a renal biopsy to confirm the diagnosis, after which commencement of immunosuppressive therapy with consultation of a nephrologist would be indicated.18,23,24
Endocrinopathies: The commonest endocrinopathies associated with both agents are hypo- and hyperthyroidism, as well as adrenal insufficiency. It is often difficult to identify the responsible agent; however, this would not influence the management of endocrinopathy. TSH and cortisol levels should be monitored during therapy. Hypothyroidism can be treated with synthetic thyroid hormones using established guidelines. Hyperthyroidism is usually transient before “burning out” to hypothyroidism. It is managed with beta-blockers and, less frequently, methimazole if symptomatic.25,26 With both agents, adrenal insufficiency can be primary and secondary. This should be treated with hormone replacement as indicated.18,27,28
Although guidelines recommend interrupting therapy for endocrinopathies, the review pragmatically recommends continuing therapy while supportively managing endocrine AEs.9
Conclusion: Proper AE management is key to maximizing the benefit of CaboNivo in metastatic RCC. This involves a multidisciplinary approach to definitively diagnose the AE, identify the responsible agent, and implement effective management, whether by withholding the agent(s), dose reduction of cabozantinib, immunosuppressive therapy, or a combination of these strategies.
Written by: Elias A. Chandran, MBBS, FRACP, and Andrea B. Apolo, MD, National Cancer Institute, Bethesda, MD
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