Strategies to Minimize Side Effects in RCC Treatment

Sumanta Pal, MD, FASCO City of Hope | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Tyrosine kinase inhibitors (TKIs), generally share a class-wide side effect profile in renal cell carcinoma (RCC).

• Dose reductions are a primary strategy for managing toxicity, but reductions should be balanced against maintaining treatment benefit.

• Belzutifan, a non-TKI agent approved in the second line, is a well-tolerated alternative for patients struggling with side effects of TKIs.

Reviewing Oral RCC Treatment Side Effects

As part of the Tox Check series on the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, invited Sumanta Pal, MD, FASCO, of City of Hope, to discuss the side effects of primary treatments for RCC. The doctors focused on managing the toxicities of approved oral therapies including axitinib, cabozantinib, lenvatinib, pazopanib, sunitinib, and belzutifan. 

Excluding belzutifan, all of these agents are TKIs and associated with class-wide toxicities such as hypertension, diarrhea, constipation, hand-foot syndrome, and hepatotoxicity. These effects are frequently dose-dependent, and dose reductions are a primary strategy for management. However, if a dose reduction is being considered, patients should be aware that clinical benefit may be compromised to some extent, Dr. Pal said.

Managing Toxicities in RCC on Frontline TKIs

Axitinib, a single-kinase inhibitor of VEGF, has a starting dose of 5 mg twice daily, with recommended stepwise reductions to 3 mg and 2 mg for toxicity. Axitinib does have criteria for escalating to 7 mg and 10 mg doses, but Dr. Pal said he encounters very few cases where he can actually uptitrate without running into side effects. Compared with multi-kinase inhibitors like cabozantinib and lenvatinib, axitinib may induce slightly less diarrhea or hand-foot syndrome effects, but potentially more hypertension.

Cabozantinib has starting doses of 60 mg once daily when given as monotherapy, or 40 mg once daily when combined with nivolumab. The recommended stepwise dose reductions for toxicity are 40 mg and 20 mg. Dr. Pal said he always starts cabozantinib at the full dose because the degree of TKI-related side effects that any given patient will experience is unpredictable. That said, he rarely expects patients to maintain the starting dose. 

Dr. Pal follows a similar approach with lenvatinib, which has a once-daily starting dose of 20 mg when combined with pembrolizumab, or 18 mg when combined with everolimus. The recommended dose reductions for toxicity are 14 mg, 10 mg, and 8 mg. “In my experience, fatigue and diarrhea are the most common dose-limiting toxicities with lenvatinib—the colitis is real,” he said. He encouraged providers to proactively consider a dose reduction in patients that experience diarrhea to guard against severe colitis.

Pazopanib and sunitinib have largely been supplanted by axitinib, cabozantinib, and lenvatinib for the treatment of RCC, but community oncologists may still have legacy patients who have continued with these agents. According to Dr. Pal, managing these patients is similar to those on newer TKIs, and dose reductions are still a primary response to substantial toxicities.

When discussing if starting patients at a reduced dose with any of these agents is ever appropriate, Dr. Pal referenced a randomized phase 2 study he led that prospectively compared starting lenvatinib doses of 18 mg and 14 mg. The study found the reduced dose did not improve safety and trended toward lower efficacy, and ultimately supported the recommended starting dose. 

Side Effects of Second-Line Therapies in RCC

Tivozanib and belzutifan are both approved treatments for RCC after first-line therapy. Tivozanib is a single-kinase inhibitor of VEGF, similar to axitinib, whereas belzutifan is a hypoxia-inducible factor-2 alpha (HIF-2⍺ ) inhibitor.

Tivozanib has a starting dose of 1.34 mg once daily for 3 weeks followed by 1 week off, and a recommended reduction for toxicity to 0.89 mg on the same cycle. Dosing can be swapped to every other day if toxicity persists. If patients are struggling towards the end of the on-treatment period, Dr. Pal said the off-treatment holiday can be started early to try easing toxicities without resorting to dose reductions.

The holiday approach can be used in patients receiving other agents as well. For patients concerned with losing efficacy by skipping doses, Dr. Pal explained that maintaining a higher dose but taking weekends off, for example, still yields cumulatively more treatment than further stepping down the daily dose. “There’s a really interesting psychology around it. I think it’s probably one of the most important conversations we have as medical oncologists,” he said.

Belzutifan is started at a dose of 120 mg once daily, with stepwise reductions to 80 mg and 40 mg for toxicity. As a HIF-2⍺ inhibitor, belzutifan has a different side effect profile that includes anemia, hypoxia, and dyspnea. While belzutifan has an excellent tolerability profile relative to TKIs, data from the pivotal LITESPARK-005 trial suggest the responses are slower to occur. “So when you talk about patients in the salvage setting where you need response or at least stabilization quickly, you may not get it from this strategy,” Dr. Pal said.

Anemia, the primary toxicity of belzutifan, occurs in about 80% of patients. Checking iron levels and supplementing with intravenous iron is absolutely critical, Dr. Pal said. He has become more comfortable giving epoetin alfa for anemia as well. “If all else fails, dose reductions are important to consider,” he said.

The other major side effect of belzutifan is hypoxia. To monitor this, Dr. Pal tells patients to get a pulse oximeter and check their levels daily. If patients drop below 92% saturation, he has them stop treatment and contact their physician. Furthermore, about 15% of patients will develop significant hypoxia. Dose reduction and trying again is the only option to stop this side effect, Dr. Pal said.