Selecting Treatments for Cases in Relapsed or Refractory RCC
Key Points
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Approved second-line therapies for relapsed or refractory renal cell carcinoma (RCC) include tyrosine kinase inhibitors (TKIs) and belzutifan, a hypoxia-inducible factor-2α inhibitor.
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The approved TKIs offer different balances of potency and toxicity, and an agent should be selected based on each patient’s disease biology and progression trajectory.
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Belzutifan could be an alternative for patients unable to manage TKI-related toxicity, but its responses may be less durable.
Challenging Cases in Relapsed or Refractory RCC
The standard upfront treatment for RCC consists of a TKI plus immunotherapy, or dual immunotherapy, combinations. In the second-line and later settings, approved options include cabozantinib, lenvatinib plus everolimus, axitinib, tivozanib, and belzutifan.
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, invited medical oncologist David Braun, MD, PhD, of Yale School of Medicine, to review two challenging cases of relapsed or refractory RCC and discuss treatment approaches.
Treating Rapidly-Progressing Relapsed or Refractory RCC
First, the panel discussed a 65-year-old woman with a history of hypertension, hyperlipidemia, smoking, and diabetes mellitus type 2. Ten years earlier, she was diagnosed with early-stage non-small cell lung cancer, for which she underwent surgical resection without any additional chemotherapy or radiation.
Recently, she presented with fatigue, ongoing weight loss, and right upper quadrant pain, and imaging showed a right kidney lesion and multiple lung lesions. A subsequent lung biopsy confirmed a diagnosis of clear cell RCC with sarcomatoid differentiation. Initially, this patient received nivolumab plus ipilimumab and achieved a partial response, but restaging imaging at around 9 months revealed disease progression with new liver and lung lesions.
Second-line treatment selection in RCC should consider both disease biology and progression trajectory. In this case, the sarcomatoid differentiation histology and the new liver lesion suggest the patient could be progressing rapidly, said Dr. Braun. Since this patient does not fully meet the study criteria under which belzutifan was approved, which required both prior immunotherapy and TKI, the question becomes which second-line TKI is most appropriate.
For patients with signals for aggressively progressing disease like this one, Dr. Braun leans toward cabozantinib or lenvatinib plus everolimus, which are more toxic compared with tivozanib or axitinib, but have shown higher response rates in clinical trials. “If [the RCC] is really taking off, I don’t want to take any chances because, at that point, if it doesn’t respond, the patient might not make it to the third line,” he said.
Options When Facing TKI-Related Toxicity
The second case detailed a 58-year-old man with a 30-pack-per-year smoking history who was diagnosed with clear cell RCC. The patient started upfront treatment with nivolumab plus cabozantinib and showed a partial response, but after 7 months of therapy, he had disease progression. Notably, during the course of treatment, he experienced diarrhea, grade 3 hand-foot syndrome, and fatigue, which resulted in cabozantinib dose holds.
While this patient appears to be TKI-sensitive, response to TKIs is dose-dependent in RCC, and as the dose went down due to toxicity, the concentration was not adequate to control the disease. This case illustrates that different TKIs’ toxicity profiles impact both quality of life and efficacy, said Dr. Braun.
Although this patient meets the prior treatment criteria for belzutifan, his previous sensitivity to TKIs led Dr. Braun to stick with a TKI, albeit a less toxic one. “This is exactly where a milder option might really hit the nail on the head, something like tivozanib, which has a really substantially improved adverse event profile,” said Dr. Braun.
If toxicity remained a problem even with a more tolerable TKI and supportive therapies, then switching to belzutifan might be a reasonable approach. For this case, the patient’s extensive smoking history may warrant even more careful monitoring for hypoxia.