Dr Singer on Toxicities Associated With First-Line IO/TKI Regimens in RCC

“In general, we see higher rates of AEs with [IO/TKI regimens], and that’s just for the TKI component—when you add in the immunotherapy component, the AEs observed with nivolumab or pembrolizumab are [similar to what is seen when] these drugs are used [in] any cancer.”

Adam E. Singer, MD, PhD, Health Sciences Clinical Instructor, medicine, division lead, kidney cancer, Division of Hematology/Oncology, UCLA Health, discusses how the safety profiles of nivolumab (Opdivo) and cabozantinib (Cabometyx) compare with those of immuno-oncology (IO)/TKI regimens in first-line renal cell carcinoma (RCC).

The adverse effect (AE) profiles of VEGF TKIs, such as axitinib (Inlyta), lenvatinib (Lenvima), and cabozantinib, are generally similar, though axitinib tends to be associated with fewer AEs compared with lenvatinib or cabozantinib, Singer begins. These AEs result from VEGF inhibition and off-target kinase effects, according to Singer. Commonly observed AEs include diarrhea, nausea, anorexia, hypertension, and fatigue, he lists. Hypothyroidism, proteinuria, and dysphonia are also reported; hand-foot syndrome is more frequently associated with cabozantinib than the other agents, Singer notes.

Although AE rates are high with TKIs alone, their use in combination with immune checkpoint inhibitors like nivolumab or pembrolizumab (Keytruda) introduces additional AEs associated with immunotherapy, Singer continues. Immune-mediated AEs include thyroid dysfunction, pruritus, and diarrhea, among others, which are consistent with these agents’ well-characterized profiles in various cancers, he details.

The combination of TKIs with immunotherapy can lead to overlapping toxicities that require close monitoring and individualized management strategies, Singer notes. For instance, although diarrhea is common to both TKIs and immunotherapy, its underlying cause may differ, necessitating distinct interventions, Singer explains. Similarly, immune-mediated AEs, such as colitis or hepatitis, may require immunosuppressive treatments, complicating care when combined with the toxicities from TKIs, he adds. Overall, the continued characterization of these AE profiles will inform strategies to minimize their effect on quality of life and ensure sustained adherence to treatment for patients with RCC, Singer concludes.