Dr Hammers on the Efficacy of IO/TKI and IO/IO Regimens in ccRCC

"There is a general sense that IO/TKI combinations have very high upfront response rates. For [a patient] who is in trouble with regards to symptomatic tumor burden, these are important regimens because the progressive disease as best response is in the single digits for at least the cabozantinib and lenvatinib combinations."

Hans Hammers, MD, PhD, professor in the Department of Internal Medicine, Division of Hematology and Oncology, and coleader of Clinical Research and Immunotherapy for the Kidney Cancer Research Program at UT Southwestern Medical Center, discussed the key efficacy distinctions between immuno-oncology (IO)/tyrosine kinase inhibitor (TKI) and IO/IO combinations for the treatment of advanced clear-cell renal cell carcinoma (ccRCC).

Hammers emphasized that while no head-to-head comparisons have been conducted between these treatment classes, long-term follow-up data provide valuable insights. IO/TKI regimens, such as cabozantinib (Cabometyx)/nivolumab (Opdivo), lenvatinib (Lenvima)/pembrolizumab (Keytruda), and axitinib (Inlyta)/pembrolizumab, demonstrate high upfront objective response rates (ORRs), ranging from 60% to 70%, and are associated with prolonged median progression-free survival (PFS) of 16 to 24 months. These features make IO/TKI combinations particularly valuable for patients with symptomatic or high-volume disease, where rapid tumor control is needed. Progressive disease as best response occurs in the single digits for regimens involving cabozantinib or lenvatinib, and is slightly more frequent with axitinib-based combinations due to narrower kinase targeting.

Despite these initial advantages, long-term disease control with IO/TKI combinations appears limited. Five-year PFS rates remain modest, with approximately 18% for axitinib/pembrolizumab and 13% for cabozantinib/nivolumab. In contrast, IO/IO combinations, such as ipilimumab (Yervoy)/nivolumab, offer the potential for more durable benefit in a subset of patients, albeit with a higher incidence of immune-related adverse effects.

Steroid requirements illustrate this trade-off: approximately 10% to 15% of patients receiving IO/TKI require prednisone for toxicity management, while rates are roughly doubled with IO/IO regimens. Nevertheless, Hammers noted that for appropriately selected patients, the quality-of-life benefits and potential for long-term remission associated with IO/IO therapy remain unmatched.