Dr Hammers on Considerations for Assessing TKI/Immunotherapy Response in ccRCC

"When you combine immunotherapy with a VEGF TKI, you typically see shrinkage across all lesions. However, if the immunotherapy was also affecting all lesions, or if lesions 2 and 3 were affected by the VEGF TKI and there was no immune effect, you would see [greater shrinkage] when you use pure immunotherapy, and you get a sense of tumor heterogeneity."

Hans Hammers, MD, PhD, a professor in the Department of Internal Medicine, a member of the Division of Hematology and Oncology, coleader of Clinical Research and Immunotherapy for the Kidney Cancer Research Program, and the Eugene P. Frenkel, MD, Scholar in Clinical Medicine at The University of Texas Southwestern Medical Center, discussed patient characteristics and disease factors that may influence whether patients with ​advanced clear cell renal cell carcinoma (ccRCC) will respond to tyrosine kinase inhibitor (TKI)/immuno-oncology (IO) or IO/IO combination therapies.

Oncologists are often unable to determine treatment responsiveness in patients with ccRCC before therapy is initiated, but early treatment phases may provide meaningful indicators, Hammers began. Patients who experience tumor shrinkage on initial radiographic assessment and report symptomatic improvement generally exhibit a favorable treatment trajectory, he noted. Such early responses serve as encouraging prognostic signals, he said.

However, the concept of homogenous response is frequently misunderstood, he emphasized. In clinical practice, when immunotherapy is combined with a VEGF TKI, radiographic assessments often reveal shrinkage across most, if not all, lesions, according to Hammers. This raises questions regarding the relative contribution of each therapeutic modality, he explained. If the VEGF TKI exerts a dominant effect on certain lesions but immunotherapy has minimal impact, the true extent of immune-mediated activity may be obscured, he reported. Conversely, with single-agent immunotherapy, differential shrinkage patterns may provide greater insight into tumor heterogeneity, he stated.

An additional consideration is whether the immune system exerts activity across all metastatic sites or selectively targets only a subset, Hammers continued. This distinction has important implications for long-term disease control and therapeutic strategy, he added. In instances where most lesions respond but a single site remains refractory, localized interventions, such as surgical resection or radiation therapy, may be appropriate to achieve comprehensive disease control, he said. Similarly, if systemic therapy induces regression of metastatic disease but the primary tumor continues to enlarge, consolidative local therapy should be strongly considered, he noted. The treatment priority remains durable control of distant metastatic disease, as the primary tumor does not always reflect the overall disease burden, he contextualized. Resistant subclones within the primary lesion may ultimately drive disease progression if not addressed, he highlighted.

From a clinical management perspective, early and homogenous responses, followed by sustained disease stability for at least 2 years, are considered highly favorable, according to Hammers. In such cases, discontinuation of systemic therapy may be reasonable, as many of these patients are likely to achieve long-term remission or potential cure, he explained. Achieving deep, consistent responses across metastatic sites without evidence of progression represents one of the most optimistic outcomes in this therapeutic setting, Hammers concluded.