Dr Haake on the Rationale for a Tumor Subtype Analysis of Cabozantinib Plus Nivolumab in Metastatic ccRCC

“We took these RNA sequencing or gene expression signatures that we identified retrospectively and then, prospectively developed a workflow where we could biopsy tumors, assign them to these different groups, and assign them to therapy based on these gene expression patterns.”

Scott Haake, MD, PhD, an assistant professor of medicine in the Division of Hematology Oncology in the Department of Medicine at Vanderbilt University Medical Center, discussed the rationale for evaluating cabozantinib (Cabometyx) plus nivolumab (Opdivo) according to transcriptional tumor subtypes in the phase 2 OPTIC RCC trial (NCT05361720), presented at the 2025 ESMO Congress.

The study was developed to address a central clinical challenge in metastatic clear cell renal cell carcinoma (ccRCC) management: although multiple frontline immunotherapy-containing doublets are FDA approved, including immune checkpoint inhibition (ICI)/TKI combinations and dual ICI regimens, there is currently no validated biomarker to guide selection between these therapeutic strategies, Haake began. He explained that treatment decisions in ccRCC are largely driven by clinical risk stratification rather than tumor-intrinsic biology. Historically, efforts to establish predictive biomarkers have been limited by the molecular heterogeneity of ccRCC, he noted. However, retrospective transcriptomic analyses from the phase 3 IMmotion151 trial (NCT02420821) identified biologically distinct gene expression clusters of this disease, including angiogenic and immune-inflamed phenotypes, which appeared to correlate with differential therapeutic responsiveness, he said. Tumors with angiogenic expression signatures were hypothesized to benefit more from potent VEGF-directed TKIs, whereas immune-inflamed tumors may respond preferentially to dual ICI therapy, he reported.

Building upon these observations, OPTIC RCC prospectively applied RNA sequencing to fresh tumor biopsies to stratify patients into 2 biologic clusters, Haake explained. Patients with immune-inflamed “cluster 1” tumors were assigned to receive nivolumab monotherapy, reflecting the hypothesis that these tumors are more immunologically active and may be adequately controlled with ICI alone. Patients with angiogenic “cluster 2” tumors were assigned to receive cabozantinib plus nivolumab, leveraging the anti-angiogenic activity of cabozantinib to target VEGF-driven disease biology while retaining immunologic synergy from PD-1 blockade.