ESMO 2025 | OPTIC RCC: efficacy of cabozantinib and nivolumab in cluster 1/2 metastatic ccRCC

So the origins of the OPTIC RCC study really date back to the IMmotion151 study. So IMmotion151 was a randomized phase three clinical trial in previously untreated kidney cancer where patients were randomized to either the control arm of sunitinib or the experimental arm of bevacizumab plus atezolizumab. And what the authors of this study did a really great job of was doing really high quality translational and genomics studies on the tumors from that trial. And so one of the types of studies they did was RNA sequencing or gene expression analyses, and that’s what we’ll be focusing on today. So the authors took all the gene expression data from these tumors and did something called unsupervised clustering, which basically means, it’s very intuitive, the tumors with similar gene expression patterns, they grouped them into little clusters. And so they ended up with seven clusters. And what we observed from the seven clusters, okay, so two of those seven clusters had very high expression of angiogenesis-associated genes. In addition, those tumors responded well to both the control arm as well as the experimental arm of IMmotion151, likely because both arms, or possibly because both arms contained a potent anti-angiogenic drug. And so we call these tumors our cluster angiotumors for these reasons. They have high expression of angiogenesis-associated genes, and they responded well to anti-angiogenic therapy. Two of the other clusters from the IMmotion151 study showed preferential response to the immune checkpoint inhibitor-containing arm of IMmotion151. They also had gene expression patterns consistent with a robust anti-tumor immune response. And so we called these clusters cluster IO. And so in OPTIC RCC, our goal was to take this observation from retrospective data that these groups of tumors correlated with a favorable drug response and to test that prospectively. And so what we did was we biopsied metastatic tumor tissue from patients with metastatic clear cell renal cell carcinoma. And we performed RNA sequencing and analysis from those tumors. And we observed a couple things. One was we observed very different proportions of clusters in the primary tumors versus the metastatic tumors. Almost all the primary tumors were angiogenic tumors, belonged to our cluster angio. Compare that to the metastatic tumors where we saw a great diversity of cluster types. And so based on that data, we amended the study so that we had to biopsy metastatic tumors in order to guide our therapy. And so again, we’re reporting on the cluster angio cohort of the study today. And so we had 27 patients which matched to this cluster angio group based off their metastatic tumor RNA sequencing data. From the 27 patients, 25 have a post-baseline scan. And so of those 25 patients, 76% had an objective response, which meant that when they received drug, their tumors shrunk by at least 30%. And so this met our primary endpoint, which was we expected to observe at least a 50% objective response rate, not 75% tumor shrinkage. That represents a 20% improvement from the historical control from previous trials. So by enriching for angiogenic tumors, we improved the objective response rate by a little over 20%. Other important findings from the study include none of our patients demonstrated progressive disease at best response. And 100% of patients enrolled on the study exhibited tumor shrinkage, which combined with the 76% objective response rate really suggests that these angiogenic tumors, selecting for them is enriching for drug response to a drug regimen here, cabozantinib plus nivolumab, which at least one of those agents is targeting angiogenesis biology.

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