Verzoni et al studied the blood of 15 patients with mRCC who were treated with cabozantinib. Immune profiling by 13-color cytofluorimetry was analyzed for patients at baseline and again at 3 months after treatment with cabozantinib. They found that there were significant reductions in the myeloid immunosuppressive cell subsets, in particular, changes in granulocytic MDSCs, monocytic MDSCs and TIM3+ myeloid cells.
There were also increased activated CD8+ and CD4+ T cells. Their conclusions mirrored the findings in bladder and prostate that cabozantinib may change the immunosuppressive tumor microenvironment and prime cytotoxic NK and T cells, making patients potentially more susceptible to immunotherapy.
Agarwal et al tested this hypothesis in a phase I study of 12 patients with treatment naïve advanced RCC. These patients were treated with the combination of cabozantinib and atezolizumab. 3 patients were favorable risk per IMDC, and 9 patients were intermediate/poor risk. Of note, 4 of these 12 patients had sarcomatoid differentiation.
At the time of this report, all patients are still receiving therapy and there have been no dose-limiting toxicities or serious adverse events. 10 of the 12 patients are currently evaluable – there has been one complete response and four partial responses, for an overall response rate of 50%. Of the 12 patients, there is 1 complete response, 7 partial responses, and 4 patients with stable disease. Disease control rate at this time is 100%.
The scientific rationale behind the combination of checkpoint inhibitors and cabozantinib has been explored in many tumor types and was re-demonstrated in RCC by Verzoni et al. This is now being tested clinically, and in the small phase I data that we currently have, the combination of atezolizumab and cabozantinib appear efficacious and safe for patients with advanced RCC. Larger studies are necessary to confirm the early signal of clinical benefit. Future studies may need to compare this combination with ipilimumab/nivolumab or atezolizumab+bevacizumab, the treatment arm of IMmotion 1516. The data presented today is certainly exciting and we eagerly await more mature data on this combination, not only for RCC but many other tumor types.
Neeraj Agarwal, MD, Professor of Medicine, Huntsman Cancer Hospital, Salt Lake City, Utah, US
Elena Verzoni, Department of Medical Oncology, IRCCS Foundation National Cancer Institute of Milan Tumor Institute of Milan, Milan, IT
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Written By: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University Twitter: @TheRealJasonZhu at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23, 2018, Munich Germany