ESMO 2018: COSMIC-021, Phase Ib Study of Cabozantinib in Combination with Atezolizumab and Potent Natural Killer, Myeloid Blood Cell Remodeling by Cabozantinib

Munich, Germany ( UroToday.com) Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL and RET1. In the sphere of metastatic renal cell carcinoma, cabozantinib is currently being used in both first line and second line therapy, based on CABOSUN for first line and METEOR for second line2,3.  In addition to being a tyrosine kinase inhibitor, there is some evidence that cabozantinib may alter the tumor immune microenvironment, altering regulatory T cells (Tregs) as well as myeloid-derived suppressor cells (MDSC)4. In a subset of patients with urothelial carcinoma who were treated with cabozantinib on a clinical trial, Tregs decreased with cabozantinib treatment and PD-1 expression. In preclinical models with castration-resistant prostate cancer, cabozantinib also been shown to attenuate the MDSC frequency and immunosuppressive activity in the tumor microenvironment. In murine models for prostate cancer, the combination of cabozantinib and a checkpoint inhibitor showed synergistic efficacy in targeting the primary and metastatic prostate cancer growth5. In the first study by Verzoni et al, the prior hypothesis tested in bladder and prostate are put to the test in patients with mRCC who are treated with cabozantinib. The second study by Agarwal et al hopes to capitalize on that synergy by treating patients with advanced RCC with the combination of cabozantinib and atezolizumab, a checkpoint inhibitor.

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. UroToday ESMO2018 COSMIC 021

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.

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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. 
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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%. 
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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.
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Presented by: 
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

References:
1. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Molecular cancer therapeutics 2011:molcanther. 0264.2011.
2. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of Clinical Oncology 2017;35:591-7.
3. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. The Lancet Oncology 2016;17:917-27.
4. Apolo AB, Tomita Y, Lee M-J, et al. Effect of cabozantinib on immunosuppressive subsets in metastatic urothelial carcinoma. American Society of Clinical Oncology; 2014.
5. Lu X, Horner JW, Paul E, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 2017;543:728.
6. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). Journal of Clinical Oncology 2018;36:578-.

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
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