ESMO 2018: Activity of Cabozantinib After PD-1/PD-L1 Immune Checkpoint Blockade In Metastatic Clear Cell Renal Cell Carcinoma

Munich, Germany ( Cabozantinib is an oral small molecule multikinase inhibitor which targets c-MET, VEGFR2, AXL, and RET, and a standard of care therapy for both first line and second line therapy of metastatic RCC. In a phase II multicenter study which randomized patients to front-line sunitinib or cabozantinib for mRCC, cabozantinib increased median progression free survival (8.2 months vs 5.6 months) with a 34% reduction in rate of death or progression (HR 0.66, 95%CI 0.46-0.95)1.

While TKI therapies such as sunitinib, cabozantinib, and pazopanib have been commonly used frontline therapies, checkpoint inhibitors have also entered this space, with the recent FDA approval of ipilimumab/nivolumab in April 2018. This approval was based on CheckMate214, a phase III randomized controlled trial which compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. In this study, 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients) and the 18-month overall survival rate was 75% with nivolumab plus ipilimumab and 60% with sunitinib2. The median progression-free survival was 11.6 months for patients receiving ipi/nivo and 8.4 months for those receiving sunitinib (HR 0.82; P=0.03). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group. These results demonstrated that ipi/nivo is an effective and tolerable therapy for intermediate and poor-risk patients with previously untreated advanced renal-cell carcinoma. However, not much is known about the efficacy of cabozantinib after checkpoint blockade.

This study examined the efficacy of cabozantinib after patients had progressed on immune checkpoint blockade. A total of 86 patients were included in this study. Most patients had progressed quickly on immune checkpoint blockade, with a median time of 4.5 months on checkpoint inhibitor therapy before progression. Many patients had been on more than one prior line of therapy as well as the median number of prior therapies was 2, with a range of 1-10.  

UroToday ESMO2018 Activity of Cabozantinib After PD 1PD L1 Immune Checkpoint Blockade
Most patients had intermediate or poor risk disease (94%). At the time of the author’s analysis, 36% of patients had a partial response, 43% of patients had stable disease, and 17% of patients had progressive disease. The median time to treatment failure was 6.5 months.

UroToday ESMO2018 Activity of Cabozantinib After PD 1PD L1 Immune Checkpoint Blockade

Notably, 30% of patients had prior VEGF inhibition in combination with immune checkpoint blockade. In the subgroup analysis of this cohort, 28% of patients had a response, with a median time to failure of 4.7 months, the lowest of any subgroup. Treatment outcomes by IMDC risk shows that the overall response rate was numerically higher in those with favorable or intermediate risk (41%), compared to lower risk (25%). 

UroToday ESMO2018 Activity of Cabozantinib After PD 1PD L1 Immune Checkpoint Blockade

Based on METEOR, which compared cabozantinib and everolimus after patients had progressed on VEGFR targeted therapies (most commonly sunitinib, pazopanib, axitinib) –  cabozantinib proved to be an effective second line therapy, with an objective response rate was 21%3. This retrospective analysis provides data that supports the use of cabozantinib after checkpoint inhibitor therapy, with the possibility of achieving disease control (stable disease or partial response) in the majority of patients (79% in this cohort).

With numerous IO/VEGF inhibitor combinations currently in phase III clinical trials, many oncologists are wondering what the efficacy of further TKI therapy will be in the second line if a VEGF inhibitor is used in the first line. This study provides evidence that cabozantinib still has efficacy if used after an IO/VEGF inhibitor – however, compared to those who have not been exposed to a VEGF inhibitor, these patients have the worst overall response rate (28%) and 1 year overall survival (40%). Future prospective studies will be important in determining the best sequence of therapies for patients with mRCC.

Presented by: Bradley A. McGregor, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, US
1. 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.
2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2018;378:1277-90.
3. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma. The New England journal of medicine 2015;373:1814-23.

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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