ASCO GU 2019: Outcomes of Patients with Metastatic Clear Cell RCC Treated with Second Line VEGFR-TKI After First Line Immune Checkpoint Inhibitor

San Francisco, CA ( Since the publication of CheckMate 214, immune checkpoint inhibitors (ICIs) have entered the first line space for the treatment of metastatic RCC1. However, the majority of patients do not have an objective response to ICI and will have either primary or secondary resistance. Standard of care second line therapies involves VEGFR-TKIs, but little is known about their efficacy after ICI treatment.  This study seeks to address this knowledge gap by providing a multicenter experience of treatment of mRCC after ICI therapy.

This is retrospective analysis of 70 patients who were treated with a TKI after progression on first line ICI. Of note, all patients included in this study had been treated with front line ICI on a clinical trial at either MD Anderson and MSKCC.
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In terms of baseline characteristics, the majority of patients were men with a median age of 59. Most patients were IMDC intermediate or poor risk with only 11% of patients being IMDC favorable risk. 20% had sarcomatoid features. The majority of patients had metastatic disease in the lung, bone, or lymph nodes. Most patients had started a TKI due to disease progression but 17% of patients had discontinued ICI due to toxicity. 
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The most frequent first line ICI was ipi/nivo (47%), followed by PD-L1 agent with anti-VEGF therapy (36%), followed by single agent ICI (17%). In terms of second line TKI, the most frequent therapy was axitinib (36%), followed by cabozantinib, pazopanib, and sunitinib.
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Objective responses were seen in 42% of patients on pazopanib, 17% of patients receiving sunitinib, 42% of patients receiving axitinib, and 47% of patients receiving cabozantinib. The overall objective response rate was 40% (28/70) with 1 CR and 27 PRs. The median time to best response was 3.9 months. Second line median PFS was 13.2 months and the median duration of therapy was 10.1 months. The majority of TKI discontinuation was for progressive disease (73%), with the remainder for toxicity. 46% of patients required dose reduction due to adverse events. 
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Given the major shift of immunotherapy to the first line treatment of patients with metastatic RCC, the question regarding optimal second line treatment is very topical and highly clinically relevant. However, I suspect that this question has gotten even more difficult given the two practice changing talks at this GU ASCO, regarding combination therapy Pembrolizumab + Axitinib and Avelumab + Axitinib for front line treatment of patients with metastatic RCC. For patients treated with front-line ipi/nivo, this data set provides nice evidence regarding the efficacy of second line TKI. Although numbers are small, this study demonstrates a high objective response rate with second line TKI with an impressive 24.4 month median progression free survival with pazopanib and 15.2 months with cabozantinib. Of note, these were all patients who had previously been enrolled on clinical trials at MD Anderson and MSKCC. Hopefully, this study will be replicated in the patients who progress after KEYNOTE-426 and JAVELIN RENAL 101 studies as combination immune checkpoint inhibitor+TKI become standard of care.
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Median progression free survival was greatest for those treated with pazopanib (24.4 months), followed by 15.2 months for cabozantinib, 13.2 months for axitinib, and 3.6 months for sunitinib. 

Presented by: Amishi Yogesh Shah, MD, Assistant Professor, MD Anderson Cancer Center

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, twitter: @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

  1. 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.