ASCO GU 2019: Results from KEYNOTE-427 Cohort B: First-line Pembrolizumab Monotherapy for Advanced Non-Clear Cell Renal Cell Carcinoma

San Francisco, CA (UroToday.com) Non-clear cell renal cell carcinoma represents up to 25% of patients with renal cell carcinoma.1 The majority of patients will have papillary RCC (15%) or chromophobe (5%), but several other types exist including collecting duct carcinoma, medullary carcinoma, translocation, and unclassified RCC.   Given the rarity of these tumors, there are relatively few clinical trials which provide high-level evidence on how to treat these cases and thus the treatment paradigm has largely mirrored the treatment strategies for clear cell RCC. In a recent retrospective review of 43 patients with non-clear cell RCC, the objective response rate was 18% with 2% complete responses and 16% partial responses.1 Patients with sarcomatoid differentiation had a 27% partial response compared to 13% of those without sarcomatoid differentiation. This study evaluates the use of pembrolizumab for patients with non-clear cell RCC.
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This abstract describes cohort B of an open-label phase 2 study of pembrolizumab for patients with non-clear cell RCC. Patients were required to be treatment naïve, have measurable disease, and a KPS≥70%. Pembrolizumab was given at 200 mg every 3 weeks until disease progression or 2 years and the primary endpoint was the objective response rate per RECIST 1.1. 
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165 patients were enrolled. The median age was 62. The majority of patients had papillary RCC (72% - pRCC), followed by unclassified (16%) and lastly chromophobe (13%). Most patients (68%) had IMDC intermediate or poor risk mRCC and 62% were classified as PD-L1 positive. All patients had been treatment naïve. 62% of patients were PDL1 positive, as defined by a CPS ≥1.  
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In terms of efficacy, after a median follow-up of 11.1 months, the objective response rate was 24.8%, with 4.8% complete responses and 20% partial responses. Unclassified RCC had the best ORR at 34.6%, followed by 25.4% for papillary, and 9.5% for chromophobe. Patients who had a CPS score≥1 had an ORR of 33.3% compared with 10.3% of patients with CPS<1. The median PFS was 4.1 months and the median OS has not yet been reached with 72% of patients alive at 1 year. 
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In terms of safety, 11% of patients had a grade 3-5 treatment-related adverse event, and 6 patients died due to adverse events, two of which were considered treatment-related. The most frequent immune-mediated adverse events were hypothyroidism (15%), hyperthyroidism (7%), colitis (2%), and hepatitis (2%).
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Single-agent pembrolizumab is safe to use for patients with previously untreated non-clear cell mRCC and has reasonable efficacy for patients with papillary or unclassified RCC. PD-L1 defined by CPS score can help separate out some responders from non-responders but additional biomarkers are necessary to determine which patients derive the most benefit from immune checkpoint inhibition in this population of patients. The results presented support further evaluation of pembrolizumab for non-clear cell RCC.

Presented by: David F. McDermott, MD, Professor of Medicine, Harvard Medical School

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

References: 
  1. McKay RR, Bossé D, Xie W, et al. The Clinical Activity of PD-1/PD-L1 Inhibitors in Metastatic Non–Clear Cell Renal Cell Carcinoma. Cancer immunology research 2018;6:758-65.
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