ASCO GU 2019: Results from KEYNOTE-427 Cohort Bb - First-line Pembrolizumab Monotherapy for Advanced Non-Clear Cell RCC

San Francisco, CA ( Most renal cell carcinoma (RCC) histology is clear cell (80%), however clinical trial data for non-ccRCC are limited as many of these patients are often excluded from clinical trials. Therapies specifically approved by the FDA for advanced non-ccRCC are lacking, resulting in a substantial unmet need for safe and effective treatment options. PD-1/L1 pathway inhibitors are effective in clear cell RCC, but efficacy of PD-1 inhibitors (or any therapy) in non-ccRCC has not been established. KEYNOTE-427 is a single-arm, open-label, phase 2 study of pembrolizumab monotherapy in patients with advanced ccRCC (cohort A) and non-ccRCC (cohort B). Among patients in cohort A, single-agent pembrolizumab showed promising antitumor activity in previously untreated ccRCC1. At the GU ASCO kidney cancer session, Dr. McDermott presented results of KEYNOTE cohort B.

The trial design for KEYNOTE-427 is as follows:
UroToday ASCOGU2019 keynote 427 1

There were 165 patients with histologically confirmed non-ccRCC, no prior systemic therapy, measurable disease (RECIST v1.1), and Karnofsky performance score ≥70%. These patients received pembrolizumab 200 mg IV Q3W for 35 cycles (~2 year) or until progressive disease, unacceptable toxicity, or withdrawal. Patients that did have progressive disease were still followed for overall survival. The primary end point for this study was objective response rate (ORR) per RECIST v1.1 by blinded independent central review. The secondary end points included the duration of response, PFS, and OS. There were several exploratory end points, including ORR by histology, PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+), and IMDC risk status.

The median patient age was 62 years (range 22-86), 66% of patients were men, and most patients were white (88%). Histology was as follows: papillary 71% (n=118), chromophobe 13% (n=21), and unclassified 16% (n=26). Most patients (68%) were intermediate/poor IMDC risk, and 62% were PD-L1+. At analysis, 49 patients had died and 3 had withdrawn. At a median follow-up duration of 11.1 months (range 0.9-21.3), 56% of patients discontinued pembrolizumab due to progressive disease or clinical progression. The overall ORR was 24.8% 

(95%CI 18.5-32.2), which included 8 patients with a complete response and 33 with a partial response. When ORR was assessed by histologic type, ORR was 25.4% (95%CI 17.9-34.3) for papillary, 9.5% (95%CI 1.2-30.4) for chromophobe, and 34.6% (95%CI 17.2-55.7) for unclassified non-ccRCC. ORR was 28.3% (95%CI 16.8-42.3) for favorable and 23.2% (95%CI 15.8-32.1) for intermediate/poor IMDC risk. ORR was 33.3% (95%CI 24.3-43.4) for CPS≥1 and 10.3% (95%CI 3.9-21.2) for CPS<1.

The Kaplan-Meier estimates for PFS and OS in the overall population was:
UroToday ASCOGU2019 keynote 427 2

Grade 3-5 treatment-related adverse events occurred in 11% of patients, and 6% discontinued treatment due to adverse events; six patients died secondary to adverse events, two that were treatment related.

Dr. McDermott concluded that KEYNOTE-427 cohort B results show promising antitumor activity with first-line pembrolizumab monotherapy in non-ccRCC. ORR in the overall population was 24.8%, slightly better in papillary (25.4%) and unclassified (34.6%) and worse in chromophobe (9.5%). The safety profile was generally as expected, based on the previously described safety profile of pembrolizumab in other tumor types. These results support further evaluation of pembrolizumab in patients with advanced non-ccRCC.
Clinical trial information: NCT02853344

Presented by: David McDermott, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Co-Authors: Jae-Lyun Lee, Marek Ziobro, Rustem Airatovich Gafanov, Vsevolod Borisovich Matveev, Cristina Suárez, Frede Donskov, Frederic Pouliot, Boris Y. Alekseev, Pawel Wiechno, Piotr Tomczak, Miguel Angel Climent Duran, Sang Joon Shin, Rachel Kloss Silverman, Rodolfo F. Perini, Charles Schloss, Michael B. Atkins; Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea, Republic of (South); Centrum Onkologii-Instytut im. Marii Sklodowskiej, Cracow, Poland; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; N. N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia; Hospital General Universitari Vall d’Hebron, Barcelona, Spain; Aarhus University Hospital, Aarhus, Denmark; CHU de Quebec and Laval University, Quebec, ON, Canada; P. A. Herzen Moscow Oncology Research Institute, Ministry of Health of the Russian Federation, Moscow, Russian Federation; Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; Clinical Hospital No. 1 of the Poznan University of Medical Sciences, Poznań, Poland; Instituto Valenciano de Oncología, Valencia, Spain; Yonsei University College of Medicine, Seoul, Korea, Republic of (South); Merck & Co., Inc., Kenilworth, NJ; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC

Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

  1. McDermott DF et al. Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427. J Clin Oncol. 2018;15(suppl):4500.