ASCO 2018: Pembrolizumab Monotherapy as First-Line Therapy in Advanced Clear Cell RCC: Results from Cohort A of KEYNOTE-427

Chicago, IL ( David F. McDermott, MD presented results from KEYNOTE-427. Programmed death-1 (PD-1) inhibitor-based combination therapy is being evaluated as first line therapy for advanced clear cell RCC:

  • Based on results of CheckMate214, nivolumab + ipilimumab was recently approved by the FDA for the treatment of patients with IMDC intermediate or poor risk, previously untreated advanced RCC [1]
  • In IMotion151, atezolizumab + bevacizumab met the primary endpoint of PFS in patients with PD-L1 positive tumors by investigator review [2]
  • Pembrolizumab + axitinib, pembrolizumab + lenvatinib, avelumab + axitinib, and nivolumab + cabozantinib are currently being evaluated in phase III studies
Atezolizumab monotherapy displayed encouraging anti-tumor activity in treatment-naïve patients in a non-randomized phase II study, however little is known about the activity of single-agent PD-1 blockade in treatment-naïve patients with clear cell RCC. The objective of KEYNOTE-427, a single-arm, open-label, two-cohort, phase II study, was to evaluate the efficacy and safety of pembrolizumab as first-line monotherapy in advanced treatment-naïve RCC. 

Key inclusion criteria for KEYNOTE-427 included:

  • Histologically confirmed advanced RCC who received no prior systemic therapy
  • Measurable disease (RECIST v1.1, independent central review)
  • Karnofsky performance status ≥70%. 
Pembrolizumab 200 mg was administered IV every three weeks for 2 years or until confirmed progressive disease, unacceptable toxicity, or patient decision to withdraw. PD-L1 expression was scored using the combined positive score (CPS), and PD-L1 positive expression was defined as CPS ≥1. The primary end point was objective response rate (ORR) per RECIST v1.1. Additional end points included duration of response, safety, biomarkers associated with response, PFS, and OS. The results of Cohort A (clear cell histology) were presented by Dr. McDermott today. 

As of the data cutoff date of March 12, 2018, the median follow-up was 12.1 (range 2.5-16.8) months, with 110 patients with clear cell RCC enrolled. All 110 patients were treated and 49 were still receiving ongoing treatment. The median age was 64 (29-87) years, 78% were male, and IMDC risk categories were as follows: (i) favorable (37.3%), intermediate (47.3%), and poor (15.5%). Confirmed ORR by blinded independent central review was 38.2% (n = 42; 95%CI 29.1-47.9), with 3 complete responses (2.7%) and 39 (35.5%) partial responses. The durable clinical response rate (complete response + partial response + stable disease for ≥6 months) was 59.1% (n=65, 95%CI 49.3-68.4%). Furthermore, 67.3% of patients experienced a reduction in tumor burden, 14.5% experience a tumor burden reduction ≥80%, and 7.3% of patients experienced 100% tumor burden reduction. The median time to response was 2.8 (95%CI 2.5-10.3) months. ORR for patients with IMDC favorable disease was 31.7% (95%CI 18.1-48.1) and was 42.0% (95%CI 30.2-54.5) for intermediate/poor risk patients. Median confirmed ORR also differed by PD-L1 expression: 50.0% (95%CI 34.9-65.1) for CPS ≥1 and 26.4% (95%CI 15.3-40.3) for CPS <1.  Overall, the median PFS was 8.7 months (95%CI 6.7-12.2) and median OS was not reached. Most patients experienced an any grade treatment-related adverse event (80%), and the most common (≥10%) were: pruritus (27.3%), fatigue (24.5%), diarrhea (19.1%), rash (15.5%), and arthralgia (12.7%); 30.2% of patients experienced a grade 3-4 treatment-related AE, and one patient had grade 5 pneumonitis.

McDermott concluded with several important take-home messages from KEYNOTE-427:

  • Pembrolizumab has shown promising antitumor activity as monotherapy in first line clear cell RCC across IMDC risk groups with an ORR of 38%
  • Encouraging activity of pembrolizumab was also observed in key subgroups, such as IMDC intermediate/poor risk (ORR 42%), and patients with PD-L1-positive tumors (ORR 50%)
  • The safety profile of Cohort A was similar to previously described safety profiles of pembrolizumab in other tumor types
  • Cohort B, assessing first-line pembrolizumab in non-clear cell RCC, is ongoing
  • The results of KEYNOTE-427 provide support for the exploration of pembrolizumab in the adjuvant setting (KEYNOTE-564), which is currently enrolling.
Clinical trial information: NCT02853344

1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378(14):1277-1290.
2. Motzer RJ, Powles T, Atkins MB, et al. IMmotion 151: A Randomized Phase III Study of Atezolizumab plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). J Clin Oncol 2018;36(suppl 6S; abstr 578).

Presented by: David F. McDermott, MD, Beth Israel Deaconess Medical Center, Boston, MA

Co-Authors: Jae-Lyun Lee, Cezary Szczylik, Frede Donskov, Jahangeer Malik, Boris Yakovlevich Alekseev, James M. G. Larkin, Vsevolod Borisovich Matveev, Rustem Airatovich Gafanov, Piotr Tomczak, Scott S. Tykodi, Poul F. Geertsen, Pawel J. Wiechno, Sang Joon Shin, Frederic Pouliot, Teresa Alonso Gordoa, Wenting Li, Rodolfo F. Perini, Charles Schloss, Michael B. Atkins; Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea, Republic of (South); Wojskowy Instytut Medyczny, Warsaw, Poland; Aarhus University Hospital, Aarhus, Denmark; Edinburgh Cancer Centre, Western General Hospital, Edinburgh, United Kingdom; P. A. Herzen Moscow Oncology Research Institute, Ministry of Health of the Russian Federation, Moscow, Russian Federation; Institute of Cancer Research, London, United Kingdom; N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; Clinical Hospital No. 1 of the Poznan University of Medical Sciences, Poznań, Poland; University of Washington Fred Hutchinson Cancer Center, Seattle, WA; Herlev Hospital, University of Copenhagen, Herlev, Denmark; Maria Skłodowska-Curie Memorial Cancer Center, Warsaw, Poland; Yonsei University College of Medicine, Seoul, Korea, Republic of (South); Université Laval, Quebec, QC, Canada; Hospital Universitario Ramón y Cajal, Madrid, Spain; MSD China, Beijing, China; Merck & Co., Inc., Kenilworth, NJ; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

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