ESMO 2017: KEYNOTE-564: Phase 3 trial of pembrolizumab in the adjuvant treatment of renal cell carcinoma

Madrid, Spain (UroToday.com) Dr. Choueiri and colleagues presented their phase III trial design of adjuvant pembrolizumab for patients with renal cell carcinoma (RCC). Effective adjuvant therapies for patients with RCC at risk of recurrence after nephrectomy are lacking, and previous adjuvant therapy trials utilizing TKIs have proven disappointing [1-3].

Programmed death ligand 1 (PD-L1) and 2 (PD-L2) expression predicts poor prognosis in RCC. Programmed death 1 (PD-1) inhibitors have demonstrated activity in metastatic RCC [4], and PD-1 may represent a novel therapeutic target in the adjuvant setting. Pembrolizumab is a PD-1 inhibitor that directly blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. The objective of this randomized, double-blind, placebo-controlled phase III trial is to evaluate the efficacy and tolerability of pembrolizumab as adjuvant therapy in patients with high-risk RCC following nephrectomy and/or metastasectomy. 

Trial design: Key inclusion criteria for this trial include: (i) age ≥18 years, (ii) histologically confirmed RCC with a clear cell component, (iii) T2 grade 4, T3, T4, N (+), or stage M1 with no evidence of disease following nephrectomy and/or metastasectomy (iv) no prior systemic therapy for advanced RCC, (v) disease-free following complete or partial nephrectomy (and metastasectomy in M1 no evidence of disease patients) with negative surgical margins, and (vi) ECOG performance status 0-1. The goal is to accrue 950 patients who will then be randomly assigned 1:1 to receive pembrolizumab 200 mg every 3 weeks by intravenous infusion, or placebo, continued for up to 17 cycles (∼1 year) or until disease recurrence or treatment discontinuation. Randomization will be stratified by metastasis stage (M0 vs M1 no evidence of disease). Within the M0 group, randomization will be further stratified by ECOG performance status (0 vs 1) and region (US vs rest of world). The primary end point is investigator-assessed disease-free survival (DFS) and radiographic imaging will be performed every 12 weeks. Secondary objectives include (i) overall survival (OS), (ii) safety, (iii) disease recurrence-specific survival, (iv) DFS and OS according to PD-L1 expression status, (v) pharmacokinetics, (vi) antidrug antibodies, and (vii) patient-reported outcomes. Molecular biomarkers that may be associated with response, safety, pharmacodynamic activity, or mechanism of action will be evaluated as exploratory objectives. Clinical trial identification: NCT03142334

References:

1. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): A double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387(10032):2008-2016.

2. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375(23):2246-2254. 

3.Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol 2017;35(suppl;abstr 4507).

4. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): A double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387(10032):2008-2016.

Speaker: Toni K. Choueiri, Dana Farber Cancer Center, Boston, United States of America

Co-Authors: T. Powles (London, United Kingdom) T. Zhang (Durham, United States of America) D. I. Quinn (Los Angeles, United States of America) J. E. Gschwend (Munich, Germany) S. S. Wan (Kenilworth, United States of America) C. Poehlein (Kenilworth, United States of America)

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
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