(UroToday.com) The 2022 GU ASCO Annual meeting included a urothelial carcinoma session featuring work from Dr. Daniel Castellano and colleagues presenting the results of a post hoc analysis of the efficacy of pembrolizumab retreatment after progression of advanced urothelial carcinoma in KEYNOTE-045 and KEYNOTE-052. Pembrolizumab has shown efficacy in advanced/unresectable and metastatic urothelial carcinoma. Pembrolizumab showed antitumor activity in first-line and second line for patients with urothelial carcinoma in the single-arm, phase 2 KEYNOTE-052 study [1] and the randomized phase 3 KEYNOTE045 [2] study, respectively. There is interest in determining whether patients should be treated subsequently with checkpoint inhibitors such as anti–PD-1 therapy if metastatic urothelial carcinoma responds then later progresses. Pembrolizumab retreatment after disease progression has shown efficacy in melanoma and NSCLC. This post hoc exploratory analysis investigated the efficacy of pembrolizumab retreatment for patients with advanced urothelial carcinoma or metastatic urothelial carcinoma enrolled in KEYNOTE-045 and KEYNOTE-052 with a best overall response of SD or better and whose disease progressed after discontinuation or completion of 2 years of therapy.
The phase 3 KEYNOTE-045 trial (NCT02256436) was designed to compare the efficacy and safety of pembrolizumab vs chemotherapy in patients with metastatic urothelial carcinoma that recurred/progressed on platinum containing chemotherapy; ≤2 prior lines of systemic chemotherapy for metastatic urothelial carcinoma were permitted. The phase 2 KEYNOTE-052 trial (NCT02335424) was designed to evaluate the efficacy and safety of first-line pembrolizumab in cisplatin-ineligible patients with advanced urothelial carcinoma. The trial design of both studies is as follows:
In both studies, pembrolizumab was administered for up to 2 years, after which patients were eligible for retreatment if they stopped pembrolizumab after CR or had a best overall response of CR, PR, or SD and completed 2 years of treatment. Patients must have investigator-confirmed radiographic PD after therapy cessation, have ECOG PS score 0-1, and not have received anticancer treatment after the last pembrolizumab dose. Best overall response to retreatment is reported.
At data cutoff for KEYNOTE-045 (October 1, 2020), 11 patients were retreated: 5 (45%) achieved objective response to retreatment (3 CR; 2 PR) and 6 had SD, for a disease control rate (CR+PR+SD) of 100%. Median treatment-free interval was 7.7 months (IQR, 3.6-16.5), median duration of retreatment was 11.4 months (IQR, 7.6-12.0), and seven patients (64%) were alive at cutoff. Response over time for patients who received pembrolizumab in KEYNOTE-045 is as follows:
At data cutoff for KEYNOTE-052 (September 26, 2020), 10 patients were retreated: 5 (50%) had objective response to retreatment (1 CR; 4 PR) and 4 had SD, for a disease control rate of 90%. Retreatment best overall response was PD for 1 patient (10%). Median treatment-free interval was 13.0 months (9.2-16.6), median duration of retreatment was 6.0 months (IQR, 4.9-9.2), and four patients (40%) were alive at cutoff. Response over time for patients who received pembrolizumab in KEYNOTE-052 is as follows:
Dr. Castellano concluded his presentation of pembrolizumab retreatment in the KEYNOTE-045 and KEYNOTE-052 trials with the following take-home messages:
- Retreatment with pembrolizumab showed antitumor activity in patients with advanced or metastatic urothelial carcinoma who experienced progression after initial pembrolizumab therapy
- Although the number of patients who received retreatment was small, objective responses were observed
- The findings are generally consistent with observations from retreatment in other tumor types (e.g., melanoma), suggesting that these patients with urothelial carcinoma may also benefit from retreatment with pembrolizumab
Co-Authors: Arjun Balar, Peter H. O'Donnell, Petros Grivas, David J. Vaughn, Thomas Powles, Jacqueline Vuky, Jae-Lyun Lee, Yves Fradet, Joaquim Bellmunt, Miguel Ángel Climent, Nicholas J. Vogelzang, Elizabeth R. Plimack, Howard Gurney, Noah M. Hahn, Cora N. Sternberg, Jin Zhi Xu, Kentaro Imai, Blanca Homet Moreno, Ronald De Wit
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022
References:
- Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18(11):1483-1492.
- Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376(11):1015-1026.