ASCO GU 2018: Docetaxel with or without Ramucirumab After Immune Checkpoint Inhibition in Platinum-refractory Metastatic Urothelial Carcinoma (Muc): Prespecified Subgroup Analysis from the Phase 3 Range Trial

San Francisco, CA ( Immune checkpoint inhibitors are revolutionizing the management of advanced and metastatic urothelial cancer. There are a growing number of approved immune checkpoint inhibitors (ICI’s) in this disease space, specifically after failing platinum-based chemotherapy, and as with ICI treatment in all cancers, the objective response rate (ORR) is between 15-20%.

RANGE,1 a randomized, double-blinded phase 3 trial comparing ramucirumab and docetaxel (R+D) to placebo+docetaxel (P+D) in patients with platinum-refractory metastatic Urothelial carcinoma (mUC). Ramucirumab is directed against the vascular endothelial growth factor receptor 2 (VEGFR2). RANGE enrolled patients with progressive mUC during or after platinum-based chemotherapy. Additional prior treatment with one ICI was permitted. Primary endpoint, investigator-assessed progression-free survival (PFS), was analyzed in the first 437 randomized patients. Secondary endpoints included overall survival, objective response, and safety. In that study, they demonstrated an ORR of 24.5% and a statistically significant improvement in progression free survival (PFS; median 4.07 vs 2.76 mo; HR 0.757) with addition of ramucirumab.

In this abstract, the authors present a pre-specified subgroup analysis of patients who had received a prior ICI – this encompassed only 33 (8%) of the 437 patients. Perhaps having received a prior ICI modified their response to ramucirumab.

The majority (91%) of these 33 patients received ICI therapy immediately following platinum and immediately prior to RANGE. In terms of the ICI utilized, patients primarily received atezolizumab (55%) or pembrolizumab (36%); ORR to prior ICI was 6% and the majority (67%) had progressive disease as best response. Median duration of the ICI was 3.5 mo (IQR 1.6-5.2). Disease sites at entry onto RANGE included lymph node (79%), lung (48%), liver (39%) and bone (18%).

At data cutoff for RANGE, responses were achieved by 5/14 (35.7%) on R+D, compared to 2/19 (10.5%) on P+D. Responses to R+D were independent of disease site. Overall, median PFS was 5.29 mo on R+D and 2.76 mo on P+D (HR 0.920). The frequency of grade ≥3 adverse events was similar between arms.

This study helps demonstrate that, even in patients previously treated with ICI, the addition of ramucirumab to docetaxel was able to salvage some patients who had progressed on platinum and ICI therapy, including those with liver metastases. Indeed, despite the fact that the R+D patients had uniformly worse disease to begin with, they had better ORR.

Speaker: Alexandra Drakaki, MD

Co-Authors: Conor J Kirby, Michiel Simon Van Der Heijden, Daniel Peter Petrylak, Thomas Powles, Kim N. Chi, Aude Flechon, Andrea Necchi, Lajos Geczi, Jae-Lyun Lee, Georgios Gakis, Sergio Bracarda, Simon Chowdhury, Chia-Chi Lin, Daniel Keizman, Ulka N. Vaishampayan, Astra M. Liepa, Annamaria Zimmermann, Katherine M Bell-McGuinn, Daniel E. Castellano

Institution(s): University of California Los Angeles, Los Angeles, CA; Marian University College of Osteopathic Medicine/ Eli Lilly and Company, Indianapolis, IN; Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Yale School of Medicine, New Haven, CT; Barts Health NHS Trust – St Bartholomew’s Hospital, London, United Kingdom; BC Cancer Agency, Vancouver, BC, Canada; Centre Léon Bérard, Lyon, France; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; National Institute of Oncology, Budapest, Hungary; University of Ulsan College of Medicine/ Asan Medical Center, Seoul, Korea, Republic of (South); University Hospital of Würzburg, Wurzburg, Denmark; San Donato Hospital, Istituto Toscano Tumori, Arezzo, Italy; Sarah Cannon Research Institute, London, United Kingdom; National Taiwan University Hospital, Taipei, Taiwan; Meir Medical Center, Kfar-Saba, Israel; Karmanos Cancer Center, Detroit, MI; Eli Lilly and Company, Indianapolis, IN; Hospital 12 de Octubre, Madrid, Spain

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA

1. Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. doi: 10.1016/S0140-6736(17)32365-6. Epub 2017 Sep 12. PMID: 28916371