ASCO 2018: Targeted Therapies in Advanced Urothelial Cancer

Chicago, IL ( Evan Yu, MD, from the Fred Hutchinson Cancer Center provided a presentation of the role of precision therapy in the treatment of advanced urothelial cancer.  RANGE was a phase III trial first presented at the ESMO 2017 Clinical Congress, a phase III randomized controlled trial assessing docetaxel with or without ramucirumab in platinum refractory advanced or metastatic urothelial carcinoma 1. For this trial, 530 patients were randomized to ramucirumab plus docetaxel (n = 263) or placebo plus docetaxel (n = 267). Over a median follow-up in the intention to treat (ITT) population of 5.0 months (IQR 2.3-8.9), the investigator assessed PFS was significantly prolonged in patients treated with ramucirumab plus docetaxel versus placebo plus docetaxel (median, 4.1 vs 2.8 months; HR, 0.757; 95% CI, 0.607-0.943). A blinded central analysis demonstrated consistent PFS results (HR, 0.672; 95% CI, 0.536-0.842). ORR in the first 437 ITT population was 24.5% (95%CI, 18.8-30.3) in the ramucirumab plus docetaxel arm and 14.0% (95% CI, 9.4-18.6) in the placebo plus docetaxel arm. Grade ≥3 adverse events were reported at a similar frequency in both arms with no unexpected toxicities; neutropenia was the most common grade ≥3 adverse events (15% ramucirumab arm vs 14% placebo arm).

Yu’s opinion and thoughts regarding the future of ramucirumab for urothelial carcinoma is:

  • The press release for overall survival stated a strong trend but was not statistically significant. He expects these results to be presented at ESMO 2018
  • Will regulatory approval be achieved given the overall survival findings?
  • If regulatory approval is achieved, where should it be positioned in the treated pathway? Immediately after combination platinum-based chemotherapy or after PD-1/PD-L1 antibody therapy?
There have also been exciting findings for FGFR biology according to Yu, some of which have been presented at this meeting. FGFR3 mutations have been the most extensively described, noting that (i) activating mutations are common (~86%) in low grade and early stage bladder tumors, (ii) the TCGA identified only 12% with mutations in MIBC, (iii) they are quite common in upper tract disease, (iv) oncogenic FGFR3 fusions are more common in high grade, invasive tumors, and (v) pharmacologic inhibition leads to cystostasis with arrest in phase G1 or G0. FGFR1 has high mRNA and protein expression, which likely has a role in invasion and metastasis. In Yu’s opinion, FGFR inhibition may be ideal for patients apt to response to PD-1/PD-L1 inhibition.

Arlene O. Siefker-Radtke, MD, presented results of the erdafitinib BLC2001 phase II trial earlier this meeting. Erdafitinib is an FGFR inhibitor with activity in patients with metastatic urothelial carcinoma and FGFR alterations, a pan-FGFR inhibitor targeting all 4 receptor subtypes. As part of this phase II study, 99 patients have treated with a median 5 cycles of optimized erdafitinib dose regimen. Of these, 12% were chemo naïve, 43% had received ≥ 2 prior lines of therapy, 79% had visceral metastases. There was a 40.4% confirmed ORR by RECIST 1.1 criteria (3% CR, 37.4% PR) and 79.8% disease control rate (CR + PR + SD). In general, responses were early, within first 1-2 months. In terms of PFS and OS:

  • PFS: Median PFS 5.5 months
  • OS: Median OS 13.8 months
Yu notes that a phase III clinical trial (THOR) is already ongoing, comparing erdafitinib to 2nd line chemotherapy or pembrolizumab. Additionally, the phase 1b/2 NORSE trial is combining erdafitinib with PD-1 inhibitor. Importantly, erdafitinib has been granted FDA breakthrough therapy designation.

Yu’s opinion and thoughts regarding the future of FGFR inhibitors for urothelial carcinoma is

  • What is the best predictive/companion biomarker? An assay or fusions vs mutations vs amplifications?
  • Should this eventually go first-line for those who harbor FGFR alterations?
  • Should we be using pan-kinase inhibitors or specific monoclonal antibodies? And which FGFR is most important to target?
  • How much will toxicity matter?
Yu also briefly described the current platform of antibody drug conjugates (ADCs) in urothelial carcinoma. There are several early developments in this disease space, highlighted briefly as follows:

  • Enfortumab vedotin ADC that targets Nectin-4 à tested in the phase I setting, with ongoing phase II trials, and a planned phase III trial vs investigators choice of chemotherapy among patients progressing after PD-1/PD-L1 therapy
  • AGS15e ADC that targets SLITRK6
  • Sacituzumab Govitecan (MMU-132) ADC that targets TROP-2
Yu concluded with several important take-home points:

  • Multiple new therapeutic options have the potential for regulatory approval with varying mechanisms of action
  • Anti-angiogenic, FGFR pan-kinase and monoclonal antibodies, antibody drug conjugates, and PARP inhibitors are all being explored
  • There is hope for molecular stratification of treatment for urothelial carcinoma in the near future

  1. Petrylak DP, Chi KN, Drakaki A, et al. RANGE: A randomized, double-blind, placebo-controlled phase 3 study of docetaxel with or without ramucirumab in platinum refractory advanced or metastatic urothelial carcinoma. ESMO 2017, abstr LBA4.
Presented by: Evan Yu, MD, Fred Hutchinson Cancer Research Center, Seattle, WA

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

Read More: The 2018 ASCO Presentation: A Subgroup Analysis of the East Asia Population in RANGE
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