Guru P. Sonpavde, MD, director of Bladder Cancer and physician at Dana-Farber Cancer Institute, discusses advancements made in the field of bladder cancer presented at the 2020 Genitourinary Cancers Symposium.
The phase Ib/II EV-103 trial (NCT03288545) examined the use of the antibody-drug conjugate enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-based chemotherapy. Updated results showed that at a median follow-up of 11.5 months, the combination led to a high objective response rate (ORR) of 73%, which was very exciting, according to Sonpavde. The ORR included a 15.6% complete response (CR) rate and a 57.8% partial response rate. Additionally, responses were observed regardless of PD-L1 expression status, indicating this is a promising regimen, says Sonpavde. The combination was also found to have a manageable toxicity profile.
Sonpavde was also involved in the phase II BLASST-1 trial, which examined the neoadjuvant regimen of the PD-1 inhibitor nivolumab (Opdivo) combined with gemcitabine and cisplatin in cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC). Notably, the combination induced a pathologic nonmuscle-invasive rate of 66% and a pathologic CR (pCR) rate of 49% in this patient population. In the ongoing phase III ENERGIZE trial, investigators hope to validate these data and determine whether the combination will also result in improved progression-free survival and overall survival (OS) outcomes for these patients.
The randomized, double-blind, placebo-controlled, phase III PROOF 302 trial is examining the use of the potent and selective pan-FGFR inhibitor infigratinib (BGJ398125) as adjuvant therapy in patients with invasive urothelial carcinoma harboring FGFR3 alterations, according to Sonpavde. Although the trial is weighted toward examining patients with urothelial carcinoma of the upper urinary tract or bladder, patients with MIBC are also included in this trial, says Sonpavde. This research is particularly exciting because no effective options are currently available in the second-line adjuvant setting for this molecularly-selected patient population, explains Sonpavde.
Through examining patients with metastatic urothelial cancer who received PD-1 or PD-L1 checkpoint inhibitors in the first-line or post-platinum setting, researchers at the Dana-Farber Cancer Institute found that tumor regression could be predicted using 3 factors: tumor mutation burden (TMB), neutrophil lymphocyte ratio, and visceral sites of metastases. To validate the 3-factor model, the investigators examined patients who had all these variables and had received atezolizumab (Tecentriq) in the phase II IMvigor210 trial. Not only did investigators validate previous data, but they also found that the 3-factor model could also be used to predict response to checkpoint inhibitors. As such, this model may help select appropriate patients with metastatic urothelial cancer for PD-1/PD-L1 inhibition, says Sonpavde, which would thus improve the cost efficiency and therapeutic index of these agents.
Many advances have been made over the past couple of years in the treatment of patients with urothelial cancer. For example, in April 2019, the FDA approved erdafitinib (Balversa) for use in those with urothelial cancer who have activating alterations in FGFR2 and FGFR3 and who progressed on prior platinum-containing chemotherapy and anti—PD-1/L1 immunotherapy. In December 2019, enfortumab vedotin-ejfv was granted an accelerated approval for select patients with locally advanced or metastatic urothelial cancer. Furthermore, with its January 2020 FDA approval, pembrolizumab was added to the treatment armamentarium for patients with Bacillus Calmette-Guerin–unresponsive, high-risk non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
Beyond approvals, first-line maintenance treatment with avelumab (Bavencio) was found to significantly improve OS in patients with locally advanced or metastatic urothelial cancer over standard of care, meeting the primary end point of the phase III JAVELIN Bladder 100 trial, according to a press release. However, a study evaluating adjuvant treatment with atezolizumab in patients with high-risk MIBC turned out to be negative, says Sonpavde.
Future research efforts will continue to focus on the combination of platinum-based chemotherapy with a PD-1/PD-L1 inhibitor in the first-line setting. Other studies are evaluating double checkpoint inhibition, combining CTLA-4 inhibitors with PD-1/PD-L1 inhibitors. All those trials possess the potential to alter the treatment landscape of urothelial carcinoma, concludes Sonpavde.