Treatment sequencing key as options increase for patients with urothelial cancer
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Optimal sequencing of therapy for metastatic urothelial carcinoma will be crucial to extend patient survival, given the number of drug approvals over the past decade, according to a speaker at Chemotherapy Foundation Symposium.
“There’s lot of data with sequencing, and because of some of the studies and potential approvals in the neoadjuvant and adjuvant setting, we’re going to have a great challenge in treating patients with our agents, as well as in designing clinical trials,” Daniel P. Petrylak, MD, professor of medicine and urology, director of the GU translational working group, and co-director of the cell signaling program at Smilow Cancer Center at Yale University, as well as a HemOnc Today Editorial Board member, said during a presentation.
Approved agents for first-line treatment of PD-L1-positive metastatic urothelial carcinoma include the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) and anti-PD-L1 therapy atezolizumab (Tecentriq, Genentech) for platinum-ineligible patients, Petrylak said.
Switch maintenance therapy with another anti-PD-L1 antibody, avelumab (Bavencio; EMD Serono, Pfizer), is standard of care for patients who respond to front-line chemotherapy, he added.
“I like using disease aggressiveness as my first-line approach, so think of controlling disease by administering chemotherapy or checkpoint therapy to a platinum-ineligible patient,” Petrylak said.
For patients with fibroblast growth factor receptor 3 (FGFR3) expression, which is detected in between 10% and 20% of metastatic urothelial carcinoma specimens, the FDA approved erdafitinib (Balversa, Janssen Oncology). The FGFR inhibitor conferred median PFS of 5.5 months and median OS of 13.8 months in the phase 2 BLC2001 study. Moreover, 21% of patients remained on treatment at median follow-up of 11 months.
The antibody-drug conjugates enfortumab vedotin (Padcev; Astellas, Seagen) and sacituzumab govitecan (Trodelvy, Gilead) have shown promising activity in patients who failed at least two previous therapies, Petrylak said. Enfortumab vedotin, which is directed against nectin-4, received full FDA approval for patients who had prior chemotherapy or immunotherapy, and sacituzumab govitecan, which targets Trop-2, is approved for patients with refractory disease.
“We really need to work on the optimal sequencing of these particular agents,” Pertylak said.
Petrylak also noted that novel combinations, such as enfortumab vedotin plus pembrolizumab, have demonstrated significant antitumor activity in cisplatin-ineligible patients. Results of the open-label, phase 1b/phase 2 EV-103 trial showed a confirmed objective response rate for the combination 64.5% (95% CI, 52.7-75.1) among previously untreated, cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. Moreover, the responses were rapid and durable.
Future trials should seek to determine whether maintenance therapy is needed after enfortumab vedotin plus pembrolizumab and the optimal duration of therapy with enfortumab vedotin, considering incidence of treatment-related peripheral neuropathy with the agent, Petrylak said.
“If [enfortumab vedotin plus pembrolizumab] turns out to be the standard of care for patients who are platinum-ineligible, as well as a positive study with the platinum-eligible patients, will cisplatin eligibility become irrelevant?” he said. “And will we start moving standard chemotherapy into the second-, third-line and beyond settings? Those are the questions I think we’re going to have to answer.”
References:
- Petrylak DP. Sequencing therapy throughout the urothelial treatment continuum. Presented at: 40th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 9-11, 2022.
- Rosenberg, JE, et al. Abstract LBA73. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
- Siefer-Radtke AO, et al. Abstract 4503. Presented at: Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
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Petrylak DP. Sequencing therapy throughout the urothelial treatment continuum. Presented at: 40th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 9-11, 2022.
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