1. Fuerst, Mark L.

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SAN FRANCISCO-A combination of enfortumab vedotin plus pembrolizumab leads to durable responses in patients with locally advanced or metastatic urothelial carcinoma, according to a new study.

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Platinum chemotherapy is the standard for patients with metastatic urothelial carcinoma in the first-line setting. In cisplatin-ineligible patients, gemcitabine/carboplatin is a standard therapy, but is poorly tolerated with limited durability and survival, lead author Jonathan E. Rosenberg, MD, Chief of the Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center, told attendees at the 2020 Genitourinary Cancers Symposium hosted by ASCO.


"Programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors, such as pembrolizumab, have shown promising durability in this setting for PD-L1 high patients," said Rosenberg. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent MMAE to cells expressing nectin-4, which is highly expressed in urothelial carcinoma. "EV has shown activity in previously treated metastatic urothelial carcinoma," he noted.


Initial data with a combination of EV plus pembrolizumab in 45 metastatic urothelial carcinoma patients were presented at the 2019 European Society for Medical Oncology by Christopher Hoimes, DO, Assistant Professor, Department of Medicine Division of Hematology and Oncology Case Western Reserve University (Ann Oncol 2019;30(suppl_5):v356-v402). Thirty-two (71%) patients had a confirmed objective response rate (ORR), and six (13%) patients experienced a complete response (CR). Responses occurred in PD-L1 high and low patients defined with the cutoff of CPS of 10 as the delineating factor. All but three patients had some degree of tumor shrinkage, translating into 93 percent of patients with some level of tumor reduction. Responses were rapid and durable, with 91 percent of responses occurring at the first assessment at 9 weeks.


In conclusion, Hoimes stated: "In first-line cisplatin-ineligible patients with locally advanced metastatic urothelial carcinoma, EV plus pembrolizumab demonstrates encouraging efficacy with a tolerable and manageable safety profile. Further evaluation of this combination is warranted."


Durability Data

At the symposium, Rosenberg presented the first durability data and an update on safety and ORR (Abstract 441). As of October 2019, the 45 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for platinum-based treatment had received 1.25 mg/kg EV (days 1 and 8) plus pembrolizumab (day 1). The primary endpoint was safety or tolerability. The patients, median age 69 years, received a median of 9 cycles of EV plus pembrolizumab.


With a median follow-up of 11.5 months, the confirmed investigator-assessed ORR was 73.3 percent, including 15.6 percent CRs; the disease control rate was 93.3 percent. The ORR in patients with liver metastasis was 53.3 percent (8 of 15 patients). The ORR in patients with available PD-L1 status was 78.6 percent in PD-L1 high (11 of 14 patients) and 63.2 percent in PD-L1 low (12 of 19 patients), Rosenberg noted.


Of the 33 responders, 18 patients (55%) have ongoing responses, including 11 responses beyond 10 months. The median duration of response has not been reached. The median progression-free survival was 12.3 months. The results compare favorably to historical data with gemcitabine and carboplatin chemotherapy, he said.


The most common treatment-emergent adverse events were fatigue (58%, 11% at least grade 3), alopecia (53%), and peripheral sensory neuropathy (53%, 4% at least grade 3). One patient died due to an adverse event reported as related (multiple organ failure).


In conclusion, Rosenberg stated: "In first-line cisplatin-ineligible patients with metastatic urothelial carcinomas, EV plus pembrolizumab, a potential platinum-free option, demonstrates promising activity and durability with a manageable safety profile."


Further evaluation of EV plus pembrolizumab in both metastatic urothelial cancer and muscle-invasive urothelial cancer is ongoing, he said.


Mark L. Fuerst is a contributing writer.


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