Enfortumab vedotin shows promise in advanced urothelial cancer
The novel antibody-drug conjugate enfortumab vedotin showed promising clinical activity in patients with advanced and metastatic urothelial cancer for whom there is a high unmet need, according to the EV-201 study presented at the ASCO 2019 Meeting.
Treatment options are limited for patients who have progressed during or after platinum-based chemotherapy or PD-1/L1 checkpoint inhibitors, said Professor Daniel Petrylak of Yale Cancer Center in New Haven, Connecticut, US.
Response rate to second-line PD-1/L1 inhibitors are 13–21 percent with few options once patients progress, and single agent chemotherapy post-platinum/checkpoint inhibitors had limited activity with an objective response rate (ORR) of approximately 11 percent, he pointed out.
“[Enfortumab vedotin is the] first novel therapeutic to demonstrate substantial clinical activity in patients who [have] progressed after platinum chemotherapy and a PD-1/L1 inhibitor,” said Petrylak.
Enfortumab vedotin contains a monoclonal antibody targeting Nectin-4, which is overexpressed in urothelial cancer; conjugated with a cytotoxic drug which disrupts microtubule and leads to cell death.
“These phase II results replicate the phase I results very closely, which is not often the case in clinical trials,” Petrylak added. “The fact that we have a therapy that can help people who don’t benefit from checkpoint inhibitors is very gratifying.”
The multicentre, single-arm, pivotal phase II study involved 125 patients (median age 69 years, 88 percent male) with metastatic or unresectable locally advanced urothelial cancer who had progressed during or following recent therapy despite previous treatment with platinum-based chemotherapy and a PD-1/L1 inhibitor (median number of prior systemic therapies=3). They received 1.25 mg/kg of enfortumab vedotin on days 1, 8, and 15 of a 28-day cycle. [ASCO 2019, abstract LBA4505]
The primary endpoint of ORR was 44 percent (95 percent confidence interval [CI], 35.1–53.2), which was clearly higher than historical value of single agent chemotherapy or immunotherapies post-progression. The ORR comprised a complete response rate of 12 percent and a partial response rate of 32 percent.
Twenty-eight percent of the patients had stable disease while 18 percent progressed in disease. Median duration of objective response (DOR) was 7.6 months, with 44 percent of having ongoing response.
Similarly high ORRs were seen across all subgroups regardless of age, ECOG performance status, primary tumour sites, and number of or response to prior therapies. In particular, ORR was 38 percent in patient subgroup with liver metastasis and 41 percent in non-responders to previous PD-1/L1 inhibitors.
Overall, there was a measurable change from baseline in tumour measurements in 84 percent of the patients, as assessed on a blinded independent central review, reported Petrylak.
Median progression-free survival total at 5.8 months, whereas median overall survival was 11.7 months.
Enfortumab vedotin was also tolerable with a manageable safety profile, said Petrylak. Fatigue (50 percent) was the most common treatment-related adverse events (TRAEs) of any grade, followed by alopecia (49 percent), decreased appetite (44 percent), and dyspepsia and peripheral sensory neuropathy (40 percent), but few TRAEs lead to discontinuation (12 percent). In addition, TRAEs of interest such as peripheral neuropathy, rash, and hyperglycaemia were mostly resolved or ongoing at grade 1 in more than three-quarter of the patients.
Invited discussant Dr Andrea Necchi of Fondazione IRCCS-Istituto Nazionale dei Tumori in Milan, Italy commented that the outcome data are “so clear and so good,” although they came from a phase II study – which warrants further investigation in phase III study.
This was confirmed by Petrylak at a press conference, who said a phase III trial in urothelial cancer is currently in the plan.