Daniel P. Petrylak, MD
Enfortumab vedotin (EV) induced a 44% response rate in patients with locally advanced or metastatic urothelial cancer, including 12% experiencing a complete response (CR) to treatment, according to results from the phase II EV-201 study presented at the 2019 ASCO Annual Meeting.
Moreover, median overall survival (OS) was 11.7 months (95% CI, 9.1-not reached), median progression-free survival (PFS) was 5.8 months (95% CI, 4.9-7.5), and median duration of response (DOR) was 7.6 months (range, 0.95-11.30+).
“There is a high unmet need for patients with advanced and metastatic urothelial carcinoma,” lead study author Daniel P. Petrylak, MD, professor of medicine and urology at Yale Cancer Center, said during a press briefing at the meeting. “Enfortumab vedotin is the first novel therapeutic agent to demonstrate substantial clinical activity in patients who progressed after platinum chemotherapy or a PD-1 or PD-L1 inhibitor.”
In the pivotal, single-arm, 2-cohort study (NCT03219333), investigators evaluated the antibody-drug conjugate—designed to target Nectin-4, which is highly expressed in urothelial carcinoma—in patients who progressed following treatment with platinum chemotherapy and a PD-1 or PD-L1 immune checkpoint inhibitor (CPI).
Patients were stratified into 2 groups: group 1 had been previously treated with both medicines (n = 128) and group 2 had not received platinum chemotherapy and were ineligible for cisplatin. Petrylak reported on results from group 1 at the meeting, while enrollment is ongoing for cohort 2.
Patients received 1.25 mg/kg enfortumab vedotin intravenously on days 1, 8, and 15 of each 28-day cycle.
ORR per RECIST 1.1 by blinded independent central review served as the primary endpoint. Secondary endpoints included DOR, PFS, OS, and safety/tolerability.
Seventy percent of the 125 patients treated with enfortumab vedotin were male and were a median of 69 years (range, 40-84). Patients received a median of 3 lines (range, 1-6) of prior systemic treatments in the locally advanced or metastatic setting but had not received treatment for at least 2 weeks prior to enrolling in the trial. Combined positive scores of PD-L1 expression were below 10 in 65% and ≥10 in 35%.
As of January 2019, the confirmed ORR was 44% (95% CI, 35.1%-53.2%), with a 12% CR rate and a 32% partial response rate. Thirty-five patients (28%) had stable disease and 23 had progressive disease (18%).
Responses were observed across all subgroups, irrespective of response to prior PD-1/L1 inhibitors or presence of liver metastases (ORR, 38%; 95% CI, 24.7%-52.8%).
Median time to response was 1.8 months (range, 1.2-9.2), with 44% of responses ongoing.
The most common treatment-related adverse events (TRAEs) of any grade were fatigue (50%), alopecia (49%), and decreased appetite (44%), while TRAEs of interest include any case of rash (all grade, 48%; grade ≥3, 12%), any peripheral neuropathy (all grade, 50%; grade ≥3, 3%), and any hyperglycemia (all grade, 11%; grade ≥3, 6%). Twelve percent of patients discontinued treatment due to a TRAE—mostly due to peripheral neuropathy. One death was reported as treatment related (interstitial lung disease), but was confounded by a suspected pulmonary infection, as per the investigator.
Results from the earlier phase I EV-101 trial demonstrated an objective response rate (ORR) of 41% (95% CI, 29.3-53.2), including 3 (4%) CRs and 26 (37%) partial responses.
In March 2018, the FDA granted a breakthrough therapy designation to enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer that has progressed during or following checkpoint inhibitor therapy based on phase I trial results.
“We feel that both of these trials support the submission to the FDA for accelerated approval,” Petrylak said, adding that 2 additional trials are ongoing: The randomized phase III EV-301 trial is evaluating enfortumab vedotin compared with standard-of-care post-platinum and a PD-1/L1 inhibitor (NCT03474107), and EV-103 will investigate the agent in combination with pembrolizumab and/or chemotherapy (NCT03288545).
“[EV-103] will be our pivotal phase III trial with this particular drug,” said Petrylak. “We are very excited about this.”
ASCO expert Robert Dreicer, MD, MS, MACP, FASCO, supported the findings, adding that there is a clear unmet need in this patient population. “Metastatic urothelial cancer is a pretty common disease and there is very limited therapeutics. For decades, frontline chemotherapy was all we had…. New therapies are badly needed.”
“I’m also compelled by this data…median survival approached a year and with frontline chemotherapy, survival is 13 months,” he added. “The reality is, I look at these data as effective. I would support accelerated approval. I hope the FDA shares that and that the confirmatory phase III trial will get done rapidly, hopefully. I think this is an important development for our patients.”
Petrylak DP, Balar AV, O'Donnell PH, et al. EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. Presented at: 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract LBA4505.
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