Jonathan E. Rosenberg, MD
Enfortumab vedotin may be a safe, well-tolerated option for patients with locally advanced or metastatic urothelial cancer who are previously treated with immunotherapy, an area for which the current alternative is platinum-based chemotherapy, explained Jonathan E. Rosenberg, MD.
“Single-agent chemotherapy might be an option for some of those patients, but [enfortumab vedotin] may be a very good alternative,” said Rosenberg, chief of the Genitourinary Cancer Service at Memorial Sloan-Kettering Cancer Center. He presented updated data from the phase I EV-101 study with enfortumab vedotin at the 2018 ASCO Annual Meeting.
The antibody-drug conjugate enfortumab vedotin consists of an anti–Nectin-4 monoclonal antibody attached to vedotin, a microtubule-disrupting agent MMAE, using proprietary linker technology from Seattle Genetics, the drug’s manufacturer.
In March, the FDA granted breakthrough therapy designation to enfortumab vedotin for the treatment of patients who previously received checkpoint inhibitors for locally advanced or metastatic urothelial cancer. The designation was based on interim results from a phase I dose-escalation/dose-expansion trial showing an overall response rate (ORR) of 41% (95% CI, 29.3-53.2), including 3 (4%) complete responses and 26 (37%) partial responses.1
The trial included 71 evaluable patients who received treatment with enfortumab vedotin 3 out of 4 weeks in a 28-day cycle until there was no further clinical benefit. In updated results presented at ASCO, the data showed that in patients who previously received a checkpoint inhibitor or had liver metastases, the ORR was 40% and 39%, respectively.2
Investigators are exploring the ADC in the ongoing, pivotal phase II EV-201 trial (NCT03219333).3
Investigators hope to recruit 100 platinum-treated patients as well as 100 platinum-naïve and cisplatin-ineligible patients at 57 sites in 8 countries. Eligible patients must have unresectable, locally advanced or metastatic urothelial carcinoma and have received previous treatment with a checkpoint inhibitor.
The agent is also being evaluated in combination with either pembrolizumab (Keytruda) or atezolizumab (Tecentriq) in the phase I EV-103 trial (NCT03288545).
In an interview with OncLive®
, Rosenberg, lead investigator for the phase II study and the updated phase I results, discussed the promise of enfortumab vedotin in patients with bladder cancer who previously received a checkpoint inhibitor, and reflected on the rapid pace of change in the urothelial cancer landscape.
OncLive: What was the rationale for the phase I trial?
: Enfortumab vedotin is an antibody-drug conjugate that targets a molecule that's overexpressed in about 93% of bladder cancers. When it's infused into patients, it circulates throughout the body but it's taken up in cells that express Nectin-4, the target of the molecule. Vedotin is released in the lysosome through cleavage by proteases, the cytotoxic then kills the cancer cell through antimicrotubular activity. That's the proposed mechanism of action. Nectin-4 is also expressed in the skin at low levels, so skin toxicity can be an on-target toxicity of the drug.
That provided the rationale for the phase I study. That study did an initial dose escalation and identified the recommended phase II dose, which is 1.25 mg/kg. The data that are presented [at the 2018 ASCO Annual Meeting] are the data from the dose expansion at 1.25 mg/kg.
More than 110 patients were included in that cohort, the majority of whom had received prior checkpoint inhibitor therapy as well as prior platinum-based chemotherapy. These are patients for whom there isn't a real standard in the United States. The ORR in that study was 41% which was quite impressive compared with historical controls of taxane monotherapy, which are in the 10% to 15% range, at best.
In addition, the estimated progression-free survival is more than 5 months and the median overall survival (OS), which is an estimated value based on the Kaplan-Meier curves, is about 13 months. In historical context, we expect a 6- to 10-month OS in this patient population. These are quite promising results for an early-phase study, and provided the rational for the ongoing, pivotal phase II study.
What have you learned about the toxicity profile of enfortumab vedotin?
Fatigue, anemia, and rash were all common side effects. The rates of grade 3 or higher individual side effects are very low—on average less than 6%. Severe hypoglycemia was identified in a very small fraction of patients; this was a serious adverse event, and the protocols were modified to deal with this. It appears that it might be related to treatment but we're not totally sure at the moment.