Preliminary findings from a phase I clinical trial indicate that enfortumab vedotin, an investigational antibody–drug conjugate targeting nectin-4, shows considerable efficacy in metastatic urothelial carcinoma. Robust responses were seen even among patients with disease progression on platinum chemotherapy and/or immune checkpoint blockade.
Preliminary findings from a phase I trial indicate that enfortumab vedotin (Astellas Pharma; Seattle Genetics) shows considerable efficacy in patients with metastatic urothelial carcinoma whose disease has progressed on platinum chemotherapy and/or immune checkpoint blockade. Daniel Petrylak, MD, of Yale University School of Medicine in New Haven, CT, presented data on this investigational antibody–drug conjugate (ADC) during the 2017 American Society of Clinical Oncology Annual Meeting in Chicago, IL.
Enfortumab vedotin is “the first and only agent targeting the cell adhesion molecule nectin-4,” Petrylak said. The ADC's cytotoxic payload is monomethyl auristatin E, a microtubule-disrupting agent that induces cell-cycle arrest and apoptosis. In an extensive tissue microarray analysis of 2,394 samples representing 34 tumor types, 69% were positive for nectin-4, with the highest frequencies observed in bladder, breast, lung, and pancreatic cancers. The same study also highlighted enfortumab vedotin's strong preclinical activity in cell lines and mouse models, leading to its evaluation in humans.
Initially, to be eligible for the trial, patients had to have their tumors assessed by IHC for nectin-4, Petrylak said. However, such prescreening is no longer required, because 97% of the tissue samples tested expressed it. The gene for nectin-4 is located in a frequently amplified region of the bladder cancer genome, “which is probably one way it becomes overexpressed,” explained senior investigator Jonathan Rosenberg, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.
To date, 81 patients with metastatic urothelial carcinoma have been treated with enfortumab vedotin at sites across the United States and Canada, Petrylak said.
The objective response rate (ORR) among 71 evaluable patients was 41%, including three complete responses.
In subgroup analyses, Petrylak reported that of 32 patients who relapsed following prior immune checkpoint inhibition, 44% responded to enfortumab vedotin. Further, among 19 patients with liver metastases—indicative of a poor prognosis—the ORR was 47%.
The drug was generally well tolerated, with nausea, pruritus, and fatigue being its main, albeit mild, side effects. Ophthalmologic adverse events, which often occur with ADCs, were “infrequent and mostly incidental in nature,” Petrylak added.
“It would appear that enfortumab vedotin is the most active single agent in the treatment of metastatic urothelial carcinoma at this point,” said Anthony Tolcher, MD, director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio. “This is a well-executed study and one that's incredibly encouraging for the ADC field.”
The ORRs are “frankly unprecedented,” Rosenberg agreed, although “the response durability remains to be seen; more data will fill that out.” He also noted that although the FDA approved a slew of anti–PD-1 therapies for bladder cancer over the last year, they benefit no more than 25% of patients. Seeking approval for enfortumab vedotin “in the post-immunotherapy setting makes sense, because that's the unmet need,” he said. A pivotal phase II trial in this patient population will start later this year.
Astellas and Seattle Genetics have been jointly developing another ADC for urothelial carcinoma, directed at the protein SLITRK6. It has a similar activity profile, but “in terms of toxicity, targeting nectin-4 looks like it may be a better option,” Rosenberg observed. Overall, he added, “bladder cancer's environment is target-rich, which could make the ADC strategy a very fruitful one.” –Alissa Poh