A Breakthrough Treatment With Enfortumab for Metastatic Urothelial Cancer

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A new agent that targets Nectin-4, a protein found in 97% of urothelial cancers, may be an option for patients with locally advanced or metastatic forms of urothelial cancer.

CHICAGO-A new agent that targets Nectin-4, a protein found in 97% of urothelial cancers, may be an option for patients with locally advanced or metastatic forms of urothelial cancer. A single-arm phase II clinical trial of 125 patients has found that treatment with enfortumab vedotin produced responses in 44% of patients. All the patients had previously been treated with platinum chemotherapy and a PD-1 or PD-L1 immune checkpoint inhibitor, but the cancer had progressed despite these treatments. These results (abstract LBA4505) were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31–June 4 in Chicago.

Lead study author Daniel P. Petrylak, MD, professor of medicine and urology at Yale Cancer Center in New Haven, Connecticut, said that these phase II results replicate the phase I results very closely, which is not often the case in clinical trials. He said the fact that this is a therapy that can help patients who don’t benefit from checkpoint inhibitors is very gratifying.

Currently, first-line therapy for urothelial cancer is platinum-based chemotherapy, and second-line therapy is a checkpoint inhibitor of which there are 5 approved for use in urothelial cancer by the US Food and Drug Administration (FDA): pembrolizumab, atezolizumab, durvalumab, nivolumab, and avelumab. However, studies show that cancer progresses in 75% to 80% of patients with advanced urothelial cancer who receive an immune checkpoint inhibitor.

In this current study, urothelial cancer patients who had been treated with platinum-based chemotherapy and/or checkpoint inhibitors were divided into two groups. Group one had been previously treated with both therapies, and group two consisted of patients who had not received platinum chemotherapy. In group one, 70% of the 125 patients were men and the median age was 69 years (range, 40–84 years). Among these patients, 34% had cancers in their upper urinary tract (a relatively uncommon site) and had a median of 3 prior systemic treatments in the locally advanced or metastatic setting, but had not received treatment for at least 2 weeks prior to enrolling in this trial.

The researchers found that 44% of patients responded to enfortumab in group one, resulting in either no growth or shrinkage in their tumors. Twelve percent had a complete response with no detectable sign of cancer, and the median overall survival (OS) time was 11.7 months. When the researchers looked at the patients with cancer who had not responded to a checkpoint inhibitor, 41% responded to enfortumab, and 38% of patients with liver metastases responded to enfortumab. 

“We see that 84% of patients had some form of tumor shrinkage,” said Petrylak. “The drug was well tolerated. The majority of side effects were grade 1 and grade 2.” He said the most common side effects included fatigue (50%), alopecia (49%), and decreased appetite (44%). Overall, 12% of patients discontinued treatment due to toxicities, and the most commonly encountered grade 3 or higher side effect was neutropenia.

Petrylak said there is a high unmet need for patients with advanced and metastatic urothelial carcinoma, and enfortumab vedotin is the first novel therapy to demonstrate substantial clinical activity in patients who progressed after platinum chemotherapy and a PD-1/PD-L1 inhibitor. A phase III study to confirm these findings is now underway. Karim Chamie, MD, an associate professor of urology at the David Geffen School of Medicine at UCLA, told Cancer Network that the study findings are a breakthrough in terms of treatment for metastatic urothelial carcinoma. “The historical response rate of chemotherapy in the platinum-refractory setting is approximately 10%, while checkpoint inhibitors are in the 13% to 21% range, for atezolizumab and pembrolizumab, respectively. With an objective response rate of 44% in the third-line setting, we find two- to threefold the activity of earlier-line FDA-approved drugs,” said Chamie.

According to Chamie, when phase II results essentially mirror the phase I findings, clinicians can take solace in the reliability of the data and efficacy among varying tumor location and burden. “This study must also be placed in the context that with ubiquitous expression of nectin-4, the oncologist doesn’t need to send the tumor out for additional testing, as is the case for erdafitinib for FGFR alteration or checkpoint inhibitors for PD-L1 expression to select for patients likely to benefit,” he said.

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