Unprecedented Response Rate in Advanced Bladder Cancer

Platinum-Free Combination Therapy

Nick Mulcahy

February 19, 2020

SAN FRANCISCO — In an early phase clinical trial, a new combination for the initial treatment of locally advanced or metastatic urothelial cancer has shown an unprecedented response rate and was described as "very promising" by one expert here at the Genitourinary Cancers Symposium (GUCS) 2020.

The first-line pairing of enfortumab vedotin (PADCEV, Seattle Genetics/Astellas) plus pembrolizumab (Keytruda, Merck) employs two drugs that are already approved by the US Food and Drug Administration for use in  later lines of treatment for this most common bladder cancer type.

Dr Jonathan Rosenberg

Jonathan Rosenberg, MD, Memorial Sloan Kettering Cancer Center, New York City, reported the first durability data from the dose escalation and expansion cohorts of the EV-103 trial, which involved 45 patients ineligible for standard therapy with cisplatin. Historically, such patients have poor outcomes with the alternative, carboplatin-based chemotherapy.

The efficacy news was notable.

The confirmed response rate with the combination is 73.3%, including 15.6% complete responses and 57.8% partial responses.

"We’ve never seen response rates of 73%" in cisplatin-ineligible patients, said session moderator Guru Sonpavde, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, in comments to Medscape Medical News.

The standard of care for such patients is either gemcitabine-carboplatin, which has a response rate of about 40% to 45%, or, for eligible individuals, pembrolizumab, which has an even lower rate, he said.

Sonpavde, who is not involved in the trial, said the results are "very promising" but he cautioned that they come from a small trial in only 45 patients, and he said oncologists are now awaiting phase 3 trial data.

The ongoing phase 3 trial compares enfortumab vedotin in combination with pembrolizumab (with and without platinum chemotherapy) vs gemcitabine plus platinum chemotherapy in the first-line setting of locally advanced or metastatic urothelial cancer.

The response rates are especially "impressive" because 91% of patients had visceral disease, observed Alison Birtle, MD, Rosemere Cancer Center, Royal Preston Hospital, Fulwood, United Kingdom, who was also not involved in the study. "This means they are poor prognosis patients. Often, nodal disease patients can predominate [in advanced disease studies] and they have significantly better prognosis," she told Medscape Medical News.

The median duration of response has not yet been reached; the median follow-up is now 10.4 months. Out of 33 responders, 18 (55%) had an ongoing response. Also, responses with the combination were "rapid," said Rosenberg, with 88% seen at first assessment. This is important because urothelial cancer can progress rapidly, added Birtle.

Median progression-free survival is 12.3 months, which is "quite long in this population," said Rosenberg.

Median overall survival has not been reached. The 12-month survival rate is 81.6%.

The adverse events (AEs) data represented a "stable safety profile over time," said Rosenberg, with immune-mediated AEs similar to pembrolizumab monotherapy. "There were no new safety signals with the combination," he told the meeting audience. The most common treatment-related adverse events were fatigue, alopecia and peripheral sensory neuropathy. Seven patients (16%) had serious AEs, including one treatment-related death from multiple organ dysfunction syndrome. Six discontinuations (13% of patients) occurred due to AEs. Also, 11% of patients experienced hyperglycemia (an AE associated with enfortumab vedotin), including 7% who had grade 3 or worse.

The study population was typical of bladder cancer, said Rosenberg, with 80% of patients being male, a median age of 69, a majority having some degree of ECOG performance limitation (64%), and most having lower tract cancer (69%).

Responses Regardless of High or Low PD-L1

The finding that responses occurred regardless of whether the tumors tested high or low for program cell death ligand-1 (PD-L1) was highlighted as important by Birtle. "This is vital because currently we can only give a first-line PD-L1 drug to cisplatin-ineligible patients who have high PD-L1 expression," she commented.

PD-L1 status was low (<10) for 42% of patients and high (>10) for 31%, and the remaining 27% of patients were not evaluable or available. Notably, the overall response rates in patients with available PD-L1 status was 78.6% in PD-L1 high (11/14) and 63.2% in PD-L1 low (12/19).

Enfortumab vedotin recently received accelerated approval in the United States for the treatment of locally advanced or metastatic urothelial cancer that has progressed on chemotherapy and immunotherapy.

Pembrolizumab was approved in 2017 for second-line use in patients who progress on chemotherapy or within 12 months of chemotherapy.

Enfortumab vedotin, which is delivered intravenously, is an antibody drug conjugate. It is a first-in-class agent directed against cell adhesion molecule Nectin-4, which is located on the surface of cells and highly expressed in bladder cancer. The antibody directs the product to these cells, and then releases the cytotoxic monomethyl auristatin E (MMAE).

As previously reported by Medscape Medical News, EV-103 investigator Daniel Petrylak, MD, Yale Cancer Center, New Haven, Connecticut, said there is a "high unmet need" among patients with advanced and metastatic urothelial cancer. Despite a flurry of new drug approvals in this setting, with five immune checkpoint inhibitors approved in recent years, the majority of these patients (75%-80%) progress after receiving immunotherapy, he said.

At this meeting, Rosenberg slanted the limitations of checkpoint inhibitors  differently, saying that PD-1 and PD-L1 inhibitor responses "have promising durability" but that their use in the first-line setting is limited to relatively high PD-L1 expression and platinum ineligibility.

This week, in a move that reflects the urgent need for additional treatment options in this setting, the FDA granted a Breakthrough Therapy designation for enfortumab vedotin in combination with pembrolizumab in the first line of treatment.

The study was funded Seattle Genetics. Rosenberg has financial ties to Seattle Genetics, Astellas, Merck, and other pharmaceuticals. Sonpavde has financial ties to Seattle Genetics and Merck. Birtle has disclosed no relevant financial relationships.

Genitourinary Cancers Symposium (GUCS) 2020: Abstract 441. Presented February 14, 2020.

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