The combination of Merck’s Keytruda and Seagen and Astella’s Padcev has made noise as a possible option for untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer.
But other questions loomed during the study period: How would Padcev work for the same indication as a monotherapy, and how much does it contribute to the combination?
Wednesday at the European Society for Medical Oncology’s annual conference, more clarity came with EV-103 trial results from a key patient population—cohort K—which indicate that the combo performed well and Padcev was a significant contributor.
Of 76 patients who received the combo, 64.5% had tumor shrinkage, with 10.5% showing complete response. Of the 73 patients on Padcev alone, the rate was 45.2%, with 4.1% responding completely.
“It shows a very nice response rate of 65%, which is about 20 points higher than you would expect from historical control data,” Scot Ebbinghaus, M.D., Merck’s vice president of clinical research, said in an interview with Fierce Pharma. “Moving the best combination up front is ultimately not only a legitimate strategy, but it’s where we’re going to end up.”
As for one of the secondary endpoints—the median duration of response—it was not reached for the combo group, as more than 50% of recipients were still responding at the study cutoff. Meanwhile, the Padcev group showed a median duration of 13.2 months.
In their original announcement of EV-103’s top-line results, Seagen and Astellas didn’t offer information on how Padcev monotherapy fared, fueling some negative speculation. But the results from cohort K indicate that Padcev is pulling its weight with response rates considering Keytruda's figure as a solo agent was 28%.
"[Padcev] has a little bit higher response rate as a monotherapy than Keytruda, but both drugs are important for the combination," Ebbinghaus said. "What Keytruda brings is a nice durability of response, and so what we really hope for in any combination is that you get the best attributes of both agents and get not only a high response rate but one which is durable."
The results are significant, as they could help the companies pursue an accelerated approval of the combo as a first-line treatment in an indication where there is high unmet need. If approved, that could help Padcev reach its blockbuster potential. Its 2021 sales were $340 million.
An approval also would secure patent protection in the indication for Keytruda, which loses its exclusivity in 2027.
Despite its mega-blockbuster status, Keytruda has suffered some key losses lately, including in metastatic bladder cancer. After the phase 3 trial raised a red flag, Keytruda’s use in front-line bladder cancer has been limited to patients who are ineligible for any platinum-based chemotherapy.
The potential combo also is another factor to consider in Merck’s rumored attempt to acquire Seagen, though those talks could be cooling down with reports of the companies failing to agree on a price.
Another question to consider is the potential scope of the approval for the combo in light of Pfizer and Merck KGaA’s full approval for Bavencio after showing it could extend lives as a first-line maintenance therapy in patients who’ve responded to one cycle of chemo.
The design of cohort K in EV-103 leaves a patient subgroup which—though not eligible for cisplatin—is eligible for carboplatin, a population that overlaps with Bavencio’s indication. Both cisplatin and carboplatin are platinum chemotherapies.
So the question is—as noted by SVB Securities’ Daina Graybosch, Ph.D.—will the FDA only give Padcev-Keytruda an accelerated approval in patients ineligible for any platinum chemo based on tumor shrinkage data when there’s a standard-of-care PD-L1 regimen for patients who are up for platinum chemo?