ESMO: Astellas, Seattle Genetics' Keytruda combo shrinks 71% of bladder cancers

Astellas and Seattle Genetics’ antibody-drug conjugate is at it again. On Saturday, the duo revealed data showing that enfortumab vedotin, along with Merck’s Keytruda, shrank 71% of tumors and wiped out 13% of them in patients with advanced urothelial cancer who had not undergone any other cancer treatment. 

The phase 1 data, presented at the annual meeting of the European Society for Medical Oncology, come from 45 patients with urothelial cancer, which primarily occurs in the bladder, but can also affect nearby organs. It tested the enfortumab-Keytruda combo in patients too frail for treatment with the typical first-line agent, cisplatin. 

Besides shrinking tumors in nearly three-quarters of patients and banishing them in 13%, the combo also stopped tumor growth in more than one-fifth of them. Overall, the combo posted a disease control rate of 93%, Andy Krivoshik, M.D., Ph.D., who heads oncology at Astellas, told FierceBiotech. This figure includes patients who saw some tumor shrinkage, but not enough to be considered responders.

Seattle Genetics' stock jumped Monday morning, 12% up from Friday's closing price.

On the safety side, one patient died from treatment-related multiple organ failure, the trial investigator determined. More than half of the patients suffered side effects of grade 3 or above, including fatigue, nausea and peripheral sensory neuropathy, that is, weakness or numbness, usually in the hands and feet. Seven patients—16%—had serious treatment-related side effects, but only four patients—9%—quit because of treatment-related side effects, the companies said, and overall safety numbers were consistent with studies of the ADC as a monotherapy.

"Four patients discontinued treatment due to an adverse event, with the most common reason being peripheral sensory neuropathy (n=2). Thus far, we do not see any new safety concerns with this combination," said Dr. Christopher Hoimes, director of genitourinary oncology at Case Western Reserve University's Case Comprehensive Cancer Center, via email. "There was one patient death on study who had high visceral tumor burden and pre-existing comorbid conditions, where a relationship to treatment could not be ruled out as assessed by the treating investigator."

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Patients responded within a median of two months, Krivoshik said. “The response occurs very rapidly," he noted, adding that the study hasn't yet reached a median for durability of response. So far, it stands at a range of one month to 10.5 months. "The upper range is likely to continue to go out,” he said. 

The antibody piece of enfortumab targets the protein Nectin-4, which is found in many solid tumors, but in nearly all urothelial tumors. Its drug component disrupts the microtubule infrastructure—commonly called the railways of the cell and used for moving organelles around as well as to support the cell and give it shape. 

Astellas and Seattle Genetics have submitted enfortumab for FDA approval as a later-line treatment for urothelial cancer, after patients have gone through checkpoint inhibitors either in tandem with, or following, chemotherapy. They looked earlier in the treatment continuum because patients who can’t receive cisplatin tend to do worse than patients who can. 

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“We decided in consultation with a lot of doctors who treat urothelial cancer that we wanted to combine enfortumab vedotin with a PD-1 inhibitor in urothelial cancer patients in a frontline setting,” Seattle Genetics CEO Clay Siegall, Ph.D., told FierceBiotech. “We decided to initially do it with patients that were ineligible for cisplatin.” 

Patients who can’t take cisplatin could take carboplatin instead, he said, but the response rate tends to be “fairly modest.” 

“We thought we could get a lot better than a response rate in the mid- to upper 30s,” he said. “[And we asked] could we do it without platinum, without carboplatin? Could we get away from a chemotherapy regimen altogether?” 

The new data have obvious implications for patients too weak to receive chemotherapy, but it could even replace chemotherapy in the treatment of urothelial cancer. The companies plan to test the enfortumab-Keytruda combo in all comers, that is, as a firstline treatment for patients regardless of whether they can or cannot undergo chemotherapy. 

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“We are very much excited to go forward and explore a chemo-free regimen in all comers with urothelial cancer. And since the expression of nectin-4 is ubiquitous, we would not need to screen patients to rule them out. Our intent in frontline would be to test the combination in anybody diagnosed with urothelial cancer."

The data come four months after Astellas and Seattle Genetics unveiled data for enfortumab on its own as a later-line treatment for urothelial cancer. The companies announced phase 2 data showing that the treatment shrank 44% of tumors and eliminated 12% of them at the annual meeting of the American Society for Clinical Oncology. The 125 patients in that study had already received chemo and checkpoint inhibitors.

Editor's note: This story was updated to clarify the safety data and add a comment from the study investigator.