Merck's Keytruda approval in newly diagnosed bladder cancer is already limited to a subset of patients. And if a group of expert FDA advisers have their way, it would be limited even further.
At a meeting of the FDA's oncology advisers Wednesday, the panel voted to back the drug's current approval in first-line bladder cancer, despite its failure in a confirmatory trial.
But some experts’ comments—and the FDA’s response—could spell trouble for Merck.
In what several of the panelists called a “hard decision,” the expert advisory committee voted 5 to 3 in favor of keeping Keytruda’s conditional front-line bladder cancer nod in place, pending additional clinical data.
The current nod allows Keytruda to be used in previously untreated patients who aren't eligible for cisplatin, a type of platinum chemotherapy, provided their tumors express PD-L1 at a combined positive score of 10 or higher. It's also approved for those who aren't eligible for any platinum chemo, regardless of their PD-L1 status.
That split is where the trouble begins. Almost all experts touched upon the possibility of limiting the approval to that latter group.
The FDA's response? The agency “can take that into consideration,” one FDA staffer said during the meeting Wednesday morning.
Scot Ebbinghaus, M.D., Merck Research Laboratories vice president of clinical research, said in a statement that the company was pleased with the committee's positive vote.
“Patients with advanced urothelial carcinoma, the most common type of bladder cancer, remain in critical need of additional treatment options," Ebbinghaus said. "We have an extensive clinical development program in bladder cancer, and we look forward to working closely with the FDA as we progress our research," he added.
In 2017, the FDA offered a conditional nod for Keytruda in first-line bladder cancer patients who aren’t eligible for cisplatin based on tumor shrinkage data. But in the middle of the confirmatory Keynote-361 trial, patients who had low PD-L1 expression levels were found to perform worse than those who took platinum chemotherapy.
The FDA immediately moved to limit the drug in cisplatin-ineligible patients to those with PD-L1 at a combined positive score of 10 or higher. Those who cannot take any platinum chemo may still be treated with the drug regardless of their PD-L1 status.
Then, when Keynote-361 finally read out, the combination of Keytruda and chemo didn’t outperform solo chemo at preventing death.
After that flop, Pfizer and Merck KGaA won a full FDA go-ahead for their PD-L1 inhibitor Bavencio in the so-called first-line maintenance setting for patients who respond to one round of chemotherapy, after showing the drug could slash the risk of death by 31% compared with best supportive care. That nod further put Keytruda’s place in front-line treatment into question.
Merck made a point Wednesday to underscore that Bavencio’s use still requires chemotherapy, so newly diagnosed patients who can’t tolerate it wouldn't be eligible for Bavencio.
But now, platinum-ineligible cancer might be just what Keytruda gets.
In explaining their voting decisions, almost all panelists singled out the patients who aren't eligible for any platinum chemo. That population is where Keytruda should be used, they suggested.
University of Colorado's Christopher Lieu, M.D., was very straightforward in saying that his reason for voting "yes" is that pulling the approval entirely would leave patients who are platinum ineligible with no available options.
Bavencio could be the treatment of choice for other patients, Lieu said. "This does bring up the issue of potentially revising the indication to specifically address this population," he said.
In voting no, Mohummad Siddiqui, M.D., of the University of Maryland pointed out that cisplatin-ineligible patients now have the Bavencio regimen, so Keytruda doesn't fill any unmet need. An approval for the platinum-ineligible group could be considered, he said, but he didn't know what kind of confirmatory trial could specifically demonstrate that use.
Meanwhile, Merck has proposed the LEAP-011 trial as follow-up confirmatory study. That trial compares the combo of Keytruda and Eisai-partnered Lenvima with solo Keytruda in PD-L1-positive, cisplatin-ineligible patients, or patients who are ineligible for any platinum chemo regardless of PD-L1 status.
Ravi Madan, M.D., of the National Cancer Institute didn't think the trial is an appropriate substitute, and he voted no partly for that reason. The LEAP-011 study will only be able to provide evidence for Keytruda monotherapy in the sense of a single-arm trial that could still leave some questions open, he said.
Merck's Keytruda vote wasn't the only session on Wednesday. Roche, which faced a second review of its PD-1 inhibitor Tecentriq—this one also for bladder cancer—faced a considerably less critical panel than did Merck on Wednesday. The advisers voted 10 to 1 in favor of maintaining the drug's conditional nod as a solo therapy for first-line bladder cancer patients who cannot take cisplatin-containing chemo and who have PD-L1 expression levels covering 5% or more of tumor-infiltrating immune cells.
The FDA's initial issue was that interim analyses of the confirmatory IMvigor130 trial produced mixed survival results. But Roche is expecting a final analysis next year—and most panel members agreed that any decision on the merits of the drug in the first-line bladder cancer setting should not be made without that data.
The only dissenter was Phillip Hoffman, M.D., chairperson of the FDA's oncologic drugs advisory committee. He alluded to the IMvigor211 trial in patients who had been treated with platinum chemo, which failed to confirm a benefit, prompting Roche to withdraw Tecentriq for that second-line indication.
"It sort of goes against most of oncologic history, where something shows benefit in a later line, more advanced disease, and then it's moved progressively earlier to show that it's equally effective or better," Hoffman said during the meeting. "And I'm struck by the fact that this is the opposite of that."
Roche said in a statement that after receiving positive votes from the committee in both bladder cancer and triple-negative breast cancer, the company "will continue to work with the FDA on next steps for Tecentriq in these indications.”