Daiichi's leukemia drug falls amid FDA adcomm's trial concerns

Daiichi Sankyo went one for two in an FDA cancer advisory committee doubleheader Tuesday, with its prospective leukemia treatment getting struck out.

The committee voted 3 to 8 against whether quizartinib’s benefits outweighed its risks—in this case, a median gain of six weeks in overall survival against relapsed or refractory acute myeloid leukemia.

Though that was enough to meet its phase 3 primary endpoint, the lack of similarly significant findings in other efficacy measures such as event-free survival combined with concerns over both the FLT3 inhibitor’s cardiac safety and the trial’s design dampen the drug’s prospects for approval.

In the days before the meeting, agency reviewers pointed to a large number of patients who dropped out of the open-label trial after being randomized to the chemotherapy in its control arm—calling interpretations of the study’s results “unreliable.”

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Nearly a quarter of the patients in the study who were assigned to chemotherapy—28 participants, or 23%—did not go on to receive the treatment and were not followed, compared to only four, or 2%, who were slated for quizartinib.

The disparity “is quite bothersome as to whether this is an adequate and well-controlled study,” said the FDA’s Richard Pazdur, director of the agency’s Oncology Center of Excellence.

“I’ve been here 20 years, and I haven’t seen this discrepancy here, of randomized but not treated patients, to this extent,” Pazdur said, questioning whether biases or equipoise existed during the study’s randomization process.

Daiichi said it was unable to follow up on patients who opted for a different treatment than the study protocol due to varying international and regional regulations governing the withdrawal of consent.

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Additionally, FDA reviewers highlighted imbalances in the subsequent treatments pursued by patients—including a much higher rate of stem cell transplants in the quizartinib arm, at 23%, compared to zero among those who received low-dose chemotherapy.

While the FDA said this may have skewed the overall survival results—and that there may have been no survival advantage for quizartinib had transplant rates been similar between treatment arms—Daiichi described those discrepancies as a positive.

Compared to those who took the oral drug, the patients randomized to chemotherapy would have seen more side effects—such as infections, lower organ activity and generally weaker overall health—that would preclude them from receiving or surviving a bone marrow transplant.

Therefore, quizartinib could be seen as a fast-acting bridge as patients prepare for hematopoietic stem cell transplants and line up donors, even with the drug’s shorter durations of response, the company said at the meeting.

That sentiment was echoed by many of the panel members as they explained the reasoning behind their votes, “no’s” notwithstanding.  

Even quizartinib’s links to QT prolongation and potential heart arrhythmias were not seen as a major issue against its approval, in light of the high risks and attentive care already seen by acute leukemia patients.

“I believe in this drug. I want to use it,” said committee member Anthony Sung, an assistant professor of medicine in the Division of Hematologic Malignancies and Cellular Therapy at Duke University, who ultimately sided against it. “I have to vote based on the data that I was shown.”

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But it wasn’t all bad news for Daiichi. Earlier in the day, the advisory committee voted 12 to 3 in favor of its pexidartinib treatment for the rare, benign cancer known as giant cell tumor of the tendon sheath, which occurs in joints.

While FDA reviewers were troubled by the drug’s potential liver toxicity, the committee members generally felt that a Risk Evaluation and Mitigation Strategy would help prevent harm, or at least catch it early. Enrollment in a phase 3 study of the oral CSF-1R inhibitor pexidartinib had previously been suspended in 2016 over two serious but nonfatal cases of liver toxicity.

Daiichi, with its development partner Plexxikon, said the study ended up being just five patients short of its enrollment goal of 126 participants. The study continued, and top-line results presented a year later showed pexidartinib meeting its primary endpoint by shrinking the size of the tumors in patients unable to undergo surgery.

The FDA is set to make a decision on pexidartinib’s approval by Aug. 3, after granting the drug priority review. Quizartinib's decision is due by Aug. 25.