Amgen's Lumakras flunks FDA expert meeting, but market withdrawal looks unlikely for now

Judgment Day has come for Amgen’s first-in-class KRAS inhibitor Lumakras as the FDA’s Oncologic Drugs Advisory Committee (ODAC) gathered Thursday to weigh the merits of the cancer med’s phase 3 clinical trial CodeBreak 200. But, despite a negative vote for Amgen, it appears Lumakras is likely to hold onto its accelerated approval—for now.

The panel of outside experts weighed in on one solitary question: whether CodeBreak’s primary endpoint—progression-free survival (PFS)—could be reliably interpreted in Amgen’s study. Overall, 10 panelists voted "no" and two voted "yes," suggesting the experts were unimpressed with Amgen’s trial design. There were no abstentions.

During Thursday’s meeting, FDA officials stressed that they weren’t asking about converting Lumakras’ accelerated approval into a full, traditional green light. Rather, the agency is more concerned about “multiple sources of systemic bias” that bring the trial’s overall adequacy into question, according to briefing documents published earlier this week.

Still, the agency doesn’t appear to be planning to force Amgen’s drug off the market after its 2021 accelerated approval—at least not immediately, officials said during Thursday’s meeting.

In light of that stance, it seems likely the FDA could demand Amgen perform another confirmatory trial on Lumakras.

As for the panelists’ takes, the University of Virginia School of Medicine’s Mark Conaway, Ph.D., who voted no, admitted that no one expects a perfect trial, but it’s reasonable to expect that studies have a “small number of issues in trial conduct and an effect large enough to withstand the uncertainties caused by those issues.” CodeBreak 200, for its part, presents the opposite scenario— “a large number of issues that cloud the interpretation of a small observed effect.”

Even those like Jorge Nieva, M.D., who voted in favor of Lumakras’ trial, admitted that the study needs “greater scrutiny from the FDA and greater transparency from [Amgen].”

Overall, many of the panelists expressed frustration with the narrow scope of the FDA’s question. Several experts vouched for Lumakras’ overall effectiveness and benefit in cancer patients and suggested they couldn’t provide a nuanced take on the drug based on the regulator’s limited inquiry.

William Gradishar, M.D., who works at the Robert H. Lurie Comprehensive Cancer Center Feinberg School of Medicine at Northwestern University, voted against Amgen’s clinical trial but stressed that Lumakras is active and is “certainly a more desirable drug, on the whole, than docetaxel,” thanks to its limited side effects and easier oral dosing compared to chemotherapy.

The FDA, for its part, earlier this week flagged “[i]ssues in study conduct, high rates of censoring, loss of follow up of patients who withdrew consent, and potential loss of randomization” that could impede adequate analysis of Amgen’s phase 3 study.

University Hospitals Seidman Cancer Center at Case Western Reserve University’s Daniel Spratt, M.D.—another naysayer—concurred with the FDA that “there is likely bias or inaccuracies in the [progression-free survival] assessment.”

Amgen’s advisory committee meeting comes at a curious time for KRAS inhibitors like Lumakras and Mirati Therapeutics' rival Krazati. Two years ago, Lumakras was the first FDA-approved therapy to target the KRAS G12C mutation that was once branded undruggable.

The therapy has been a growth driver for Amgen, even if its early commercial performance has disappointed at times. Last year, Lumakras generated $285 million in full-year sales.

Meanwhile, Mirati appears to be attracting interest from French pharma juggernaut Sanofi, according to a Bloomberg report.