Amgen’s groundbreaking KRAS inhibitor, Lumakras, faced a pivotal moment as the FDA’s Oncologic Drugs Advisory Committee (ODAC) convened to evaluate the merits of its phase 3 clinical trial, CodeBreak 200. While the verdict from the panel tilted negatively for Amgen, Lumakras appears poised to maintain its accelerated approval—for the time being.
The committee of external experts zeroed in on a single critical question: whether the primary endpoint of CodeBreak—progression-free survival (PFS)—could be reliably interpreted within Amgen’s study. The outcome revealed a resounding “no” from ten panelists, while two voted “yes,” underscoring their lack of enthusiasm for Amgen’s trial design. Notably, there were no abstentions.
During the meeting, FDA officials emphasized that their inquiry did not revolve around converting Lumakras’ accelerated approval into a traditional green light. Rather, their concerns centered on the existence of “multiple sources of systemic bias” that cast doubt on the overall adequacy of the trial, as elucidated in briefing documents released earlier in the week.
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However, the agency does not seem inclined to immediately remove Amgen’s drug from the market, considering its accelerated approval in 2021. In light of this stance, it appears probable that the FDA may request Amgen to conduct another confirmatory trial for Lumakras.
In assessing the panelists’ viewpoints, Mark Conaway, Ph.D., from the University of Virginia School of Medicine, who voted against Lumakras, acknowledged that perfection in trials is an unrealistic expectation. Nevertheless, he asserted that trials should have “a small number of issues in trial conduct and an effect large enough to withstand the uncertainties caused by those issues.” In contrast, CodeBreak 200 appeared to present an inverse scenario, featuring “a large number of issues that cloud the interpretation of a small observed effect.”
Also Read: FDA Identifies ‘Systemic Bias’ In Amgen’s Late-Stage Lumakras Trial Ahead Of Adcomm
Even supporters of Lumakras’ trial, like Jorge Nieva, M.D., acknowledged the need for “greater scrutiny from the FDA and greater transparency from Amgen.” Many panelists expressed frustration at the FDA’s narrow focus, underscoring Lumakras’ overall efficacy and benefits for cancer patients, which they believed could not be adequately assessed within the limited scope of the regulator’s inquiry.
William Gradishar, M.D., from the Robert H. Lurie Comprehensive Cancer Center Feinberg School of Medicine at Northwestern University, voted against Amgen’s clinical trial. However, he emphasized Lumakras’ positive attributes, highlighting its superiority over docetaxel in terms of limited side effects and easier oral dosing compared to chemotherapy.
The FDA had previously flagged issues such as “issues in study conduct, high rates of censoring, loss of follow-up of patients who withdrew consent, and potential loss of randomization.” These concerns were identified as factors that could hinder a thorough analysis of Amgen’s phase 3 study.
Another dissenter, Daniel Spratt, M.D., from University Hospitals Seidman Cancer Center at Case Western Reserve University, concurred with the FDA, suggesting the presence of “likely bias or inaccuracies in the progression-free survival assessment.”
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Amgen’s advisory committee meeting unfolded at an intriguing juncture for KRAS inhibitors like Lumakras and its rival, Mirati Therapeutics’ Krazati. Two years ago, Lumakras made history as the first FDA-approved therapy targeting the once-deemed “undruggable” KRAS G12C mutation. While its commercial performance had occasional disappointments, Lumakras served as a growth driver for Amgen, with $285 million in full-year sales in the preceding year.
Notably, Mirati has been garnering interest from the French pharmaceutical powerhouse, Sanofi, as per a Bloomberg report, adding an extra layer of intrigue to the evolving landscape of KRAS-targeted therapies.
