By Tristan Manalac

Pictured: Amgen's office in Massachusetts/iStock, hapabapa
The FDA’s Oncologic Drugs Advisory Committee on Thursday voted against Amgen, which is seeking to convert the accelerated approval of its oral G12C KRAS inhibitor Lumakras (sotorasib) to full approval in non-small cell lung cancer.
In a 10-2 vote, the panel of external experts found that Amgen’s progression-free survival (PFS) data from the Phase III confirmatory CodeBreaK 200 study could not be reliably interpreted. In particular, the adcomm noted the high number of study dropouts, the small sample size and potentially biased behavior of the trial’s investigators.
“No one expects a perfect [randomized controlled trial] but what we hope for is a small number of issues in trial conduct and an effect large enough to withstand the uncertainties caused by those issues,” committee member Mark Conaway, professor at the Division of Translational Research and Applied Statistics at the University of Virginia School of Medicine, said during Thursday’s meeting in explaining his vote against Amgen.
“For this trial, we seem to have the opposite—a large number of issues that cloud the interpretation of a small observed effect,” Conaway said.
At the same time, some panelists pointed out that the question posed to the committee is not one that directly addresses Lumakras’ clinical efficacy, but instead narrowly focuses on the reliability of Amgen’s PFS data for Lumakras.
“I hated the question,” James Pantelas, a patient advocate from Michigan, said during the adcomm meeting. Pantelas also voted against Lumakras but clarified that “it’s not a question about the drug or what I feel about the drug, or the importance that it offers my community of lung cancer patients and survivors.”
Amgen is seeking full approval for Lumakras, which was authorized in May 2021 under the FDA’s accelerated pathway. In a briefing document posted ahead of the adcomm meeting, the company provided data from CodeBreaK 200, which showed that Lumakras met its primary endpoint leading to a statistically significant reduction in the risk of disease progression or death compared with docetaxel.
However, FDA staff in their briefing document for the adcomm meeting raised concerns of “systemic bias” in CodeBreaK 200. They contend that there was a much higher rate of study dropouts in the docetaxel comparator group in comparison to the Lumakras study arm, which the FDA detected as “one of the first indications of possible systemic bias” in the study.
The agency also flagged the early crossover from the docetaxel to Lumakras arms—even before disease progression had been assessed—as well as investigator assessments that might have favored the investigational intervention.
The FDA’s decision on Lumakras’ traditional approval is due on Dec. 24. The regulator is not required to follow the recommendations of its advisory committee, though it often does.