Amgen’s hopes for gaining full approval for its non-small cell lung cancer drug, Lumakras (sotorasib), encountered a significant setback as FDA staff expressed concerns about the drug’s efficacy in a briefing document released on Tuesday.
The FDA’s Oncologic Drugs Advisory Committee is scheduled to meet on Thursday to discuss Amgen’s application for full approval of sotorasib in non-small cell lung cancer.
The drug, which is an oral inhibitor targeting G12C-mutated KRAS and marketed as Lumakras, received accelerated approval from the FDA in May 2021 for advanced lung cancer patients with KRAS mutations who had either not responded or stopped responding to initial treatment.
The follow-up Phase III trial, CodeBreaK 200, was conducted to confirm the clinical benefit of the drug, a requirement for converting accelerated approval to traditional approval.
However, the FDA staff identified several issues with the trial in their briefing document. They raised concerns about “multiple sources of systemic bias” in the study, including a higher dropout rate among patients receiving docetaxel compared to those on sotorasib.
They also noted that investigator assessments of disease progression favored the sotorasib arm and that patients were switching from docetaxel to sotorasib before blinded independent central review (BICR) assessment of disease progression.
Furthermore, the FDA staff suggested that the primary endpoint of progression-free survival might not be reliable due to its magnitude relative to the imaging interval.
While the data did show a 34% improvement in the risk of disease progression in patients with advanced lung cancer, this improvement was comparable to chemotherapy. Additionally, there was no significant difference in overall survival, although Amgen pointed out that the trial was not designed to detect such a difference.
Sotorasib targets the G-12C-mutated KRAS, a mutation present in approximately 13% of non-small cell lung cancers and about 85% of all diagnosed lung cancers annually.
The FDA acknowledged the initial enthusiasm in the oncology community for the promising results of the CodeBreaK 100 trial due to the importance of the KRAS mutation in lung cancer. However, the agency raised concerns about issues in the conduct of CodeBreaK 200, including high rates of censoring, loss of follow-up for patients who withdrew consent, and potential loss of randomization.
In light of these concerns, the FDA requested that the advisory committee’s discussion on Thursday focus on whether the results of CodeBreaK 200 can be reliably interpreted and whether the trial can be considered adequate and well-controlled.
The news had a mild dampening effect on Amgen’s stock price, with a reported 1.3% drop to $262.92 per share. The FDA is expected to make a final decision on sotorasib’s approval on or before December 24th.