KRAS crisis? FDA will gather advisers to weigh full approval for Amgen's Lumakras

First came doubts about the combinability of Amgen’s Lumakras with a standard PD-1 inhibitor. Now, the company will need to defend its first-in-class KRAS inhibitor at an upcoming advisory committee meeting.

The FDA will hold an advisory committee meeting on Oct. 5 to discuss Amgen’s bid to turn Lumakras’ accelerated approval into a full nod, a government filing (PDF) shows. The proposed indication covers patients with KRAS G12C-mutated non-small cell lung cancer after at least one prior systemic therapy.

In May 2021, Lumakras became the first KRAS inhibitor cleared for that type of lung cancer. At that time, the accelerated approval was based on tumor response data from the CodeBreaK 100 trial.

For the upcoming meeting, the FDA will ask its external experts to discuss new data from the phase 3 CodeBreaK 200 trial. In a statement to Fierce Pharma, an Amgen spokesperson said the company cannot speculate on what specific questions the FDA might pose to its experts.

Results from CodeBreaK 200 left some room for debate about the drug’s benefit-risk profile. In the study, the treatment cut the risk of disease progression or death by 34% compared with the chemotherapy docetaxel.

But the Amgen drug only added an extra 1.1 months to patients’ median progression-free survival (PFS) time, for a total of 5.6 months in the Lumakras arm. The PFS and overall response rates both came below previous numbers in CodeBreaK 100.

In another data point that could undermine Lumakras’ case, survival rates between the two groups were not significantly different, according to data presented at last year’s European Society for Medical Oncology annual congress.

At that time, Amgen pointed out that the trial wasn’t powered for an overall survival analysis. That’s partly because Amgen cut its planned trial enrollment after the positive CodeBreaK 100 readout raised ethical concerns of exposing more patients to chemo. Plus, about a third of patients in the chemo group of CodeBreak 200 actually went on to receive Lumakras after disease progression, the company said.

Monday, Amgen’s spokesperson said the company has no new overall survival data to share at this point.

Meanwhile, because of various side effects, the FDA has also asked Amgen to evaluate a lower, 240-mg daily dose of Lumakras—compared with the currently approved 960-mg strength—as a post-marketing requirement. Amgen has yet to share data on that dose optimization study, but the company did include those data in its filing for a full approval.

“The totality of evidence from the CodeBreaK development program and real-world experience demonstrates the clinical value Lumakras provides for patients with previously treated KRAS G12C-mutated locally advanced and unresectable or metastatic NSCLC,” the spokesperson said.

The second-line monotherapy data marked a blow to Lumakras in its competition with Mirati Therapeutics’ Krazati, although few have questioned the Amgen drug’s approvability.

The more alarming problem, however, is the liver safety signal researchers flagged last summer for Lumakras’ potential addition to treatment with PD-1/L1 inhibitors. The liver toxicity has put Lumakras’ long-term market potential into serious question.

Meanwhile, with much better liver safety data and some promising efficacy analysis, Mirati has laid out a plan to test Krazati in tandem with Keytruda in newly diagnosed KRAS G12C-mutated NSCLC patients with high PD-L1 expressions.