Amgen has bagged the first randomized clinical trial win in the KRAS inhibitor class of cancer medicines. But for potential runner-up Mirati Therapeutics, it could bode ill beyond just a temporary data disadvantage.
Amgen’s Lumakras beat chemotherapy at staving off tumor progression or death in previously treated patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC), the company said Tuesday.
The exact details on Lumakras’ performance were sparse. Amgen said the drug’s progression-free survival improvement showed “statistical significance and superiority” over the chemotherapy docetaxel and that the phase 3 CodeBreaK 200 trial therefore hit its primary goal. The company didn’t share any information on whether Lumakras extended patients’ lives, a key secondary endpoint of the study.
Still, CodeBreaK 200 marks the first success for a KRAS inhibitor in a randomized clinical trial. It also tees up a potential conversion of Lumakras’ current FDA accelerated approval in second-line NSCLC into a full nod—and that could spell trouble for Mirati’s KRAS contender adagrasib.
The FDA accepted Mirati’s application for adagrasib in previously treated NSCLC back in February. But in a surprise move, the FDA adopted a regular review timeline—rather than a faster priory review—with a target decision date set for Dec. 14.
Like Amgen, Mirati is aiming for an initial accelerated approval based on tumor shrinkage data. However, a full approval for Lumakras would close that accelerated pathway for adagrasib and delay the Mirati drug’s potential FDA nod until its own randomized phase 3 readout. Based on a recent precedent, that scenario isn’t unlikely.
In October 2021, Agenus was forced to withdraw an application for PD-1 inhibitor balstilimab in previously treated cervical cancer after the FDA granted Merck’s Keytruda a full nod in the same indication. In that case, Merck unveiled Keytruda’s confirmatory trial win in June 2021 and received the full nod less than four months later.
Right now, Mirati’s adagrasib is less than four months away from its FDA target decision date. But, importantly, the FDA spent less than four months to dole out Lumakras’ landmark first nod last May, which indicates a sense of urgency at the agency to review the first-in-class drug. In contrast, the regular review timeline for adagrasib—versus a priority review—suggests the opposite sentiment toward the Mirati medicine.
Four weeks ago, Mirati didn’t seem too concerned about the regulatory risk. During an investor call early August, Mirati CEO David Meek said the company had completed a midcycle review of the adagrasib application with the FDA and that the interactions were productive. What’s more, the biotech had already assembled a 100-plus person U.S. field force, which Meek said could support a launch as early as the end of September.
As for adagrasib’s own confirmatory trial, KRYSTAL-12, Mirati expects to complete enrollment in the first half of 2023, R&D chief Chuck Baum, M.D., Ph.D., said on the call.
Meanwhile, industry watchers are keeping a close eye on the two KRAS inhibitors’ combination data with Keytruda in newly diagnosed NSCLC. Earlier this month, Amgen gave a first look at the Lumakras-Keytruda data in NSCLC. A notable liver toxicity problem and subsequent high discontinuation rate raised serious questions about the viability of the combination, especially given its disappointing tumor response data compared with Lumakras monotherapy. But the results were drawn from a very small population of patients who took various dosages of Lumakras and two different PD-1 dosing strategies.
Despite all the unanswered questions, Amgen is now moving forward with a low, 240-mg dose of Lumakras for a lead-in period before adding Keytruda in a dose-expansion phase of the early-stage study in treatment-naïve NSCLC patients.