Mirati Challenges Amgen in KRAS Space with FDA Accelerated Approval

Lung cancer

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On Monday, the FDA approved Mirati Therapeutics' adagrasib, now to be marketed as Krazati, making it the second KRAS therapeutic to hit the market, behind Amgen’s Lumakras (sotorasib).

Krazati is indicated for adult non-small cell lung cancer patients harboring the G12C mutation in the KRAS gene, with locally advanced or metastatic disease. To be eligible for Krazati treatment, patients must pass an FDA-approved test and should have undergone at least one prior line of systemic therapy.

Following the approval, Mirati’s shares ticked up 9% in post-market trading Monday.

Data from the Phase II, registration-enabling cohort of the KRYSTAL-1 study supported Krazati’s regulatory nod. In the trial, twice-daily treatment with 600 mg capsules induced a 43% objective response rate, with 80% of patients achieving disease control. Response to Krazati lasted for a median of 8.5 months.

In a pooled analysis including data from a Phase I/Ib assessment of Krazati, Mirati’s KRAS drug performed slightly better, with an ORR of 44% and a disease control rate of 81%. Patients in this pooled population survived for a median of 14.1 months.

Regarding safety, Krazati was commonly associated with side effects such as nausea, diarrhea, vomiting, dyspnea, weaker appetite and renal impairment. 13% of treated patients discontinued Krazati due to toxicities.

These findings reflect results from a separate and earlier-stage study, KRYSTAL-7, which assessed Krazati with Merck’s Keytruda (pembrolizumab). Early data from this trial, presented last week at the 2022 ESMO Immuno-Oncology Annual Congress, show the drug combo had an acceptable tolerability profile and promising clinical activity.  

Under the accelerated approval pathway, Mirati is required to run a post-market confirmatory trial to keep Krazati on the market.

The KRAS Showdown

Ahead of Mirati in the KRAS game is Amgen, whose Lumakras won FDA approval in May 2021. Lumakras is similarly indicated for patients with KRAS G12C-mutated NSCLC, as confirmed by an approved test, who have progressed beyond one previous line of systemic therapy.

Data from the Phase II cohort of the CodeBreaK 100 trial supported Lumakras’ green light, with an ORR of 37.1% and a DCR of 80.6%. The median duration of response to Lumakras was 10 months, while treated patients saw a progression-free survival of 6.8 months.

In September, Amgen presented findings from the Phase III CodeBreaK 200 trial, showing that Lumakras induced a 28% ORR, significantly higher than the 13% rate in docetaxel-treated patients. The disease control rate was likewise significantly better in the Lumakras arm, as was the time to demonstrate treatment response.

However, Lumakras failed to distinguish itself from chemotherapy in terms of overall survival, a key secondary endpoint. Nevertheless, Amgen is presenting these data to regulatory bodies worldwide.

Joining Amgen and Mirati in the KRAS race is Roche, which in October signed a $950 million deal with Hookipa to develop the latter’s HB-700 program, an investigational arenaviral immunotherapy for KRAS-mutated cancers.

Novartis is also developing a KRAS therapeutic, JDQ443. At the American Association for Cancer Research (ACCR) in April, the company unveiled data showing the candidate had promising anti-tumor activity and a favorable safety profile.

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