Mirati Therapeutics got its approval on December 12, 2022: the FDA granted accelerated approval to Krazati (adagrasib). It is for adults with non-small cell lung cancer that is advanced or has spread, carries the KRAS G12C mutation, and has already been treated with at least one systemic therapy. The catch is in the words “accelerated approval.”
What accelerated means
The agency cleared the drug on the strength of two measures, objective response rate and duration of response, rather than proof that patients live longer. Continued approval depends on a confirmatory trial verifying clinical benefit. In effect, it is a conditional licence.
The numbers
The evidence comes from the phase 2 KRYSTAL-1 study. The registration cohort enrolled 116 patients whose tumors carried the mutation and who had already been treated with platinum chemotherapy and an immune checkpoint inhibitor. They took 600 mg of adagrasib by mouth twice a day. Mirati reported an objective response rate of 43% and disease control in 80% of patients, with a median duration of response of 8.5 months.
A pooled analysis of 132 patients, adding earlier cohorts, put the response rate at 44% and disease control at 81%, with a median duration of response of 12.5 months and a median survival of 14.1 months. At the ASCO meeting in 2022, investigators also reported results for 33 evaluable patients with stable, treated brain metastases: an intracranial response rate of 33%.
Alexander Spira, a medical oncologist at Virginia Cancer Specialists, put the drug in context ahead of the decision. Sotorasib was already approved, he said, but the two have “slightly different toxicity profiles,” and “it’s always good to have more than one class because some people do tolerate one better than the other.”
The market, the tablet and the tests
Mirati CEO David Meek said the approval matters for thousands of patients, including the roughly 14% of NSCLC adenocarcinomas that carry a KRAS G12C mutation. The company says it is making Krazati available as a tablet. The trial, notably, used capsules.
The FDA approved two companion diagnostics alongside the drug: QIAGEN’s therascreen KRAS RGQ PCR kit, run on tissue, and Agilent’s Resolution ctDx FIRST assay, run on plasma. Mirati worked with both companies to develop them. If the plasma test finds no mutation, the tissue should be tested. Mirati said it was also launching a program called Mirati & Me.
Side effects
Safety was assessed in a pooled group of 366 patients, some with lung cancer and some with other solid tumors. Reactions reported by at least 25% included nausea, diarrhea, vomiting, fatigue, muscle and bone pain, liver toxicity, kidney impairment, swelling, shortness of breath and reduced appetite. Thirteen percent permanently stopped treatment because of a reaction.
CancerNetwork’s account of the FDA announcement adds cough, pneumonia, dizziness, constipation, stomach pain and a longer QTc interval among documented adverse effects, plus a string of laboratory abnormalities, from decreased lymphocytes to raised liver enzymes.
Sources
- FDA Grants Accelerated Approval to Adagrasib for KRAS-G12C-Mutated NSCLC (Pharmacy Times)
- FDA Grants Accelerated Approval to Adagrasib for KRAS G12C-Mutated NSCLC (CancerNetwork)
- Mirati Therapeutics Announces U.S. FDA Accelerated Approval of KRAZATI (Mirati)
