Watch out, Amgen. Mirati kicks off KRAS showdown with FDA approval for Krazati

Once considered an undruggable target, KRAS now has two FDA-approved therapies vying for a blockbuster cancer market.

Mirati Therapeutics’ Krazati, also known as adagrasib, will take on Amgen’s first-to-market Lumakras thanks to an FDA accelerated approval in previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC).

Krazati marks Mirati’s first commercial product, and the biotech will focus on efficacy in its marketing pitch, CEO David Meek told Fierce Pharma in an interview ahead of the approval. J.P. Morgan analyst Eric Joseph, Ph.D., has in late November put Krazati’s risk-weighted peak sales estimate across multiple indications at $1.7 billion but then lowered the number to $1.3 billion a few days ago, as blockbuster hopes for the drug have dwindled since a Keytruda combination readout.

Mirati is charging Krazati at a list price of $19,750 for a 30-day supply, a company spokesperson told Fierce Pharma. Krazati is given in 600-mg capsules twice daily. By comparison, Lumakras costs slightly less with a list price of $17,900 per month

In the phase 2 registrational portion of the KRYSTAL-1 trial, Krazati shrank tumors in 43% of patients when used in patients with previously treated NSCLC bearing KRAS G12C mutations. By comparison, Lumakras, given 960 mg once daily, showed a 36% tumor response rate in its own phase 2 trial. And the number dropped to 28% in a larger phase 3 trial.

Similar to Lumakras’ situation, the FDA has required Mirati to run a postmarketing study to test a lower 400-mg twice daily regimen of Krazati. The FDA’s oncology department has recently put an emphasis on dose optimization under Project Optimus. The agency has criticized drugmakers for pushing for the highest tolerable dose in early clinical testing without carefully examining the benefit-risk balance.


RELATED: UPDATED: KRAS battle heats up as Mirati pressures Amgen with Keytruda combo show in lung cancer


About 25% to 50% of NSCLC cases develop brain metastases during the course of the disease. In another key component of Mirati’s commercial campaign, Krazati has shown a brain tumor response rate of 33% versus 25% for Lumakras in patients with baseline brain metastases in its own study. A label with that brain metastases information would be a “nice-to-have” that can differentiate Krazati from the competition, but the data are not included, J.P. Morgan’s Joseph pointed out in a Tuesday note.

In a pooled analysis of the phase 1/2 KRYSTAL-1 trial, patients on Krazati lived a median 14.1 months. By comparison, Lumakras takers survived a median 12.5 months in its phase 2 trial and 10.6 months in the phase 3 study. Krazati’s own phase 3 confirmatory trial, KRYSTAL-12, which compares Krazati with the chemotherapy docetaxel, is underway.

Cross-trial comparisons come with intrinsic problems such as patient characteristics differences. But Meek stressed that Krazati’s response data are best-in-class so far.

In what Meek calls a “halo” effect, Mirati also hopes doctors will notice the company’s recent early results for Krazati’s combination with Merck’s PD-1 inhibitor Keytruda. The early-stage KRYSTAL-7 trial showed what Barclays analysts called “good safety but modest activity” in newly diagnosed NSCLC. In contrast, Merck’s Keytruda combo reported lackluster efficacy data while raising a serious liver safety concern.

“I think we’re the KRAS leader,” Meek said in the interview. “We will set the direction where this KRAS agent goes.”

But while Mirati’s KRAS-Keytruda combo data looked better than Amgen’s, Krazati’s commercial potential is under question as well. The company’s stock price has been about halved after the KRYSTAL-7 combo study, reflecting investors’ concern that the companies’ planned phase 3 trials might not succeed.

Although Krazati is Mirati’s first commercial launch, it’s not the first for the Mirati people. The company has built a sales force with average 19 years of experience in oncology, and the staffers were hired based on their experience in lung cancer, Meek noted.

Mirati has talked to nearly all of the top payer plans and received positive feedback, Chief Commercial Officer Ben Hickey told investors during the company’s third-quarter earnings call last month. Mirati expects to have broad coverage within the first few months of launch, he said.

Krazati’s launch comes as Lumakras experienced a sequential sales decline in the third quarter to $75 million. Amgen attributed the slowdown to a price adjustment as part of reimbursement deal in Germany.

Next up, Mirati plans to launch two phase 3 trials of Krazati—at the 400-mg twice daily dose—in combination with Keytruda in front-line NSCLC this year. The company is discussing a potential accelerated approval pathway for Krazati in third-line colorectal cancer and will have more to share in early 2023, Meek said. The confirmatory KRYSTAL-10 trial for a cocktail of Krazati and Eli Lilly’s Erbitux in second-line colorectal cancer is also expected to read out later next year. In addition, the company has a candidate for KRAS G12D mutations that’s slated to enter clinical testing next year.

With all the pipeline advancement, Mirati has recently reportedly attracted buyout interest from Big Pharma. Mirati has tapped an adviser, and larger pharmas are considering the “merits of a transaction,” Bloomberg reported late November.

“We’re real busy,” Meek said in his interview with Fierce Pharma. “We’re really focused on executing our clinical plans and our launch plans.”

However, any potential acquirer might have pulled out by now, BMO Research analyst Evan David Seigerman said in an investor note after the KRYSTAL-7 combo readout. The phase 3 combo trials Mirati plans to run will take a long time to read out, and existing early-stage data don’t bode well, he said.