Mirati’s KRAS Inhibitor Demonstrates Encouraging Clinical Profile in Latest Data Drop (Updated)

Mirati’s adagrasib demonstrated a solid safety profile in new data released Monday. Despite this, the company’s stock fell 8% in after-hours trading.

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Despite reporting positive data from adagrasib for patients with first-line non-small cell lung cancer (NSCLC), shares of Mirati Therapeutics’ dipped about 8% in after-hours trading Monday.

Adagrasib combined with Merck’s Keytruda (pembrolizumab) showed positive preliminary data from the KRYSTAL-7 Phase II study and KRYSTAL-1 Phase Ib cohort in first-line advanced/metastatic NSCLC patients with KRASG12C mutations.

“These data reinforce the potential of adagrasib as a strong treatment option for NSCLC patients with a KRASG12C mutation,” David Meek, CEO and board director at Mirati told BioSpace. Adagrasib is currently under review for accelerated FDA approval in this patient population, with a target action date of December 14.

Meek noted that this was the largest dataset to date evaluating the combination of a checkpoint inhibitor and a KRASG12C inhibitor as a front-line treatment option for patients with NSCLC with a KRASG12C mutation.

“Based on these data, we look forward to initiating a Phase III trial,” said Chuck Baum, president, founder and head of research and development for Mirati, in a press statement.

Mirati will hold a conference call Wednesday.

“We believe the data continue to support the regimen’s differentiated positioning relative to standard of care and are far more favorable than that of [Amgen’s] Lumakras plus (immunotherapy),” wrote JP Morgan analyst Eric Joseph in a research note to investors.

Adagrasib is a highly selective and potent oral small molecule engineered to inhibit KRASG12C. Keytruda is Merck’s anti-PD-L1 checkpoint inhibitor.

In various studies, adagrasib has shown a long half-life and extensive distribution throughout the body with a reasonable safety profile. It is being evaluated in several clinical studies in combination with other drugs in advanced solid tumors, with registration-enabling studies ongoing in NSCLC and colorectal cancer.

The latest data showed the drug combination helped approximately half of the previously untreated mNSCLC patients with manageable side effects. Mirati suggested the biggest advantage would be in patients with lower PDL1 levels and expects to initiate a Phase III trial in that patient population only, Meek said.

In the studies, 75 patients were enrolled and evaluable with a median follow-up of 3.5 months. Treatment-related adverse events (TRAEs) were primarily Grade 1, 2 and 3, with only 4% Grade 4 and none Grade 5. Only two patients discontinued both drugs due to TRAEs and two discontinued Keytruda. No patients discontinued adagrasib.

The two-drug combination demonstrated promising early clinical results across all PD-L1 subgroups in evaluable patients, showing an objective response rate of 49%. The ORR in a subset of response-evaluable patients enrolled at least six months before the data cutoff was 56%.

Of seven patients in the KRYSTAL-1 Phase Ib cohort, there was an ORR of 57% and a disease control rate (DCR) of 100%. The four patients who responded maintained that response for more than nine months, and two continued receiving treatment and maintained a response beyond 18 months.

“Initial results across all cohorts suggest the concurrent combination of adagrasib and pembrolizumab may provide a chemotherapy-free option for treatment-naïve NSCLC with a manageable safety profile and encouraging clinical activity,” said Pasi A. Janne, M.D., Ph.D., with the Dana Farber Cancer Institute in a press release.

Late last week, Mirati announced plans to complete analysis of another program in NSCLC. The Phase III SAPPHIRE trial is evaluating sitravatinib in combination with Bristol Myers Squibb’s checkpoint inhibitor Opdivo. The combination is being developed as a third- or fourth-line treatment for NSCLC patients. The company expects final data analysis by mid-2023.

Buyout Rumors Continue

Mirati has been a rumored acquisition target for some time. Last year, Merck was said to be considering buying the company. About two weeks ago, rumors swirled yet again that Mirati was a takeover target, although no specific buyers were mentioned, according to Bloomberg.

The company has a market cap of $5.1 billion and would be a target for companies interested in bolt-on deals to bolster their oncology pipelines. Its pipeline includes adagrasib, MRTX1133, sitravatinib and MRTX1719, a synthetic lethal PRMT5 inhibitor.

Mirati also has discovery programs for mutant KRAS inhibitors in solid tumors and programs for KRAS signal-modifying compounds that inhibit SOS1 in solid tumors.