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Mirati Therapeutics Sees First-Line Potential in Adagrasib-Keytruda Combo

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NEW YORK – Based on favorable safety and tolerability data from two early clinical trials for its KRAS G12C inhibitor adagrasib combined with a PD-1 inhibitor in first-line non-small cell lung cancer, Mirati Therapeutics will execute a Phase III registrational plan, company officials said on a conference call Wednesday.

Mirati reported results this week from its ongoing KRYSTAL-7 Phase II and KRYSTAL-1 Phase Ib trials of adagrasib plus Merck's Keytruda (pembrolizumab) in patients with advanced, unresectable NSCLC bearing the KRAS G12C mutation who had not received prior systemic therapy.

Results from KRYSTAL-1 included seven patients who received 400 mg adagrasib orally twice a day plus Keytruda. At a median follow-up of 19.3 months, objective responses were observed in four out of seven of the patients (57 percent) across all PD-L1 tumor proportion score (TPS) levels, and the disease control rate was 100 percent. Four patients experienced grade three treatment-related adverse events, and there were no grade four or five events.

In KRYSTAL-7, 75 patients were treated with 400 mg adagrasib twice daily with Keytruda. At a median follow-up time of 3.5 months, with median duration of treatment of two months, an objective response was observed in 26 out of 53 patients who received at least one post-baseline tumor assessment. The disease control rate was 89 percent. No dose-limiting safety signals were identified, and there were no grade five treatment-related adverse events. Two patients out of 75 discontinued both drugs due to an adverse event, and one discontinued Keytruda only.

"In the first-line setting, the efficacy and safety results are supportive of our expanded development program, and we're very confident in our approach in the first line," Mirati CEO David Meek said on the conference call. "We have the potential to establish adagrasib as the first KRAS G12C inhibitor approved in the first line."

Meek said the company estimates that there are about 25,000 KRAS G12C-positive lung cancer patients in the US each year across all lines of treatment and about 13,000 in the first-line setting. In order to market the drug to first-line patients with the KRAS G12C mutation, the company will aim to show an advantage over the standard-of-care therapy. However, at the response rate of 49 percent from KRYSTAL-7, adagrasib plus Keytruda is in line with standard of care for first-line non-small cell lung cancer, chemotherapy plus Keytruda, which has a reported response rate 47.6 percent.

Mirati CSO James Christensen highlighted data from a cohort of 25 KRYSTAL-7 patients who had been enrolled more than six months before the analysis cutoff date showing an overall response rate of 56 percent. "A review of these patients suggests the majority of tumor responses continue to deepen between the first scan at six weeks and the second scan at three months, and also that approximately one quarter of the responses occur at three months or later. Thus, we would expect clinical activity to improve with additional follow-up in a more mature dataset," Christensen said. He also noted that patients with TPS scores of less than 50 percent fared worse compared to what has been observed for all non-small cell lung cancer patients, regardless of KRAS G12C status.

Mirati Chief Medical Officer Alan Sandler said that adagrasib-Keytruda is the company's highest priority for development. To that end, Mirati will begin a new Phase III registrational trial of the combination in first-line KRAS G12C-mutated NSCLC patients with TPS scores of less than 50 percent, enabled by conversion of the KRYSTAL-7 trial to a Phase III study. In parallel, the company will begin a second Phase III study of adagrasib and Keytruda in patients with TPS scores above 50 percent.

The company also will continue to explore monotherapy approaches in the first-line setting, where Sandler said outcomes for standard of care in KRAS G12C-mutant non-small cell lung cancer patients with TPS scores of less than 1 percent provide the potential for an accelerated development path. "Our own preliminary data, along with historical improvements in objective response rates and durability for non-small cell lung cancer targeted therapies in first-line non-small cell lung cancer versus second-line, portend the possibility of further improved objective response rates for adagrasib in this setting," said Sandler. Mirati also plans to evaluate adagrasib with other targeted therapies.

Mirati's main competitor for adagrasib is Amgen's Lumakras (sotorasib), which was approved by the US Food and Drug Administration in 2021 as a second-line therapy for patients with KRAS G12C-mutated NSCLC. Amgen is also pursuing combinations of Lumakras with PD-1/PD-L1 inhibitors and other targeted therapies. However, its Phase I/II Codebreak 100/101 trial of Lumakras with two different checkpoint inhibitors was hampered by a high rate of treatment-related adverse events. About half of the patients receiving the highest doses of Lumakras plus anti-PD-1/PD-L1 therapy discontinued treatment, which resulted in the relatively weaker 29 percent response rate compared to 40.7 percent previously reported for Lumakras monotherapy, according to Amgen.