Adagrasib for KRAS G12C+ Lung Cancer Granted Breakthrough Therapy Designation by FDA

The FDA has granted a breakthrough therapy designation (BTD) from the FDA for patients with advanced non-small cell lung cancer (NSCLC) with a KRAS^G12C mutation following prior systemic treatment, according to a press release by Mirati Therapeutics, Inc.

Adagrasib is a small-molecule inhibitor of KRAS^612C that is meant to sustain target inhibition. This sustained inhibition is meant to treated KRASG12C cancers as the KRAS^G12C protein regenerates every 24-48 hours. In addition to NSCLC, adagrasib has shown efficacy in colorectal cancer, pancreatic cancer, and other KRAS^G12C mutated solid tumors. It is being evaluated as both a monotherapy and in combination with other anti-cancer therapies.

"We are pleased to receive this breakthrough therapy designation for adagrasib, which emphasizes the significant need for new treatment options for patients with lung cancer who harbor the KRAS^G12C mutation," said Charles M. Baum, MD, PhD, president, and chief executive officer, Mirati Therapeutics, Inc in a press release. "We look forward to submitting a New Drug Application for adagrasib in the second half of this year and further advancing adagrasib across a broad development plan with the goal of improving clinical outcomes in patients with KRAS^G12C mutated cancers."

The BTD is based on results from the phase 1/2 KRYSTAL-1 trial (NCT03785249). The non-randomized, sequential assignment trial has an estimated enrollment of 391 participants and an estimated completion date of September 2022. The primary outcomes of the study are the safety of adagrasib, the pharmacokinetics of the agent, and the clinical efficacy of the drug. Secondary outcomes include maximum-tolerated dose, the safety of adagrasib in combination with other anti-cancer therapies, the pharmacokinetics of the agent in an oral formula, and the pharmacokinetics of the agent when administered with food.

During the phase 1 dose exploration arm, patients were given the drug different dose levels once or twice daily in order to determine maximum tolerated dose. During the phase 1b expansion cohort, adagrasib was tested for safety. Phase 1b also contained 3 additional arms that tested adagrasib with pembrolizumab (Keytruda), cetuximab (Erbitux), and afatinib (Gilotrif). During phase 2 portion of the study, the agent was tested for efficacy.

In order to participate, patients must have a diagnosis of a solid tumor with a KRAS^G12C mutation, have unresectable or metastatic disease where the standard of treatment is not available to the patient or the patient declines it, and must had adequate organ function. Patients with a history of intestinal disease, major gastric surgery, or is unable to swallow oral medications are not eligible to participate. Additionally, patients with other active cancers are not eligible to participate.

Results of the KRYSTAL-1 trial presented during the European Lung Cancer Virtual Conference 2021found that 600 mg of the agent twice-daily was associated with an overall response rate of 43% in phase 1 and 45% in phase 1b. Additionally, in phase 1/1b cohort, the disease control rate was 100% and 96% in the phase 1/1b and 2 cohorts. Respectively, 57% and 51% of patients had stable disease. No incidents of disease progression were recorded in the phase 1/1b cohort but did occur in 2% of the pooled phase 2 cohort.

_REFERENCE:

_{Mirati Therapeutics' adagrasib receives breakthrough therapy designation from U.S. Food and Drug Administration for patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation. News release. Mirati Therapeutics, Inc. June 24, 2021. Accessed June 25, 2021. https://bit.ly/3gV2gHF}