Can the KRYSTAL-1 study’s data of Mirati’s Adagrasib ± Cetuximab could support accelerated approval in advance CRC?

Over 40% of metastatic colorectal cancer (mCRC) has KRAS mutations, which are unfavorable prognostic indicators for anti-EGFR treatment. Up to 3–4% of CRC patients carry the KRAS^G12C mutation. The three cancer types with the highest KRAS mutation prevalence are pancreatic cancer, colorectal cancer, and Non-Small Cell Lung Cancer (NSCLC). Adagrasib (oral small-molecule inhibitor of KRAS^G12C) in combination with Cetuximab (EGFRi) is currently being investigated in a KRYSTAL-10 study (Phase III) in second-line CRC (randomized to FOLFIRI or FOLFOX). Along with this, it is also being evaluated as a monotherapy in the KRYSTAL-1 study in second-line and above in NSCLC, CRC, Pancreatic, and other indications. Not only that, but there have been several proof-of-concept combination studies for the treatment of NSCLC and CRC using SHP2, SOS1, Pan-EGFR, and CDK4/6 inhibitors in second-line and higher. Initiation of the data readouts is anticipated in 2023.

Mirati Therapeutics will be presenting updated clinical research data from a cohort of Phase I/II KRYSTAL–1 study at the 2022 ESMO Annual Meeting. Earlier in 2021, data from this cohort were presented at the ESMO 2021 conference. Results showed that adagrasib alone and with cetuximab demonstrated significant clinical activity and broad disease control in these patients.

Based on the findings of Phase II registration-enabling cohort of the KRYSTAL-1 study (Subpart H), adagrasib’s New Drug Application (NDA) is currently being reviewed by the US FDA for accelerated approval for NSCLC harboring the KRAS^G12C mutation who have received at least one prior systemic therapy. The Prescription Drug User Fee Action (PDUFA) date for adagrasib is December 14, 2022. The company has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for the same. The Company has an ongoing confirmatory Phase III trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients with second-line KRAS^G12C-mutated NSCLC.

In comparison to NSCLC indication, where Amgen's LUMAKRAS received accelerated FDA approval in 2021 (with confirmatory data expected in late 2022), Mirati may have a lead over its rivals in CRC with superior data. According to earlier data, adagrasib has demonstrated a higher response rate when combined with cetuximab than LUMAKRAS. Adagrasib is only slightly superior to LUMAKRAS in treating NSCLC, but it has a poor safety profile (QT prolongation). Adagrasib, however, may supersede in the CRC setting as the frontrunner KRAS inhibitor, given the precedence of strong results. Regarding Mirati's rivals, Amgen began a phase III combo study in CRC this year (NCT05198934; CodeBreak 300)., Amgen will present the results of CodeBreak 101 (NCT04185883) at ESMO 2022. Additionally, Roche will soon release GDC-6036 (KRAS^G12C inhibitor) phase I solid tumor findings.

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