Roche is a relative latecomer in the chase to block a protein called KRAS G12C to treat lung cancer, but the pharmaceutical company has been testing its contender head-to head against approved medicines from Amgen and Bristol Myers Squibb and is now claiming its next-generation drug is better.
In preliminary Phase 3 results, the Roche drug divarasib met the main and secondary trial goals with clinically meaningful and statistically significant improvement, the Swiss company said Thursday. There were no new safety signals. Roche said more detailed data would be presented at a future medical conference and submitted to health authorities “with the aim of bringing this potential treatment option to people with KRAS G12C [non-small cell lung cancer] as soon as possible.”
RAS is a family of genes that code for proteins that act like on/off switches to regulate cell growth. KRAS is one of the most frequently mutated proteins from this family. When a mutation keeps KRAS in the “on” position, the protein contributes to the uncontrolled cell growth that drives cancer. While the role that mutated KRAS plays in cancer is known, KRAS has eluded many efforts to drug it.
The Roche drug divarasib is an oral small molecule designed to block KRAS G12C, a subset of KRAS mutations found in an estimated 14% of cases of non-small cell lung cancer (NSCLC). This drug locks KRAS G12C in its inactive or “off” state to prevent the abnormal signaling that drives cancer. That’s the same approach taken by Lumakras, the Amgen drug that in 2021 became the first FDA-approved KRAS inhibitor for NSCLC. This drug class also includes the Bristol Myers Squibb product Krazati (from Mirati Therapeutics), which received FDA approval in 2022.
Roche describes divarasib as a next-generation KRAS G12C inhibitor designed to offer greater potency and selectivity compared to the Amgen and BMS products. The preliminary data reported Thursday come from an open-label Phase 3 study that enrolled 338 adults with KRAS G12C-positive NSCLC that had progressed after at least one but no more than three prior lines of systemic therapy. Study participants were randomly assigned to receive Roche’s once-daily divarasib, Amgen’s once-daily Lumakras, or BMS’s twice-daily Krazati.
Measuring progression-free survival is the main trial goal of this pivotal study. Secondary endpoints include measures of overall survival, confirmed objective response, and duration of response. Despite the lack of data disclosure, Roche executives are claiming an advantage over the Amgen and BMS products.
“The superior survival demonstrated in this global head-to-head comparison of KRAS G12C inhibitors confirms the potential of divarasib to improve clinical outcomes for people with KRAS G12C non-small cell lung cancer,” Roche Chief Medical Officer and Head of Global Product Development Levi Garraway said in a prepared statement. “These results should establish divarasib as a new standard of care for previously-treated lung cancer patients with this genetically defined tumor subtype.”
Two other Phase 3 studies are ongoing, one evaluating divarasib alongside the Merck immunotherapy Keytruda as a first-line treatment for NSCLC and the other testing the Roche drug as an adjuvant, a therapy that keeps cancer from coming back after it has been surgically removed.
Roche isn’t the only company developing a next-generation KRAS G12C inhibitor. Contenders designed to inhibit the protein in its “off” state include glecirasib from Jacobio Pharma, olomorasib from Eli Lilly, and calderasib from Merck. Revolution Medicines, which has been in the headlines for its potentially practice-changing RAS inhibitor daraxonrasib for pancreatic cancer, is in early clinical development with a KRAS G12C “on” inhibitor called elironrasib.
Meanwhile, BridgeBio Oncology Therapeutics, whose website modestly proclaims it to be “best-in-RAS,” is developing BBO-8520 to block KRAS G12C in both the “on” and “off” states. A Phase 1a/1b study is enrolling NSCLC patients.
Photo by Roche
