Roche's divarasib to take on approved KRAS inhibitorsKRAS inhibitors in Phase III study
12 Jul 2024
Roche is set to initiate the Phase III KRASCENDO 1 trial later this month, pitting its KRAS-blocking drug divarasib (GDC-6036) against established competitors in second-line non-small-cell lung cancer (NSCLC). The head-to-head study, recently posted on ClinicalTrials.gov, marks a bold move by Roche as it looks to set its treatment apart in the increasingly competitive KRAS inhibitorKRAS inhibitor landscape.
The trial gets under way this month and aims to enroll 320 participants with KRAS G12C-positive advanced or metastatic NSCLC who have received at least one prior systemic therapy, but no more than three in the metastatic setting. Patients will be randomised to receive oral divarasib once daily, Amgen's Lumakras (sotorasib) once daily or Bristol Myers Squibb's Krazati (adagrasib) twice a day.
The primary endpoint compares progression-free survival (PFS) between divarasib and either of the two other drugs. Key secondary goals include overall survival, objective response rate and duration of response, among others. The study is expected to reach primary completion around mid-2026, with full completion anticipated by mid-2028.
Promising early data
The head-to-head trial follows early-stage data for divarasib presented last year. Results published in the NEJM from a Phase I study showed durable clinical responses across various KRAS G12C-positive tumours. In NSCLC patients, divarasib demonstrated a 53.4% confirmed response rate and a median PFS of 13.1 months. The drug's safety profile appeared manageable, with mostly low-grade adverse events reported.
Lumakras received accelerated FDA approval in 2021 for second-line KRAS G12C-mutated NSCLC based on response rate data. However, despite achieving top-line success, subsequent PFS results fell short of expectations, showing only a five-week improvement over chemotherapy. The slim benefit prompted US regulators to issue Amgen a complete response letter requesting an additional confirmatory study to support conversion to full approval.
Meanwhile, Krazati secured its own accelerated FDA nod for second-line KRAS-mutated NSCLC in late 2022, also based on response rate data. The drug met its primary endpoint in the confirmatory KRYSTAL-12 trial, but detailed results presented at this year's ASCO annual meeting showed a benefit of less than 1.7 months compared to docetaxel. For more, see – BMS's Krazati adds another underwhelming KRAS datapoint.
Crowding field
The pending start of KRASCENDO 1 comes as Novartis recently announced the discontinuation of its KRAS G12C inhibitorKRAS G12C inhibitor programme. In May, the company said it halted development of opnurasib (JDQ443) across all studies, including the Phase III KontRASt-02 trial in NSCLC, citing "increasing options available to patients with KRAS G12C-driven cancers."
Other KRAS contenders in development include Eli Lilly's second-generation KRAS inhibitor olomorasib (LY3537982), currently in the Phase III SUNRAY-01 study for untreated advanced NSCLC, as well as Merck & Co.'s MK-1084, which is in Phase III testing in combination with Keytruda (pembrolizumab), also as a first-line NSCLC treatment.
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