Revolution Medicines has posted positive clinical results from a duo of studies evaluating its Rat sarcoma (RAS)-targeting therapies – potentially teeing the company up for movement into late-stage pipeline development efforts.
In the ongoing Phase I/II RMC-GI-102 study (NCT06445062), the California-based biotech is evaluating its G12D-selective RAS(ON) inhibitor, zoldonrasib, alongside a standard of care (SoC) chemotherapy regimen in frontline, RAS G12D-mutated metastatic pancreatic cancer. Patients received either zoldonrasib plus modified FOLFIRINOX (mFFX) or the targeted therapy alongside gemcitabine plus nab-paclitaxel (GnP).
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At interim, treated patients experienced an objective response rate (ORR) of 82% when receiving zoldonrasib-mFFX – a result Jefferies analysts called “impressive.” Meanwhile, 61% of patients given zoldonrasib-GnP achieved an ORR, while the mFFX and GnP regimens prompted a disease control rate (DCR) of 96% and 90% in tandem with zoldonrasib, respectively.
Patients tolerated the zoldonrasib-chemotherapy regimens, though 61% and 80% of patients receiving the drug in combination with mFFX and GnP experienced a treatment-emergent adverse event (TEAE) rated Grade 3 or above. The most common TEAE impacting patients was a decreased neutrophil count, which affected 37% and 35% of patients treated with mFFX and GnP, respectively.
These data will put Revolution in a positive position as it continues its pivotal RASolute 305 study (NCT07621718), which is pitting zoldonrasib plus SoC chemotherapy against SoC plus placebo in frontline RAS G12D pancreatic ductal adenocarcinoma (PDAC).
Zoldonrasib shows second-line potential
Atop promising results in the frontline setting, zoldonrasib has also demonstrated its potential as an effective second-line treatment setting alongside Revolution’s pan-RAS inhibitor, daraxonrasib. GlobalData analysts have touted daraxonrasib as a “turning point for pancreatic cancer” after the drug nearly doubled overall survival (OS) in a pivotal study as per results presented earlier this year at the American Society of Clinical Oncology (ASCO) annual congress,
During the Phase I RMC-9805-001 trial (NCT06040541), which enrolled patients with RAS G12D-mutated advanced solid tumours, the duo triggered an ORR of 50% and a DCR of 97%.
Alongside this win, zoldonrasib-daraxonrasib also posted a median progression free survival (PFS) of 9.6 months in the second line cohort, while achieving an mPFS of 7.6 months in third-line-plus patients. Meanwhile, median overall survival (OS) was not yet estimable in the second-line group, and reached 10.5 months in the third-line-plus setting.
This data, the biotech says, supports its plans to kick off the pivotal Phase III clinical trial, dubbed RASolute 309, evaluating zoldonrasib-daraxonrasib versus GnP in frontline RAS G12D-mutated metastatic PDAC.
According to Jefferies analysts, Revolution has set “a very high bar” for other companies developing RAS G12D-targeting therapies – including Verastem and Incyte.
Verastem dosed its first patient with its candidate, VS-7375, in the Phase II, registration-directed TARGET-D 201 trial, while Incyte is exploring its therapy, INCB161734 in a Phase I study.
