Revolution Medicines reported positive Phase 1/2 data at ESMO GI 2026 for zoldonrasib combinations in KRAS G12D pancreatic cancer, advancing into pivotal Phase 3 trials with encouraging efficacy and manageable safety.
Written By: Meghana Jinka. PharmD
Reviewed By: Pharmacally Editorial Team
Revolution Medicines has presented positive Phase 1/2 clinical data for two zoldonrasib-based combination regimens in patients with KRAS G12D metastatic pancreatic ductal adenocarcinoma (PDAC), reinforcing its strategy to expand RAS(ON) inhibition into earlier lines of treatment.
The findings, presented during a proffered paper session at the 2026 European Society for Medical Oncology (ESMO) Gastrointestinal Cancers Congress, demonstrated encouraging efficacy and manageable safety in both treatment-naïve and previously treated patients.
The data include zoldonrasib combined with standard chemotherapy as first-line therapy and zoldonrasib combined with daraxonrasib, the company’s oral RAS(ON) multi-selective inhibitor, in patients who had progressed after prior treatment. Both approaches have now advanced to pivotal Phase 3 development.
Targeting the Most Common KRAS Mutation in Pancreatic Cancer
Zoldonrasib is an investigational oral covalent inhibitor that selectively targets active KRAS G12D proteins, the most common KRAS mutation in pancreatic cancer. Approximately 40% of patients with PDAC harbor this mutation, yet no targeted therapy has received regulatory approval for this population.
PDAC remains one of the most lethal malignancies because most patients present with advanced disease and experience limited benefit from existing chemotherapy. Selective KRAS inhibition, either alongside chemotherapy or combined with broader RAS blockade, may offer a new strategy to improve tumor control and delay disease progression.
First-Line Combination with Chemotherapy Produced Encouraging Responses
The ongoing Phase 1/2 RMC-GI-102 trial (NCT06445062) is evaluating zoldonrasib 1,200 mg once daily in combination with investigator’s choice of modified FOLFIRINOX (mFFX) or gemcitabine plus nab-paclitaxel (GnP) in previously untreated metastatic KRAS G12D PDAC. At the February 8, 2026 data cutoff, 81 patients had been enrolled across both treatment arms.
The combination demonstrated a manageable safety profile that was broadly consistent with the established toxicities of each chemotherapy regimen. Grade 3 or higher treatment-related adverse events occurred in 61% of patients receiving zoldonrasib plus mFFX and in 80% of those receiving zoldonrasib plus GnP. Neutropenia and anemia were the most frequently reported severe toxicities, and no Grade 5 treatment-related adverse events were observed.
The regimen also produced substantial antitumor activity. Patients treated with zoldonrasib plus mFFX achieved an objective response rate (ORR) of 82% and a disease control rate (DCR) of 96%. In the GnP cohort, the ORR reached 61% while the DCR was 90%. These findings provided the clinical rationale for the ongoing global Phase 3 RASolute 305 trial (NCT07621718), which is comparing zoldonrasib plus standard chemotherapy with placebo plus chemotherapy in previously untreated metastatic KRAS G12D PDAC.
Dual RAS(ON) Inhibition Showed Durable Activity After Prior Therapy
The Phase 1 RMC-9805-001 trial (NCT06040541) evaluated zoldonrasib 1,200 mg once daily together with daraxonrasib 300 mg once daily in 60 patients with previously treated KRAS G12D metastatic PDAC.
The dual RAS(ON) inhibition strategy demonstrated a manageable safety profile that was consistent with previous experience using daraxonrasib. Grade 3 or higher treatment-related adverse events occurred in 35% of patients, with rash, anemia, and stomatitis or mucositis representing the most common severe toxicities. Treatment discontinuations due to adverse events remained uncommon, affecting only 2% of patients receiving zoldonrasib and 5% receiving daraxonrasib.
Clinical activity remained encouraging across later treatment settings. Among patients receiving second-line therapy, the combination achieved an ORR of 50% and a DCR of 97%, with a median progression-free survival of 9.6 months. Median overall survival had not yet been reached, while the six-month overall survival rate was 89%. In patients treated in the third-line or later setting, the ORR was 47% and the DCR reached 90%. Median progression-free survival was 7.6 months, and median overall survival was 10.5 months, with an estimated six-month overall survival rate of 82%.
Phase 3 Program Expands into Earlier Treatment Settings
Chief Development Officer Alan Sandler, MD, said the new findings build on the clinical validation established by the Phase 3 RASolute 302 trial of daraxonrasib and support two complementary development strategies for KRAS G12D pancreatic cancer. One strategy combines selective KRAS inhibition with standard chemotherapy, while the other pairs two RAS(ON) inhibitors to achieve broader suppression of RAS signaling.
Revolution Medicines is currently enrolling patients in the Phase 3 RASolute 305 study and plans to initiate the global Phase 3 RASolute 309 trial, which will compare zoldonrasib plus daraxonrasib with gemcitabine plus nab-paclitaxel as first-line treatment for metastatic KRAS G12D PDAC. Together, these studies aim to establish targeted RAS inhibition as a new treatment option for one of the most aggressive molecular subtypes of pancreatic cancer.
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About the Writer
Meghana Jinka (LinkedIn) is a Pharm.D graduate with a strong interest in clinical pharmacy, clinical research, pharmacovigilance, and medical writing. She has developed expertise in evaluating scientific literature, interpreting clinical data, and communicating complex medical information in a clear and accessible manner. Through clinical training, patient counseling, and healthcare awareness activities, she has gained practical experience in evidence-based medicine and patient-centered care. Passionate about healthcare communication, Meghana is committed to developing accurate, engaging, and evidence-based healthcare documents that support healthcare professionals and the wider community.