Zoldonrasib Combos, Including With Daraxonrasib, Yield High Response Rates in PDAC

Zoldonrasib produced substantial response rates in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) when combined with chemotherapy in the first-line setting and with daraxonrasib in the second-line setting, according to phase 1/2 data presented at the 2026 European Society for Medical Oncology (ESMO) Gastrointestinal (GI) Cancers Congress.¹

The results for zoldonrasib (RMC-9805), an oral RAS(ON) G12D-selective covalent inhibitor, were shared in 2 separate abstracts highlighting the investigational agent’s efficacy specifically in patients with RAS G12D–mutated PDAC.

“The phase 3 RASolute 302 results provided clinical validation of RAS(ON) inhibition with daraxonrasib in second line metastatic pancreatic cancer and established a strong foundation for evaluating this therapeutic approach across additional RAS genotypes, treatment settings and combination strategies. The results presented at ESMO GI demonstrate compelling proof-of-concept for two zoldonrasib-based regimens in RAS G12D disease: combination with standard of care chemotherapy in previously untreated patients and a RAS(ON) inhibitor doublet with daraxonrasib in previously treated patients,” Alan Sandler, MD, chief development officer of Revolution Medicines, stated in a news release.¹

Zoldonrasib Plus Chemotherapy in First-Line RAS G12D PDAC

In the zoldonrasib plus modified FOLFIRINOX (mFFX) arm, the objective response rate (ORR) was 82% (95% CI, 60%-95%) and the disease control rate (DCR) was 96% (95% CI, 77%-100%). In the zoldonrasib plus gemcitabine and nab-paclitaxel (GnP) arm, the ORR was 61% (95% CI, 42%-78%) and the DCR was 90% (95% CI, 74%-98%).¹

Zoldonrasib demonstrated a manageable tolerability profile in combination with both chemotherapy backbones. The adverse event profile was broadly consistent with the established toxicity profiles of each respective chemotherapy regimen. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 61% of patients in the zoldonrasib plus mFFX arm and 80% of patients in the zoldonrasib plus GnP arm.

The most common grade 3 or higher TRAEs with zoldonrasib plus mFFX were decreased neutrophil count (37%), anemia (12%), and decreased platelet count (7%). With zoldonrasib plus GnP, the most common grade 3 or higher TRAEs were decreased neutrophil count (35%), anemia (28%), and fatigue (25%). No grade 5 TRAEs were reported in either arm.

Overall, RMC-GI-102 (NCT06445062) is an ongoing phase 1/2 trial evaluating zoldonrasib 1200 mg once daily in combination with investigator's choice of standard-of-care chemotherapy in patients with previously untreated metastatic RAS G12D PDAC. Investigator's choice includes mFFX or GnP. As of the February 8, 2026, data cutoff, 41 patients had been enrolled in the zoldonrasib plus mFFX arm and 40 patients in the zoldonrasib plus GnP arm.1 These results support the ongoing phase 3 RASolute 305 trial (NCT07621718), a global, randomized, double-blind, placebo-controlled study evaluating zoldonrasib plus investigator's choice of standard-of-care chemotherapy vs placebo plus chemotherapy in patients with previously untreated metastatic RAS G12D PDAC.¹

Zoldonrasib Plus Daraxonrasib in Second-Line-Plus RAS G12D PDAC

In the second-line (2L) cohort (n = 30), the ORR was 50% (95% CI, 31%-69%) and the DCR was 97% (95% CI, 83%-100%). The median progression-free survival (PFS) was 9.6 months (95% CI, 7.1-not estimable), with a 6-month PFS rate of 71%. The median overall survival (OS) was not yet estimable, with a 6-month OS rate of 89%.¹

Zoldonrasib plus daraxonrasib was also assessed in a third-line-plus (3L+) cohort (n = 30); in these patients, the ORR was 47% (95% CI, 28%-66%) and the DCR was 90% (95% CI, 74%-98%). The median PFS was 7.6 months (95% CI, 4.6-10.5), with a 6-month PFS rate of 59%. The median OS was 10.5 months (95% CI, 6.7-not estimable), with a 6-month OS rate of 82%.¹

Across the cohorts, the combination of zoldonrasib plus daraxonrasib demonstrated a manageable safety profile broadly consistent with the established profile of daraxonrasib monotherapy. Grade 3 or higher TRAEs occurred in 35% of patients. Among TRAEs occurring in 10% or more of patients, the most common grade 3 or higher events were rash (12%), anemia (10%), and stomatitis/mucositis (7%). Discontinuations due to TRAEs were infrequent: 2% of patients discontinued zoldonrasib and 5% discontinued daraxonrasib.

Overall, RMC-9805-001 (NCT06040541) is a phase 1 trial evaluating zoldonrasib 1200 mg once daily plus daraxonrasib 300 mg once daily in patients with advanced solid tumors harboring RAS G12D mutations. As of the February 9, 2026, data cutoff, 60 patients with RAS G12D metastatic PDAC who had received one or more prior lines of therapy were treated with the combination.¹ Revolution Medicines has announced plans to initiate the pivotal phase 3 RASolute 309 trial, which will evaluate zoldonrasib plus daraxonrasib vs GnP in patients with previously untreated RAS G12D metastatic PDAC.¹

Historic Progress in PDAC

The ESMO GI presentations build on the landmark phase 3 RASolute 302 results presented at the 2026 ASCO Annual Meeting plenary session, in which daraxonrasib reduced the risk of death by 60% compared with chemotherapy in patients with previously treated metastatic PDAC (HR, 0.40; 95% CI, 0.30-0.54; P = 5.9 × 10^-10), with a median OS of 13.2 months vs 6.6 months.² Together, the RASolute 302 findings and the zoldonrasib phase 1/2 data support a broad clinical development strategy targeting the RAS(ON) pathway across lines of therapy and RAS G12D disease specifically.

Daraxonrasib has received several FDA designations supporting accelerated development, including breakthrough therapy designation and orphan drug designation. Following the RASolute 302 data, the FDA authorized an expanded access treatment protocol for daraxonrasib on May 1, 2026, just 2 days after Revolution Medicines submitted the application, allowing oncologists to request access to the drug for patients with previously treated metastatic PDAC outside of a clinical trial.³

In an interview with Targeted Oncology during the 2026 ASCO Annual Meeting, Shubham Pant, MD, MBBS, discussed the clinical and historical significance of the RASolute 302 daraxonrasib data:

“Personally, having treated patients with pancreatic cancer for over 20 years, I think these findings are truly remarkable. Most of the trials in pancreatic cancer have been negative trials, meaning they haven't shown any benefit, and even if the trials have been positive, they've shown a benefit of like 2 weeks to 2 months. So this doubling of overall survival is truly, truly remarkable.”

Pant is a professor in the Department of GI Medical Oncology and director of Clinical Research at The University of Texas MD Anderson Cancer Center.

References

1. Revolution Medicines presents Phase 1/2 clinical data for zoldonrasib combination regimens in patients with RAS G12D metastatic pancreatic cancer at ESMO Gastrointestinal Cancers Congress 2026. News release. Revolution Medicines. July 2, 2026. Accessed July 3, 2026. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-phase-12-clinical-data-zoldonrasib

2. Wolpin BM, Wainberg ZA, Hendifar AE, et al; RASolute 302 Trial Investigators. Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer. N Engl J Med. 2026. doi:10.1056/NEJMoa2605555

3. FDA permits expanded access for investigational pancreatic cancer drug. News release. US Food and Drug Administration. May 1, 2026. Accessed July 3, 2026. https://www.fda.gov/news-events/press-announcements/fda-permits-expanded-access-investigational-pancreatic-cancer-drug