Investigational KRAS(ON) Inhibitor Zoldonrasib Showed Effective and Durable Responses in Patients With Advanced G12D-mutated Lung Cancer
An interview with:
Jonathan Wesley Riess MD, Professor of Medicine, Director of Thoracic Oncology, Director of Early Phase Therapeutics, University of California Davis Comprehensive Cancer Center, USA
SAN DIEGO, USA—In a study of patients whose KRAS G12D mutated non-small cell lung cancers had become refractory to prior therapies, treatment with the drug zoldonrasib, an oral KRAS (ON) G12D-selective tri-complex inhibitor, was found to be clinically active and was safe. At the American Association for Cancer Research 2026 Annual Meeting Peter Goodwin heard from the lead study author Jonathan Wesley Riess MD, Professor of Medicine, Director of Thoracic Oncology and Director of Early Phase Therapeutics at the University of California Davis Comprehensive Cancer Center, USA:
AUDIO JOURNAL OF ONCOLOGY: Jonathan W Riess MD
IN: [GOODWIN]”I am here at………
OUT: ……..I’m Peter Goodwin. 8:01 secs
Abstract:
“Preliminary safety and clinical activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with previously treated KRAS G12D non- small cell lung cancer (NSCLC)”
Authors:
- Riess1, E. B. Haura2, R. Yaeger3, M. Johnson4, J. Luo5, A. R. Parikh6, D. Orr7, S. R. Punekar8, K. Papadopoulos9, J. H. Strickler10, J. Powderly11, J. S. Wang12, P. LoRusso13, A. Spira14, M. Filippou-Frye15, H. Patel15, S. Lally15, M. Yang15, D. S. Hong16, K. C. Arbour3;
Institutions:
1UC Davis Comprehensive Cancer Center, Sacramento, CA,
2H Lee Moffitt Cancer Center and Research Institute, Tampa, FL,
3Memorial Sloan Kettering Cancer Center, Author Block: New York, NY,
4SCRI Oncology Partners, Nashville, TN,
5Dana Farber Cancer Institute, Boston, MA,
6Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA,
7SCRI Oncology Partners, Dallas, TX,
8NYU Langone Perlmutter Cancer Center, New York, NY,
9South Texas Accelerated Research Therapeutics (START), San Antonio, TX,
10Duke Cancer Institute, Durham, NC,
11Carolina BioOncology Institute and BioCytics Human Applications Lab, Huntersville, MN,
12Florida Cancer Specialists & Research Institute, Sarasota, FL, 13Yale School of Medicine, New Haven, CT,
14NEXT Oncology Virginia, Virginia Cancer Specialists Research Institute, Fairfax,
Abstract Body:
VA, 15Revolution Medicines, Inc., Redwood City, CA, 16The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX
Background:
Patients (pts) with previously treated advanced NSCLC have a high unmet medical need, with a median reported overall survival (OS) of <1 year. KRAS G12D mutations occur in approximately 4% of pts with NSCLC, for which there is currently no approved RAS-targeted therapy. Zoldonrasib (RMC-9805) is a potent, oral, covalent, RAS(ON) G12D-selective, tri-complex inhibitor targeting the active, GTP-bound state of RAS G12D isoforms. Here we present an updated analysis for zoldonrasib monotherapy in previously treated pts with KRAS G12D NSCLC from the ongoing Phase 1 Study (NCT06040541).
Methods:
Pts with KRAS G12D solid tumors received escalating zoldonrasib doses (150- 1200 mg once daily [QD] or 300-600 mg twice daily). 1200 mg QD was identified as the recommended Phase 2 dose in NSCLC. Antitumor activity was assessed every 6 weeks for the first 24 weeks followed by every 9 weeks. Safety and tolerability are reported for all NSCLC pts (across all lines of therapy) treated at 1200 mg QD (N=40). Clinical efficacy is reported for pts with NSCLC treated at 1200 mg QD, who had received a prior immune checkpoint inhibitor and platinum chemotherapy (concurrent or sequential), and had not previously received docetaxel (N=27).
Results: As of Dec 1, 2025, 40 pts were evaluated for safety and had received a median of 2 prior lines of therapy. 68% of pts had an ECOG status of 1 and 45% were never smokers. The median study follow up was 13.1 mo (range: 9.1, 19.9) in both the safety and efficacy populations. Treatment-related adverse events (TRAEs) occurring in ≥15% of pts were nausea (43%), vomiting (33%), diarrhea (30%), and rash (18%). TRAEs were primarily Grade 1 (58%) or Grade 2 (20%) in severity. Grade 3 TRAEs were reported in 13% of pts, including diarrhea (3%) and anemia (3%); no Grade 4 or 5 TRAEs were observed. TRAEs led to dose interruptions in 15% of pts, dose reductions in 3% of pts, and dose discontinuations in 5% of pts. The mean relative dose intensity was 94%. In the 27 pts evaluated for efficacy, the confirmed objective response rate was 52% (95% CI: 32, 71) and the disease control rate was 93% (95% CI: 76, 99). Median duration of response was not estimable (NE) (95% CI: 8.3m, NE). Median progression free survival was 11.1 mo (95% CI: 5.3, NE). The median OS was not reached (95% CI: NE, NE) with a 12 mo OS landmark rate of 73%.
Conclusions:
Zoldonrasib (1200 mg QD) demonstrated durable clinical efficacy in pts with previously treated KRAS G12D NSCLC with a favorable safety and tolerability profile, requiring minimal dose modification. Further evaluation of zoldonrasib in KRAS G12D NSCLC is ongoing both as monotherapy in previously treated pts and in combination with standard of care in treatment naive pts (NCT06162221).
PRESS RELEASE:
Investigational KRAS(ON) Inhibitor Zoldonrasib Showed Effective and Durable Responses in Patients With Advanced G12D-mutated Lung Cancer
SAN DIEGO – The investigational KRAS G12D inhibitor zoldonrasib showed evidence of clinical activity and a favorable safety profile in patients with previously treated non-small cell lung cancer (NSCLC) whose tumors harbored a KRAS G12D mutation, according to an updated trial analysis presented at the American Association for Cancer Research (AACR) Annual Meeting 2026, held April 17-22.
While two KRAS inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for treatment of KRAS G12C-mutated NSCLC, no RAS-targeted therapy is currently available for patients whose tumors harbor KRAS G12D mutations. These mutations are found approximately in 4% of patients with NSCLC and are also present in a substantial portion of patients with pancreatic cancer and other gastrointestinal cancers, among others, explained presenter Jonathan W. Riess, MD, professor of medicine, director of Thoracic Oncology, and director of Early Phase Therapeutics at University of California (UC), Davis Comprehensive Cancer Center. “Targeting and overcoming KRAS G12D-driven cancers, including NSCLC, with next-generation KRAS inhibitors represents a major unmet need for our patients,” said Riess.
KRAS functions by cycling between an active (ON) state and an inactive (OFF) state. Mutations lock KRAS in its active state, which is bound to the GTP molecule, resulting in uncontrolled oncogenic signaling. Zoldonrasib is an oral, G12D-selective tri-complex RAS(ON) inhibitor that forms a ternary complex with KRAS and the intracellular protein cyclophilin A. This complex prevents KRAS from engaging and activating key downstream effector proteins involved in cell survival and growth.
Safety and efficacy of zoldonrasib are being tested in a phase I clinical trial in patients with KRAS G12D- mutant solid tumors who have received at least one prior line of treatment. Early trial results showed encouraging responses and safety profile in a subgroup of patients with NSCLC. Based on these observations, zoldonrasib received FDA Breakthrough Therapy designation in January 2026 for this patient population.
In the most recent analysis, safety and tolerability were assessed in all trial participants with NSCLC who had received prior therapies and were treated at the recommended phase II dose of 1,200 mg once daily (40 patients). After 13.1 months, no grade 4 or higher treatment-related adverse events (TRAE) were observed. Grade 3 TRAEs were reported in 13% of patients and included diarrhea and anemia. TRAEs led to dose interruptions in 15% of patients, dose reductions in 3% of patients, and dose discontinuations in 5% of patients.
Clinical efficacy was evaluated in 27 patients who received the recommended phase II dose and who had been previously treated with immune checkpoint inhibitor therapy and platinum chemotherapy (concurrent or sequential) but not with docetaxel. In this subgroup, investigators reported a confirmed objective response rate of 52% and a disease control rate of 93%. Median duration of response was not estimable, median progression-free survival was 11.1 months, and median overall survival was not reached. The overall survival rate at 12 months was 73%.
“Zoldonrasib demonstrated a favorable safety and tolerability profile, a promising response rate with durable responses, and an encouraging rate of disease control in patients whose lung cancer had progressed on prior chemotherapy and immunotherapy,” said Riess. “Our findings suggest that KRAS G12D-mutated lung cancer is treatable with promising efficacy of zoldonrasib.”
“While the safety signals and preliminary antitumor activity are encouraging, the results are based on a small sample size,” added Riess. “This study provides a preliminary encouraging signal of zoldonrasib activity in KRAS G12D-mutant NSCLC. Additional ongoing studies will help further define zoldonrasib’s potential benefit in this context.”
Jonathan Wesley Riess MD 2026 AACR Audio Journal of Oncology
