KRAS G12D mutations are present in approximately 4% of non-small cell lung cancer (NSCLC) cases, representing a significant unmet therapeutic need, as no targeted therapies are currently approved for this patient population. Zoldonrasib (RMC-9805), an investigational, oral, covalent KRAS(ON) G12D-selective tri-complex inhibitor being developed by Revolution Medicines, has demonstrated promising antitumor activity and a favorable safety profile in patients with previously treated KRAS G12D–mutated NSCLC. Updated results from the ongoing Phase 1 study evaluating zoldonrasib monotherapy (NCT06040541) were presented during the annual meeting of the American Association for Cancer Research (AACR). held April 17 – 22, 2026, in San Diego, CA. The study was funded by Revolution Medicines.[1]
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) comprising 80–85% of all cases, with more than 197,000 people diagnosed in the United States each year. [2][3][4] Despite recent therapeutic advances, outcomes for patients with advanced NSCLC remain poor. Patients diagnosed with NSCLC harboring specific oncogenic drivers, such as KRAS G12D, are most commonly treated with chemotherapy and immune checkpoint inhibitors, but often do not benefit substantially from these therapies. While two KRAS G12C inhibitors have been approved by the US Food and Drug Administration (FDA) for NSCLC, there are currently no approved RAS-targeted therapies available specifically targeting the KRAS G12D mutation. This mutation, characterized by a glycine-to-aspartic acid substitution at codon 12, is the most common RAS variant in human cancers and is associated with resistance to conventional therapies.
“These mutations are found in 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 the University of California (UC), Davis Comprehensive Cancer Center. [5]
“Targeting and overcoming KRAS G12D-driven cancers, including NSCLC, with next-generation KRAS inhibitors represents a major unmet need for our patients,” Riess added.
KRAS functions by cycling between an active (ON) state and an inactive (OFF) state. Mutations lock KRAS in its active state, bound to GTP, leading to uncontrolled oncogenic signaling. Zoldonrasib is an oral, G12D-selective tri-complex RAS(ON) inhibitor that forms a ternary complex with KRAS. This complex prevents KRAS from engaging and activating key downstream effector proteins involved in cell survival and growth, and delays or prevents resistance because the cell cannot circumvent the blockade by boosting upstream signaling to maintain KRAS in its active conformation.
Breakthrough Therapy
Zoldonrasib is a potent, oral, covalent tri-complex inhibitor that selectively binds and inactivates the active, GTP-bound state of KRAS G12D via a novel cyclophilin A–mediated interface. The investigational agent displayed a favorable safety profile with low rates of grade ≥3 adverse events and minimal need for dose modification. Most notably, zoldonrasib demonstrated robust and durable antitumor activity in heavily pretreated patients with advanced KRAS G12D–mutated NSCLC, a population with historically poor outcomes and limited treatment options. The observed ORR and DCR compare favorably to historical controls for second-line therapies, such as docetaxel, which are associated with response rates of 10–15%.
These results provided the basis for the U.S. Food and Drug Administration (FDA) granting Breakthrough Therapy Designation to zoldonrasib for previously treated, KRAS G12D–mutated, locally advanced or metastatic NSCLC in January 2026. Ongoing trials are evaluating zoldonrasib both as monotherapy and in combination with standard-of-care agents in treatment-naïve and previously treated patients.
Phase 1 Study
The ongoing open-label, multicenter, Phase 1/1b trial enrolled patients with advanced solid tumors harboring KRAS G12D mutations who had received at least one prior line of systemic therapy. Dose-escalation and expansion cohorts received zoldonrasib at doses ranging from 150 to 1,200 mg once daily (QD) or 300–600 mg twice daily (BID).
Based on the most recent analysis, the recommended Phase 2 dose (RP2D) was 1,200 mg QD. Safety and efficacy analyses focused on patients with advanced NSCLC who received the RP2D, who had progressed following immune checkpoint inhibitor and platinum-based chemotherapy, and had not received prior docetaxel.
Results
As of December 1, 2025, 40 patients with NSCLC treated at the RP2D were included in the safety analysis. The median number of prior therapy lines was two (range: 1–5); 68% had an ECOG performance status of 1, and 45% were never-smokers. The median study follow-up was 13.1 months (range: 9.1–19.9). Treatment-related adverse events (TRAEs) occurred in ≥15% of patients and included nausea (43%), vomiting (33%), diarrhea (30%), and rash (18%). Most TRAEs were grade 1 or 2 in severity; grade 3 TRAEs occurred in 13% of patients (diarrhea and anemia, 3% each), with no grade 4 or 5 TRAEs observed. TRAEs led to dose interruptions, reductions, and discontinuations in 15%, 3%, and 5% of patients, respectively. Mean relative dose intensity was 94%.
Efficacy was evaluated in 27 NSCLC patients meeting eligibility criteria for prior therapies. The confirmed objective response rate (ORR) was 52% (95% CI: 32%–71%), and the disease control rate (DCR) was 93% (95% CI: 76%–99%). Median duration of response was not estimable (95% CI: 8.3 months, not estimable), median progression-free survival was 11.1 months (95% CI: 5.3 months, not estimable), and median overall survival was not reached. The 12-month overall survival rate was 73%.
Clinically meaningful
Zoldonrasib (RMC-9805) demonstrated clinically meaningful and durable responses with manageable toxicity in patients with advanced KRAS G12D–mutated NSCLC, representing a promising therapeutic advance for this molecularly defined subset.
“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 the 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.
Study limitations and further evaluation
“This study provides a preliminary encouraging signal of zoldonrasib activity in KRAS G12D-mutant NSCLC,” Riess concluded. However, the study authors agree that, given the small number of participating patients, additional studies are warranted. Hence, to further evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of zoldonrasib in KRAS G12D NSCLC, an open-label, platform Phase 1b/2 study (NCT06162221) is ongoing, both as monotherapy in previously treated patients and in combination with Standard of Care (SOC) in treatment-naïve patients.
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Clinical trials
Study of RMC-9805 in Participants With KRAS G12D-Mutant Solid Tumors – ClinicalTrials.gov ID NCT06040541
Study of RAS(ON) Inhibitors in Patients With Advanced RAS-mutated NSCLC – ClinicalTrials.gov ID NCT06162221
References
[1] Riess J, Haura EB, Yaeger R, Johnson M, Luo J, Parikh AR, Orr D, Punekar SR, Papadopoulos K, Strickler JH, Powderly J, Wang JS, LoRusso P, Spira A, Filippou-Frye M, Patel H, Lally S, Yang M, Hong DS, Arbour KC. 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). In: Proceedings of the 117th Annual Meeting of the American Association for Cancer Research;
2026 April 17-22; San Diego, CA.: AACR; 2026. Abstract nr CT021.
[2] American Cancer Society. What is Lung Cancer? Online. Last accessed on April 19, 2026
[3] National Cancer Institute. Non-Small Cell Lung Cancer Treatment. Online. Last accessed on April 19, 2026.
[4] American Cancer Society. Key Statistics for Lung Cancer. Online. Last accessed on April 19, 2026.
[5] Ricciuti B, Alessi JV, Elkrief A, Wang X, Cortellini A, Li YY, Vaz VR, Gupta H, Pecci F, Barrichello A, Lamberti G, Nguyen T, Lindsay J, Sharma B, Felt K, Rodig SJ, Nishino M, Sholl LM, Barbie DA, Negrao MV, Zhang J, Cherniack AD, Heymach JV, Meyerson M, Ambrogio C, Jänne PA, Arbour KC, Pinato DJ, Skoulidis F, Schoenfeld AJ, Awad MM, Luo J. Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer. Ann Oncol. 2022 Oct;33(10):1029-1040. doi: 10.1016/j.annonc.2022.07.005. Epub 2022 Jul 22. PMID: 35872166; PMCID: PMC11006449.
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DOI
 Demonstrates Effective and Durable Response in Patients With Advanced KRAS G12D-mutated Lung Cancer){kind=link}