Setidegrasib Demonstrates Tolerability for Solid Tumors Harboring KRAS G12D Variants
Preliminary clinical trial findings, presented at the 2026 European Lung Cancer Congress (ELCC), demonstrated early antitumor activity and tolerability of setidegrasib, an investigational KRAS G12D-targeted protein degrader, in patients with advanced non-small cell lung cancer (NSCLC) and advanced pancreatic ductal adenocarcinoma.
The phase I open-label study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of setidegrasib in patients with advanced unresectable or metastatic solid tumors harboring KRAS p.G12D variants.1 The primary endpoint was safety, assessed by dose-limiting toxicities and adverse events (AEs), as well as determining the phase II dose.1 Secondary endpoints included disease control rate (DCR), overall response rate (ORR), and duration of response (DOR).1
Eligible patients had locally advanced or metastatic solid tumors, including NSCLC, harboring a KRAS G12D mutation, and who had previously received standard-of-care therapy.2 Participants were administered setidegrasib intravenously at doses ranging from 10 to 800 mg.1
The trial enrolled a total of 203 patients, of whom 76 received 600 mg of setidegrasib.1 Among the 45 evaluable patients with NSCLC who were administered 600 mg of setidegrasib—the phase II dose—nearly 40% (39.5%) were classified as having light or no history of tobacco use.2
The ORR was 35.6% among all 45 patients with NSCLC harboring KRAS G12D mutations, 34.8% among those who had received prior platinum-based chemotherapy or immune checkpoint inhibitors (ICIs) only (n = 23), and 47.1% in the light or nonsmoking cohort.2 Patients in the light/nonsmoking cohort demonstrated the highest DCR rate (94.1%), compared with 84.4% in the overall patient cohort and 78.3% who had received only prior platinum/ICI treatment.2 The median progression-free survival (PFS) among all patients with NSCLC harboring KRAS G12D mutations was 8.3 months.2
The median duration of exposure among enrolled patients with NSCLC was 36 weeks.2 Safety evaluations revealed that treatment-related adverse events (TRAEs) occurred in 97.8% of patients, although most were grade 1 or 2.2 Infusion-related reactions (IRRs) were the most frequent TRAEs, reported in 78% of patients, followed by nausea (35.6%) and increased alanine aminotransferase levels (28.9%).2
All IRRs were grades 1–2, commonly presenting as rash, pruritus, or urticaria after the first dose, with a decreased incidence thereafter.2 TRAEs of grade 3 or higher occurred in 13.3% of and 6.7% patients, respectively, with no TRAEs leading to treatment discontinuation or death.2
KRAS G12D mutations occur in around 5% of patients with NSCLC; however, there are currently no therapies available that specifically target these mutations. Given the manageable safety profile and durable clinical activity observed in previously treated patients with NSCLC, the data support further evaluation of setidesigrab.2
Zoldonrasib Displays Early Efficacy in Pretreated KRAS G12D–Mutant NSCLC
Investigators recently presented data from a phase I/Ib trial evaluating zoldonrasib at the 2026 American Association for Cancer Research (AACR) Annual Meeting. The oral RAS(ON) G12D inhibitor has demonstrated promising clinical activity and tolerability in patients with previously treated KRAS G12D-mutated NSCLC, according to the data presented.3
Zoldonrasib was previously granted breakthrough therapy designation by the US Food and Drug Administration (FDA) in January 2026, marking the first time this designation was granted to an investigational drug specifically targeting the RAS G12D mutation.4 The FDA’s recent designation was based on data from the monotherapy cohort of the phase 1 RMC-9805-001 clinical trial, in which zoldonrasib demonstrated encouraging antitumor activity, along with acceptable safety and tolerability.4
The trial’s primary endpoints included safety, tolerability, pharmacokinetics, and antitumor activity. The study also featured a dose-escalation phase where zoldonrasib was administered once or twice daily at varying doses.3 Eligible patients were required to have received prior standard therapy appropriate for their tumor type and stage, have an ECOG performance status of 0 or 1, and have no active brain metastases.3
Across a median follow-up period of 13.1 months, 27 patients who received zoldonrasib at 1200 mg daily and had previously undergone ICI and platinum-based chemotherapy, without prior docetaxel treatment, showed favorable outcomes.3 These patients achieved an ORR of 52% and a DCR of 93%. The median time to response was 1.4 months, while the median DOR was not estimable.3
In terms of safety, TRAEs of any grade were reported in 90% of patients.3 The most common any-grade TRAEs occurring in at least 10% of patients included nausea, vomiting, and diarrhea. Grade 3 TRAEs were reported in 13% of patients, while no grade 4 or 5 TRAEs were observed.3
Investigators reported that no dose-limiting toxicities occurred, and a maximum tolerated dose was not reached for zoldonrasib. Based on these results, the recommended phase II dose was established at 1200 mg once daily for patients with NSCLC.3
In his concluding remarks, Jonathan Wesley Riess, MD, MS, stated that the preliminary results support the continued development of zoldonrasib in combination with other therapies.3
References:
- 1. Park W, Kasi A, Spira AI, et al. Setidegrasib in Advanced Non-Small-Cell Lung Cancer and Pancreatic Cancer. N Engl J Med. 2026;394(14):1409-1420. doi:10.1056/NEJMoa2600752
- 2. Cassier, P. (2025, March 25). Efficacy and safety of setidegrasib in patients (pts) with advanced NSCLC with KRAS G12D mutation. Presented at: European Lung Cancer Congress 2026, Copenhagen, Denmark.
- 3. Riess J, Haura EB, Yaeger R, et al. 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). Presented at: 2026 AACR Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract CT021.
- 4. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-fda-breakthrough-therapy-1
