Novel KRAS G12D-Targeted Agent Shows Early Activity in KRAS+ NSCLC

Early activity and tolerability were observed among patients who received setidegrasib, an investigational KRAS G12D-targeted protein degrader, for non–small cell lung cancer (NSCLC) harboring KRAS G12D mutations, according to data from a phase 1 trial presented at the 2026 European Lung Cancer Congress (ELCC) and published in The New England Journal of Medicine.^1,2

The study’s primary end point was safety, with secondary end points of overall response rate (ORR), disease control rate, and duration of response (DOR). In 45 evaluable patients with NSCLC, the rate of treatment-related adverse events (TRAEs) was 97.8% (n = 44), with most grade 1 or 2. Only 13.3% (n = 6) of TRAEs were grade ≥3, and 6.7% (n = 3) were serious TRAEs. No TRAEs led to discontinuation or death. The most common TRAE was infusion-related reaction, occurring in 78% of patients; most cases were low grade, manageable, and occurred at the first infusion.¹

Efficacy Data

The ORR was 35.8% (n = 16/45) in all patients, 37.5% in second- or third-line patients, and 47.1% in light or nonsmokers. Responses were durable, with the median DOR not reached in all patients (range, 5.6-not evaluable [NE]), not reached (range, 3.1-NE) in second- and third-line patients, and 9.7 months (range, 5.6-NE) in light or nonsmokers. The 6-month DOR estimate was 76% in second- and third-line patients.^1,2

Data for progression-free survival (PFS), an exploratory end point, were also encouraging. In the second- and third-line setting, the median PFS was 11.2 months (95% CI, 5.6-NE).

Patient Characteristics and Study Design

The phase 1 open-label study evaluated setidegrasib in adults with locally advanced unresectable or metastatic solid tumors harboring KRAS G12D variants; the presentation at ELCC 2026 included only data from the NSCLC cohort who received setidegrasib at 600 mg, the recommended phase 2 dose (RP2D). Weekly intravenous doses ranged from 10 mg to 800 mg to identify the RP2D; 800 mg was deemed clinically infeasible due to low solubility requiring large volumes and extended infusion times.

The study enrolled 203 patients: 59 with NSCLC, 124 with pancreatic ductal adenocarcinoma, and 20 with other solid tumors. The median patient age in the NSCLC cohort was 68 years, 62.2% of patients were female, and 77.8% had an ECOG performance status of 1. The median number of prior lines of therapy was 2, with 93.3% previously receiving platinum-based chemotherapy and immune checkpoint inhibition.

Pharmacodynamics and Biomarkers

The study utilized circulating tumor DNA (ctDNA) and tumor biopsies to confirm target engagement and molecular response. The median KRAS G12D protein degradation in tumor biopsies was 70.6% in the NSCLC cohort. Robust reductions in KRAS G12D variant allele frequency (VAF) in ctDNA were observed as early as cycle 1 Patients with a 50% decrease in VAF ctDNA had a median PFS of 9.6 months, while patients with a < 50% decrease had a median PFS of 2.6 months. Treatment also led to increased intratumoral CD8+ T-cell infiltration in most patients, suggesting potential immunomodulatory activity that could support deeper, more durable responses.

Therapeutic Mechanism: Targeted Protein Degradation

Setidegrasib utilizes a mechanism of action distinct from traditional small-molecule inhibition. While KRAS G12C can be targeted via covalent binding to a reactive cysteine residue, KRAS G12D lacks this feature, making it historically difficult to inhibit.

Setidegrasib acts as a proteolysis-targeting chimera that forms a ternary complex between the KRAS G12D protein and the VHL E3 ligase.This complex facilitates the ubiquitination of the target protein, leading to its selective degradation via the proteasome. By eliminating the oncogenic protein rather than merely blocking it, setidegrasib provides robust inhibition of downstream signaling pathways.

Looking Ahead

As study presenter Philippe Cassier, MD, PhD, noted in his conclusion, a phase 3 trial evaluating setidegrasib as a monotherapy for patients with previously treated advanced NSCLC is advancing. Additionally, setidegrasib is being evaluated in combination with standard-of-care immune checkpoint inhibition in first-line advanced NSCLC.

“I think, overall, there [are] compelling data to support the combination of KRAS inhibition with immune checkpoint inhibition because KRAS contributes to the immune desert or the immune escape,” said Cassier, medical doctor and phase 1 researcher at Centre Léon Bérard in Lyon, France.¹ “The fact that we're relieving the immune suppression probably helps the T-cell infiltration. Regarding the positioning of the combination, I think that it will have to be positioned in the first line.”

References

1. Cassier P. Efficacy and safety of setidegrasib in patients with advanced NSCLC with KRAS G12D mutation. Presented at: 2026 ELCC; March 25–28, 2026; Copenhagen, Denmark. Abstract 1O.
2. Park W, Kasi A, Spira A, et al. Setidegrasib in Advanced Non–Small-Cell Lung Cancer and Pancreatic Cancer. N Engl J Med. Published online ahead of print March 25, 2026. DOI: 10.1056/NEJMoa2600752