News|Articles|March 25, 2026

KRAS G12d-Targeted Setidegrasib Shows Activity in Non–Small Cell Lung Cancer

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Key Takeaways

Treatment-related AEs occurred in 97.8%, driven by mostly low-grade infusion-related reactions (78%); grade ≥3 TRAEs were 13.3%, serious TRAEs 6.7%, with no discontinuations or fatalities.
Antitumor activity was notable at 600 mg: ORR 35.8% overall, 37.5% in second-/third-line, and 47.1% in light/nonsmokers, with median DOR not reached in key subsets.
Exploratory efficacy suggested durable benefit in later lines, including 6-month DOR estimate of 76% and median PFS of 11.2 months in second-/third-line patients.
Biomarker analyses supported on-target effect: tumor KRAS G12D protein reduced by 70.6%, and ≥50% ctDNA decline associated with markedly longer median PFS (9.6 vs 2.6 months).
Development is moving toward phase 3 monotherapy in previously treated advanced NSCLC and first-line combinations with immune checkpoint inhibitors, leveraging KRAS-driven immune evasion reversal.

KRAS G12d-targeted protein degrader setidegrasib demonstrated antitumor activity and a manageable safety profile in patients with KRAS G12d-mutant non–small cell lung cancer.

KRAS G12D-targeted protein degrader setidegrasib showed antitumor activity with tolerable safety profile in patients with KRAS G12D-mutant non–small cell lung cancer (NSCLC), according to data from a phase 1 study presented at the 2026 European Lung Cancer Congress (ELCC) and published in The New England Journal of Medicine.

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 side effects (TRAEs) was 97.8% (44 patients), with most grade 1 (mild) or 2 (moderate). Only 13.3% (6 patients) of TRAEs were grade greater than or equal to 3 (severe), and 6.7% (3 patients) 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.

Main data that supported the findings

The ORR was 35.8% (16 patients) 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, not reached in second- and third-line patients, and 9.7 months in light or nonsmokers. The 6-month DOR estimate was 76% in second- and third-line patients.

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.

Study design and patient characteristics

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.

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 looked at patients’ blood and tumor samples to see if setidegrasib was hitting its target. In tumor samples, the KRAS G12D protein was reduced by 70.6%. Changes in the cancer-related DNA in the blood were seen as early as the first treatment cycle. Patients whose blood showed a 50% or greater decrease in this DNA had a median time without cancer growth of 9.6 months, while those with less than a 50% decrease had a median of 2.6 months.

How setidegrasib works

Setidegrasib works differently from traditional treatments. Instead of blocking the cancer-causing protein, it helps break it down and remove it from cancer cells, which may lead to stronger and longer-lasting effects.

What is next?

As study presenter Dr. Phillippe Cassier 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's 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. “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

“Efficacy and safety of setidegrasib in patients with advanced NSCLC with KRAS G12D mutation” by Dr. Cassier, et al., presented at 2026 ELCC
“Setidegrasib in advanced non–small-cell lung cancer and pancreatic cancer” by Dr. Park, et al., N Engl J Med

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