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New Generation KRAS G12C Inhibitor Brings Promising Responses Even in Patients with Advanced Lung Cancers Refractory to Previous KRAS-targeted Therapy
An interview with
Byoung Chul Cho MD PhD, Thoracic Medical Oncologist, Professor, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
SAN DIEGO, USA—In a phase 1/2 study in which patients with advanced non-small cell lung cancer were treated with the next-generation KRAS-G12C inhibitor elisrasib, responses were seen not only in patients who were not treated with prior KRAS G12C inhibitors but also in those whose disease progressed on prior KRAS G12C inhibitors.
Study findings were reported at the 2026 Annual Meeting of the American Association for Cancer Research by Byoung Chul Cho MD PhD, a professor and thoracic medical oncologist at the Yonsei Cancer Center, in Yonsei University College of Medicine, Seoul, South Korea. He discussed his findings with our reporter Peter Goodwin.
PODCAST: Byoung Chul Cho MD PhD
IN: [GOODWIN]”I’m here at the American
OUT:…….for Cancer Research. I’m Peter Goodwin 7:58secs
AACR 2026 abstract:
Session Type: Clinical Trials Plenary Session
Session Title: New Frontiers in Precision Oncology
Presentation CT020
Publishing Title:
Safety and efficacy of Elisrasib (D3S-001), a next generation GDP-bound KRAS G12C inhibitor, as monotherapy in advanced non-small cell lung cancer (NSCLC) previously treated with or without a KRAS G12C inhibitor: Results from a phase 1 / 2 study
Authors:
Byoung Chul Cho1, Shun Lu2, Ziming Li2, John Park3, Jun Zhao4, Herbert Ho Fung Loong5, Antoine Hollebecque6, Bin Yang7, Binchao Wang8, Cheng Chen9, Jia Wang9, Shaonan Wang9, Yandong Shen9, Zifei Fan9, Qian Chen9, Hui Wang9, Jing Zhang9, George Zhi Jian Chen9, Melissa Johnson10, Tony Shu Kam Mok5
1Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of
Medicine, Seoul, Korea, Republic of,
2Department of Medical Oncology, Shanghai Chest Author Block: Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China,
3Macquarie Medical School, Macquarie University, Sydney, Australia,
4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China,
5The Chinese University of Hong Kong, Hong Kong, China,
6Gustave Roussy, Villejuif, France,
7Hubei Cancer Hospital, Hubei, China,
8Guangdong General Hospital- Huifu Branch, Guangzhou, China,
9D3 Bio Inc., Shanghai, China,
10Sarah Cannon Research Institute, Nashville, TN
Background:
Elisrasib is a next-generation KRAS-G12C inhibitor (G12Ci) designed to improve target engagement (TE) efficiency and overcome growth factor-induced nucleotide exchange. This unique MoA distinguishes elisrasib from first-generation G12Ci and has led to robust anti-tumor activity in G12Ci-naïve/-resistant PDX models. Ph1 results demonstrated favorable safety and promising efficacy across NSCLC, CRC and PDAC. Here, we present updated findings in previously treated locally advanced or metastatic NSCLC patients (pts) (naïve and refractory to G12Ci) from the ongoing Ph1/2 trial (NCT05410145).
Methods: Pts with locally advanced or metastatic KRAS G12C-mutated NSCLC were eligible. All pts must had received at least one prior line of systemic treatment, including IO and/or platinum doublet chemotherapy. For G12Ci-refractory pts, they were required to have radiologically or clinically documented PD following a KRAS G12Ci. Elisrasib was administered orally QD in 21-day cycles at 6 planned dose levels (50-900mg) in the dose escalation and 600mg was selected as the treatment dose for expansion cohorts. The key objectives included safety, efficacy, and ctDNA kinetics by liquid biopsy
(Guardant360® CDx or OncoCompass® Target).
Results: As of 06 Jan 2026, total 165 NSCLC pts across 9 countries received elisrasib monotherapy (2 in 50mg, 5 in 100mg, 4 in 200mg, 6 in 400mg, 144 in 600mg and 4 in 900mg). Median study follow up time for 2L+ G12Ci-naive and G12Ci-refractory NSCLC were 11.3m and 10.6m, respectively. TRAEs of any grade occurred in 143/165 (87.9%) pts, ≥G3 TRAEs occurred in 19/165 (11.5%) pts. The safety profile in NSCLC pts is comparable with overall population. In 2L+ G12Ci-naïve NSCLC (50-900mg QD), 84 pts were evaluable for efficacy. ORR was 57.1% (48/84) with 1 CR and DCR of 98.8%. mPFS, mDOR and 12m OS rate (OS was not matured) were 8.8m, 12.5m, and 67%, respectively. At 600mg QD (68 evaluable pts), ORR was 55.9% (38/68) with 1 CR and DCR of 98.5%. mPFS, mDOR and 12m OS rate (OS was not matured) were 11.8m, 14.9m, and 71%, respectively. In 2L+ G12Ci-refractory NSCLC (600mg QD), 31 pts were evaluable for efifcacy. ORR was 32.3% (10/31) and DCR of 83.9%. mPFS, mDOR and 12m OS rate (OS was not matured) were 8.1m, 8.2m, and 69%, respectively. PK at 600mg QD achieved Ctrough exposure (5.6 nM) which was 5x greater than required exposure (1 nM) for complete TE. Baseline ctDNA G12C+ was detected in 68% (54/80, 4 pts were excluded due to incomplete data) of G12Ci-naïve and 68% (21/31) G12Ci- refractory pts, with 93% (50/54) and 76% (16/21) achieved molecular response (≥90% G12C MAF reduction), respectively. Notably, 4/5 G12Ci-refractory pts with G12C amplification, a known resistant MoA, showed tumor shrinkage, including three achieved cPR.
Conclusions:
Elisrasib monotherapy demonstrates robust and durable efficacy and favorable tolerability in 2L+ NSCLC pts, naïve and refractory to G12Ci.
PRESS RELEASE
SAN DIEGO – Treatment with the investigational next-generation KRAS-G12C inhibitor elisrasib led to clinical benefit in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbored a KRAS G12C mutation and whose disease progressed after prior therapies, according to results presented at the American Association for Cancer Research (AACR) Annual Meeting 2026, held April 17-22.
The G12C mutation is the most common KRAS alteration in NSCLC. Two first-generation inhibitors targeting this mutation, sotorasib (Lumakras) and adagrasib (Krazati), have been approved by the U.S. Food and Drug Administration (FDA) for treatment of this patient population. However, these drugs benefit only approximately 30% of patients, half of whom experience disease progression within six months, and safety remains a challenge in the clinic, explained Byoung Chul Cho, MD, PhD, a professor in the Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine in Korea, who presented the study.
“Research is now focused on next-generation inhibitors aiming for safer, more effective, and longer- lasting results,” said Cho. “These new treatments may address challenges such as brain metastases and resistance to earlier drugs, potentially improving outcomes and redefining care for lung cancer patients with KRAS G12C mutations.”
Similar to the first-generation KRAS inhibitors, elisrasib selectively binds to mutant KRAS G12C and locks it in its inactive state, thus inhibiting its oncogenic function. However, elisrasib was designed for faster and stronger target engagement, resulting in sustained inhibition, Cho explained.
Safety and efficacy of elisrasib alone and in combination with other drugs are being tested in an ongoing phase I/II clinical trial in patients with KRAS G12C-mutant solid tumors. Early data from a subgroup of NSCLC patients showed promising results.
The new analysis included a larger cohort of 165 patients with locally advanced or metastatic NSCLC who were previously treated with immunotherapy and/or chemotherapy. Some of them also received first- generation KRAS G12C inhibitor therapy and experienced progressive disease. Elisrasib was administered orally once daily in 21-day cycles at six dose levels ranging from 50 to 900 mg, and 600 mg was selected as the recommended treatment dose.
Median follow up time was 11.3 months in patients who had not been previously exposed to KRAS G12C inhibitor therapy (naïve) and 10.6 months in patients with G12C inhibitor-refractory disease. Grade 3 and higher treatment-related adverse events were observed in 11.5% of patients. “Elisrasib demonstrated a favorable safety and tolerability profile,” said Cho.
The efficacy analysis included 84 participants who were naïve for KRAS G12C inhibitor therapy and 31 with KRAS G12C inhibitor-refractory disease. Among the naïve cohort, for patients treated at the recommended dose of 600 mg, overall response rate and disease control rate were 58.8% (including one complete response) and 98.5%, respectively. Median progression-free survival (mPFS) was 12.2 months; median duration of response (mDoR) and overall survival (OS) rate at 12 months were 16.5 months and 72%, respectively. “In our study, elisrasib demonstrated a significantly higher response rate and prolonged tumor responses than first-generation KRAS G12C inhibitors, indicating that its molecular design may be translating into improved clinical outcomes for patients,” said Cho. He added that elisrasib has received Fast Track and Breakthrough Therapy designations from the FDA for the indication of second-line therapy in KRAS G12C inhibitor-naïve patients.
Among patients who experienced disease progression on earlier KRAS G12C inhibitor therapy, all of whom were treated at the 600 mg elisrasib dose, overall response rate was 32.3%, and disease control rate was 83.9%. Further, mPFS, mDoR, and OS rate at 12 months were 8.1 months, 15.6 months, and 71%, respectively. Tumor responses were also observed in patients with brain metastases, a difficult-to- treat population, said Cho.
KRAS G12C-positive circulating tumor (ctDNA) was detected in 70% of patients before treatment. Molecular responses, defined as reductions of 90% or greater in the fraction of KRAS G12C-mutant ctDNA, were observed with elisrasib in 93% of G12C inhibitor-naïve patients and 80% of those whose disease had progressed on previous G12C inhibitor therapy.
“Among patients whose disease progressed on first-generation inhibitors, we found five cases of KRAS gene amplification, an important mechanism of evasion of KRAS G12C inhibitor efficacy,” said Cho. “Out of those five KRAS amplification cases, four experienced tumor shrinkage, three showed a clinical response, and the disease control rate was 100%, indicating elisrasib’s effectiveness in this biomarker- defined group.”
Cho added, “Elisrasib demonstrates the ability to provide deeper, longer-lasting tumor responses, even in cases where first-generation KRAS G12C inhibitors failed. Overall, these findings indicate that elisrasib may significantly improve treatment for lung cancer patients with KRAS G12C mutations.”
Commenting on the limitations of the study, Cho said that it was an early-phase, single-arm trial, so its primary purpose was to assess safety and early efficacy and establish the correct dose. “Although the safety and initial efficacy findings are encouraging, larger randomized studies are necessary to confirm effectiveness and tolerability. Additionally, longer follow-up will be crucial for evaluating how durable the responses truly are.”