Elisrasib, a next-generation KRAS G12C inhibitor, demonstrated disease control in a majority of patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC), whether exposed to a prior KRAS G12C inhibitor or not, according to findings from an ongoing phase I/II clinical trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2026 (Abstract CT020).
“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 presenting author Byoung Chul Cho, MD, PhD, Professor in the Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine in Korea.
Background and Study Methods
According to Dr. Cho, elisrasib was designed for faster and stronger target engagement, unlike the first-generation KRAS G12C inhibitors approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with KRAS G12C–mutated NSCLC. “Research is now focused on next-generation inhibitors aiming for safer, more effective, and longer-lasting results,” Dr. Cho said. “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.”
Elisrasib is currently being studied as monotherapy and in combination with other drugs in an ongoing phase I/II study of patients with solid tumors harboring KRAS G12C mutations. Early data from a small subgroup of patients with NSCLC in the study who were resistant to a first-generation KRAS G12C inhibitor (n = 20) showed a disease control rate of 80% and tumor shrinkage in 60%.
The population presented at the 2026 AACR Annual Meeting included patients with locally advanced or metastatic NSCLC who were previously treated with at least one prior line of systemic therapy, including immunotherapy and/or platinum doublet chemotherapy (n = 165). Patients who were refractory to a prior KRAS G12C inhibitor had progressive disease prior to starting on elisrasib.
Treatment was given at one of six planned dose levels from 50 mg to 900 mg orally once daily in 21-day cycles in the dose-escalation portion of the study. For the expansion cohorts, 600 mg was chosen as the preferred treatment dose.
Elisrasib has achieved FDA Fast Track and Breakthrough Therapy designations for the treatment of patients in the second-line setting who are naive to KRAS G12C inhibitors.
Key Findings
Among patients who were not exposed to a prior KRAS G12C inhibitor (n = 84 evaluable patients), the objective response rate was 57.1%, including one complete response; the disease control rate was 98.8%. The median progression-free survival was 8.8 months and the median duration of response was 12.5 months. At 12 months, the overall survival rate was 67%.
At the chosen expansion cohort dose (n = 68 evaluable patients), the objective response rate was 55.9%, with one complete response; the disease control rate was 98.5%. The median progression-free survival was 11.8 months, and the median duration of response was 14.9 months. At 12 months, the overall survival rate was 71%.
In patients who were refractory to a prior KRAS G12C inhibitor (n = 31 evaluable patients), the overall response rate was 32.3% and the disease control rate was 83.9%. The median progression-free survival was 8 months, and the median duration of response was 8 months. At 12 months, the overall survival rate was 69%.
Dr. Cho said, “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 patients with lung cancer with KRAS G12C mutations.”
At 600 mg once daily, the Ctrough exposure was 5.6 nM, which was five times more than the target engagement requirement.
At baseline, KRAS G12C positivity by circulating tumor DNA was found in 68% of evaluable patients who were not previously exposed to a KRAS G12C inhibitor (n = 80, due to four patients with incomplete data) and in 68% of patients who were refractory to a prior KRAS G12C inhibitor (n = 31); in these groups, 93% and 76%, respectively, achieved molecular responses of at least 90% KRAS G12C mutant allele frequency reduction.
Four of five patients with a KRAS G12C amplification who were refractory to a KRAS G12C inhibitor had tumor shrinkage from elisrasib treatment; three of these patients achieved a partial response.
“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 Dr. 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.”
"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," Dr. Cho said, commenting on the limitations of the study by noting that it was an early-phase, single-arm trial, so its primary purpose was only to assess safety and early efficacy and to establish the correct dose.
DISCLOSURES: The study was funded by D3 Bio. Dr. Cho received royalties from Champions Oncology, Crown Bioscience, Imagen, PearlRiver Bio GmbH, and grant/research support from CJ Bioscience, Cyrus Therapeutics, ImmuneOncia, Johnson & Johnson, J INTS bio, MSD, Yuhan, Dong-A ST, and LigaChem Biosciences. He is a consultant for Amgen, ArriVent, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, CJ Bioscience, Cyrus Therapeutics, Gilead, GSK, Regeneron, Johnson & Johnson, MSD, and Yuhan. Dr. Cho serves on the advisory board of KANAPH Therapeutics Inc., Cyrus Therapeutics, and J INTS Bio. He was an invited speaker for the American Society of Clinical Oncology (ASCO), AstraZeneca, Guardant, Roche, the European Society For Medical Oncology (ESMO), the International Association for the Study of Lung Cancer (IASLC), the Korean Cancer Association, the Korean Society of Medical Oncology, the Korean Society of Thyroid-Head and Neck Surgery, the Korean Cancer Study Group, Novartis, MSD, the Chinese Thoracic Oncology Society, Pfizer, and Zai Lab. He owns stocks or shares from J INTS BIO and KANAPH Therapeutics Inc. He is the founder of DAAN Biotherapeutics and a member of the board of directors of J INTS BIO. For full disclosures of the other study authors, visit abstractsonline.com.
