Elisrasib (D3S-001), a next-generation GDP-bound KRAS G12C inhibitor, generated durable antitumor activity in patients with second-line or later KRAS G12C–mutant non–small cell lung cancer (NSCLC) who were either naive to or refractory to prior KRAS G12C inhibitors, according to data from a phase 1/2 trial (NCT05410145) presented at the
Among KRAS G12C inhibitor–naive patients treated at the recommended phase 2 dose (RP2D) of 600 mg once daily (n = 68), elisrasib elicited a confirmed objective response rate (ORR) of 52.9% and an overall ORR of 58.8%, including 1 complete response (CR), with a disease control rate (DCR) of 98.5%. The median duration of response (DOR) was 16.5 months (95% CI, 10.2-20.8) and median progression-free survival (PFS) was 12.2 months (95% CI, 7.2-18.1). Across all doses (n = 84), the confirmed ORR was 53.6%, the median DOR was 14.9 months (95% CI, 7.1-17.9), and the median PFS was 9.4 months (95% CI, 8.1-14.1). Median overall survival (OS) was immature, with 12-month OS rates of 68% and 72% in the all-dose and 600-mg populations, respectively, at a median follow-up of 12.2 months.
"The response to elisrasib was rapid, deep, and durable," lead study author Byoung Chul Cho, MD, PhD, said in the presentation.
Cho is a professor in the Division of Medical Oncology at Yonsei Cancer Center and Yonsei University College of Medicine in Seoul, South Korea.
First-generation KRAS G12C inhibitors such as sotorasib (Lumakras) and adagrasib (Krazati) have been constrained by the depth and duration of clinical responses, a limitation attributed in part to the dynamic cycling of KRAS between its GDP- and GTP-bound states.2 Elisrasib was engineered to maximize target engagement efficiency and to outpace growth factor–stimulated nucleotide exchange between GDP and GTP, and it is also CNS penetrable.1 Moreover, elisrasib has shown a terminal half-life of approximately 8 hours supporting once-daily dosing, with 600 mg achieving approximately 4 times the geometric mean trough free-drug concentration required for complete target inhibition.
The present expansion provides efficacy and safety data in a second-line or later KRAS G12C–mutant NSCLC population spanning both KRAS G12C inhibitor–naive disease and a defined KRAS G12C inhibitor–refractory cohort.
The trial comprised a phase 1 dose-escalation portion in patients with locally advanced or metastatic KRAS G12C–mutant solid tumors, followed by phase 2 proof-of-concept expansion. Eligible patients had measurable disease per RECIST 1.1, an ECOG performance status of 0 or 1, at least one prior line of systemic therapy in dose escalation, and could have treated or untreated neurologically asymptomatic brain metastases. KRAS G12C inhibitor–refractory patients were required to have received only one prior KRAS G12C inhibitor and to have achieved a best response of partial response (PR) or CR regardless of duration, or stable disease (SD) for at least 6 months.
Across escalation, no dose-limiting toxicities occurred and the maximum tolerated dose was not reached; 600 mg once daily was selected as the RP2D.3 The data cutoff was March 11, 2026.1
In the KRAS G12C inhibitor–naive cohort (all dose, n = 86), the median age was 66.0 years, 77.9% of patients were male, and 20.9% had brain metastases at screening; 90.7% had received at least one checkpoint inhibitor and 76.7% had received both a checkpoint inhibitor and platinum-based chemotherapy. In the refractory cohort (n = 32), 53.1% had received at least 3 prior lines of treatment, 40.6% had received prior sotorasib, and best response to the prior G12C inhibitor had been PR (53.1%) or SD (31.3%).
In the KRAS G12C inhibitor–naive cohort, the majority of patients achieved tumor shrinkage; among 50 responders, 70.0% had a first response by week 6. In the KRAS G12C inhibitor–refractory cohort treated at 600 mg (evaluable n = 31), 10 patients (32.3%) achieved a PR as best response, 8 (25.8%) of which were confirmed, with a DCR of 83.9%. The median DOR was 15.6 months (95% CI, 1.5-not calculable) and median PFS was 8.1 months (95% CI, 3.8-10.9); median OS was immature with a 12-month OS rate of 71%.
Activity was retained in biologically adverse subsets: among patients with STK11 and/or KEAP1 co-alterations, which were present in 47% of the naive cohort, the ORR was 55% (n = 12 of 22) vs 76% (n = 19 of 25) in those without such alterations. In 5 refractory patients with KRAS amplification, a known G12C inhibitor resistance mechanism, the ORR was 60% (3 confirmed PRs) and the DCR was 100%, with molecular response in 60% by day 8 of cycle 1 and complete G12C clearance by day 1 of cycle 4.
Cho also described a 55-year-old patient with untreated brain metastases who had progressed on a prior KRAS G12C inhibitor–based combination. "This case highlights the CNS activity of elisrasib in G12C inhibitor–refractory patients with untreated brain metastases," he said.
Baseline KRAS G12C was detected by circulating tumor DNA (ctDNA) in 70% (n = 47 of 67) of the naive cohort and 68% (n = 21 of 31) of the refractory cohort, with reductions observed as early as cycle 1 day 8. The molecular response rate was 93% (n = 42 of 45) in naive and 80% (n = 16 of 20) in refractory patients, with complete clearance rates of 80% and 65%, respectively. Among ctDNA-positive patients, complete clearance during treatment was associated with markedly higher ORR than incomplete clearance (naive, 75% vs 22%; refractory, 62% vs 13%). In paired baseline–end-of-treatment analysis of 18 naive patients with PFS of at least 3 months, no KRAS amplification was detected at progression, which investigators indicated may reflect elisrasib's complete and rapid target engagement.
Elisrasib was tolerable in this heavily pretreated population, with a profile consistent with phase 1 dose escalation. The median duration of treatment was 8.7 months in the naive cohort and 7.0 months in the refractory cohort.
In the naive cohort (all dose, n = 86), any-grade treatment-related adverse effects (TRAEs) occurred in 89.5% of patients and grade 3 or higher TRAEs in 14.0%; serious TRAEs occurred in 8.1%, and TRAEs led to discontinuation in 1.2%. The most common TRAEs were nausea (64.0%), diarrhea (41.9%), and vomiting (30.2%), predominantly grade 1. Any-grade aspartate aminotransferase and alanine aminotransferase elevations occurred in 11.6% and 14.0% of patients, respectively, mostly grade 1; interstitial lung disease or pneumonitis occurred in 1.2%. There was a single case of asymptomatic grade 4 transient hypokalemia and no grade 5 TRAEs. In the refractory cohort (n = 32), any-grade TRAEs occurred in 84.4% of patients and grade 3 TRAEs in 15.6%, with no grade 4 or 5 events.
Disclosures: Cho reported employment with Yonsei University Health System; grant/research support/funding from MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GI Innovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Eli Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, BridgeBio Therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center, and Vertical Bio AG; serving as a consultant for Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences, Janssen, Takeda, MSD, Medpacto, Blueprint Medicines, RandBio, and Hanmi; serving on advisory boards for Kanaph Therapeutic, BridgeBio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec, J INTS Bio, Therapex, Gilead, and Amgen; serving as an invited speaker for ASCO, AstraZeneca, Guardant, Roche, ESMO, 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, and Pfizer; holding stocks/shares in TheraCanVac, Gencurix, BridgeBio Therapeutics, Kanaph Therapeutic, Cyrus Therapeutics, Interpark Bio Convergence Corp, and J INTS Bio; serving as a member of the board of directors of J INTS Bio; receiving royalties (PDX, PDO, PDC licensing contract—not patent) from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio; and serving as founder of DAAN Biotherapeutics.
