Two investigational KRAS inhibitors showed activity in previously treated KRAS-mutant non–small cell lung cancer (NSCLC), according to findings presented during the Clinical Trials Plenary Session at the 2026 American Association for Cancer Research (AACR) Annual Meeting in San Diego. Elisrasib was evaluated in KRAS G12C–mutated NSCLC, including patients previously treated with a KRAS G12C inhibitor, whereas zoldonrasib was studied in KRAS G12D–mutated NSCLC, a subset with no approved RAS-targeted therapy.
The studies highlight two different challenges in KRAS-mutant lung cancer. In KRAS G12C–mutated disease, newer agents must compete in an increasingly crowded field and show whether they can improve durability, tolerability, central nervous system (CNS) activity, and outcomes after prior KRAS G12C inhibition. In KRAS G12D–mutated disease, the field is still in its earlier days, and the central question is whether early activity can be confirmed and extended in later studies.
Elisrasib in KRAS G12C–Mutated NSCLC
Two KRAS G12C inhibitors—sotorasib and adagrasib—have been approved by the U.S. Food and Drug Administration for previously treated NSCLC. However, not all patients respond, and acquired resistance remains a major challenge. Elisrasib (D3S-001), a next-generation KRAS G12C inhibitor, was designed to improve target engagement and outpace growth factor–stimulated nucleotide exchange.
Results from the phase I to II study were presented1 by Byoung Chul Cho, MD, PhD, Professor in the Division of Medical Oncology at Yonsei Cancer Center, Yonsei University College of Medicine, Seoul. Dr. Cho described elisrasib as CNS-penetrable and noted that preclinical studies showed activity in models resistant to earlier KRAS G12C inhibitors, including those with KRAS G12C amplification.
Byoung Chul Cho, MD, PhD
“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.”
The ongoing phase I to II study enrolled patients with locally advanced or metastatic KRAS G12C–mutated solid tumors. In the NSCLC expansion cohorts, elisrasib was evaluated in patients who were KRAS G12C inhibitor–naive and in those whose disease was refractory to prior KRAS G12C inhibition. After dose escalation, 600 mg once daily was selected as the recommended phase II dose. The updated presentation had a data cutoff of March 11, 2026.
Among patients in the KRAS G12C inhibitor–naive cohort, most had received prior checkpoint inhibitor therapy and platinum chemotherapy. At the recommended phase II dose, the objective response rate was 58.8%, including one complete response, and the confirmed objective response rate was 52.9%. The disease control rate was 98.5%. Median progression-free survival was 12.2 months, median duration of response was 16.5 months, and median overall survival was not mature; the 12-month overall survival rate was 72%.
“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,” he said.
Dr. Cho also reported activity in patients with poor-prognosis co-alterations. STK11 and/or KEAP1 alterations were found in approximately half of patients, he noted, but elisrasib showed activity regardless of STK11 or KEAP1 alteration status, with an objective response rate of 76% in patients without these alterations and 55% in those with them.
In the KRAS G12C inhibitor–refractory cohort, all patients received elisrasib at 600 mg once daily. The objective response rate was 32.3%, including 25% confirmed partial responses, and the disease control rate was 83.9%. Median progression-free survival was 8.1 months, median duration of response was 15.6 months, and median overall survival was not mature; the 12-month overall survival rate was 71%.
This cohort was heavily pretreated: about half of patients had received at least three prior lines of therapy, about 90% had previously received both checkpoint inhibitor and platinum-based chemotherapy, and about half had previously received sotorasib or adagrasib. Dr. Cho characterized the group as a “truly refractory population” with few treatment options.
Among five patients with KRAS amplification, a known mechanism of resistance to KRAS G12C inhibition, the objective response rate was 60% and the disease control rate was 100%. Tumor responses were also observed in patients with brain metastases, including a representative case of a patient with KRAS G12C inhibitor–refractory disease and an untreated brain lesion who remained on elisrasib for nearly 10 months.
KRAS G12C was detectable in baseline circulating tumor DNA in about 70% of patients in both cohorts. Dr. Cho reported rapid and deep reductions in KRAS G12C variant allele fraction, and complete ctDNA clearance was strongly associated with radiologic response. In paired baseline and end-of-treatment ctDNA analyses of 18 KRAS G12C inhibitor–naive patients with progression-free survival longer than 3 months, no KRAS amplification was detected at end of treatment.
The safety profile was generally manageable. In the KRAS G12C inhibitor–naive cohort, grade 3 or higher treatment-related adverse events occurred in 14.0% of patients; in the refractory cohort, they occurred in 15.6%. Treatment-related discontinuations were uncommon, occurring in 1.2% and 3.1% of patients, respectively. Elisrasib has received FDA Breakthrough Therapy and Fast Track designations in NSCLC, and Dr. Cho said the findings warrant advancement to pivotal trials of elisrasib monotherapy and combination therapy with checkpoint inhibition in the front-line setting.
Discussant Perspective
Discussant Adrian Sacher, MD, of UHN Princess Margaret Cancer Centre, placed elisrasib in a crowded KRAS G12C field. He opened with the question he said he always asks when evaluating a new agent in this space: “Does the world need another KRAS G12C ‘OFF’ inhibitor?”—referring to agents that bind the inactive, GDP-bound state of KRAS G12C.
His answer was measured. Dr. Sacher said he evaluates new KRAS G12C inhibitors by response rate, progression-free survival, toxicity barriers, ability to overcome acquired resistance, and activity in difficult-to-treat subsets. Using that framework, he said elisrasib showed a favorable response rate compared with other potent KRAS G12C inhibitors and evidence of durable progression-free survival.
However, he cautioned that autoimmune hepatitis, a class concern for KRAS G12C OFF inhibitors, remains important to monitor. He also suggested the risk may be underestimated in this study, since some patients had not received prior checkpoint inhibitor therapy and many were more than 60 days from their last checkpoint inhibitor exposure.
Dr. Sacher also urged caution in interpreting the refractory cohort. Because many patients had previously received older, less potent KRAS G12C inhibitors, and because some had been off prior KRAS G12C inhibition for more than 60 days, he questioned how much of the observed activity represented true circumvention of acquired resistance vs re-response after growth of sensitive clones.
Still, he concluded that the early-phase data support elisrasib as a promising KRAS G12C OFF inhibitor, both as monotherapy and as a potential foundation for combination therapy.
“If you came to this talk hoping that I would give you clear direction on which approach or strategy was going to win in this field, I unfortunately will have to disappoint you,” Dr. Sacher said. “Truly, I think the only thing we can say at this point is that it’s still anyone’s game.”
Zoldonrasib in KRAS G12D–Mutated NSCLC
While the KRAS G12C space is crowded with approved and investigational agents, patients with KRAS G12D–mutated NSCLC have had no approved RAS-targeted therapy. KRAS G12D is the most common oncogenic RAS mutation across human tumors and occurs in approximately 4% of patients with NSCLC.
Jonathan W. Riess, MD, MS
Updated results from a phase I study of zoldonrasib (RMC-9805) were presented2 by Jonathan W. Riess, MD, MS, Professor of Medicine, Director of Thoracic Oncology, and Director of Early Phase Therapeutics at UC Davis Comprehensive Cancer Center.
“Targeting and overcoming KRAS G12D–driven cancers, including NSCLC, with next-generation KRAS inhibitors represents a major unmet need for our patients,” Dr. Riess said.
Based on earlier clinical activity in this population, zoldonrasib received FDA Breakthrough Therapy designation in January 2026.
Zoldonrasib is an oral, mutant-selective, covalent inhibitor targeting the active, GTP-bound, or RAS(ON) state of KRAS G12D. Through a tri-complex with cyclophilin A and RAS(ON), zoldonrasib sterically blocks RAF interaction and suppresses downstream signaling.
Dr. Riess emphasized that after progression on platinum-based chemotherapy and immune checkpoint inhibitors, standard treatment options are limited, generally consisting of docetaxel, with consideration of ramucirumab. KRAS G12D–mutated NSCLC also has distinct clinical and biologic features, including associations with never or light smoking history, lower tumor mutational burden, and lower PD-L1 expression compared with non-G12D KRAS-mutant tumors.
The ongoing phase I study enrolled patients with KRAS G12D–mutant solid tumors who had received prior standard therapy. Patients with active brain metastases were excluded, although treated/stable or asymptomatic brain metastases were represented. No dose-limiting toxicities were observed, the maximum tolerated dose was not reached, and 1,200 mg once daily was selected as the recommended phase II dose in NSCLC and pancreatic ductal adenocarcinoma.
Safety was assessed in 40 patients with NSCLC treated at 1,200 mg once daily. Efficacy was evaluated in a subgroup of 27 patients who had received prior immune checkpoint inhibitor therapy and platinum-based chemotherapy and had not received prior docetaxel. Dr. Riess said this subgroup was intended to approximate the second-line setting in which docetaxel is a standard treatment option.
At a median follow-up of 13.1 months, zoldonrasib demonstrated a confirmed objective response rate of 52% and a disease control rate of 93%. Median time to response was 1.4 months, and median duration of response had not been reached. Median progression-free survival was 11.1 months, with 48% of patients progression-free at 12 months. Median overall survival was not reached, and the 12-month overall survival rate was 73%.
Among 15 patients with detectable KRAS G12D in ctDNA at baseline, 13 patients, or 87%, achieved at least 50% KRAS G12D variant allele frequency clearance, and 11 patients, or 73%, achieved 100% clearance.
Among the 40 patients in the safety population, treatment-related adverse events were primarily grade 1 and gastrointestinal. The most common treatment-related adverse events were nausea (43%), vomiting (33%), diarrhea (30%), and rash (18%). Grade 3 treatment-related adverse events occurred in 13% of patients; no grade 4 or 5 treatment-related adverse events were reported. Dose interruptions occurred in 15% of patients, dose reductions in 3%, and discontinuations in 5%.
“Zoldonrasib demonstrated a favorable safety and tolerability profile, a promising response rate with durable responses, and an encouraging rate of disease control in patients whose lung cancer had progressed on prior chemotherapy and immunotherapy,” Dr. Riess said. “Our findings suggest that KRAS G12D-mutated lung cancer is treatable with promising efficacy of zoldonrasib.”
Discussant Perspective
Discussant Daniel Tan, MD, of the National Cancer Centre Singapore, titled his remarks “KRAS G12D: Tackling the Next Frontier in Molecularly Defined Non–Small Cell Lung Cancer.” He emphasized that KRAS G12D is not simply another KRAS mutation, but a biologically distinct subset with allele-specific demographics, immune biology, co-mutation patterns, and therapeutic vulnerabilities.
Daniel Tan, MD
Dr. Tan described the zoldonrasib results as one of the longer follow-up data sets currently available for this class of compounds. He highlighted the 52% response rate and 11.1-month median progression-free survival, along with the favorable tolerability profile.
However, he identified several open questions, including whether outcomes differ between never-smokers and patients with current or prior tobacco exposure, and whether zoldonrasib has CNS activity. He also highlighted ctDNA persistence as a potential emerging endpoint that could help identify patients at higher risk of earlier progression and create an opportunity to escalate therapy with rational combinations.
Looking ahead, Dr. Tan said the favorable safety profile of zoldonrasib makes it a candidate for further evaluation in combination strategies, including with immune checkpoint inhibitors. Still, he cautioned that the low frequency of KRAS G12D NSCLC and its biologic heterogeneity will make randomized trial design increasingly challenging.
“With its favorable safety profile, zoldonrasib is ideal for further evaluation in combinations specific to KRAS G12D–mutant non–small cell lung cancer, but also other tumor types,” Dr. Tan said, adding that the field eagerly awaits data on combinations and sequencing with immune checkpoint inhibitors.
A Pivotal Moment for KRAS-Targeted Therapy
The two studies point to different challenges in KRAS-mutant NSCLC. For elisrasib, the question is how a next-generation KRAS G12C inhibitor will fit into an increasingly crowded field and whether it can retain activity after prior KRAS G12C inhibition. For zoldonrasib, the question is whether early activity in KRAS G12D–mutated NSCLC can be confirmed and extended, including in patients with CNS disease and in combination strategies.
DISCLOSURE: Dr. Riess has served as a consultant for Daiichi Sankyo, BMS, Janssen, Regeneron, Genentech, Merck, Pfizer, GSK, Replimune, OncoHost, ArriVent, Nuvation, Nuvalent, Taiho Pharmaceuticals, Verastem, Boehringer Ingelheim, AstraZeneca, and Foundation Medicines; has received research support from AstraZeneca, Novartis, Merck, Revolution Medicines, Prelude, Blossom Hill, SummitPharmaceuticals, Pfizer, Nuvalent, IO Biotech, Boehringer Ingelheim, Bicycle Therapeutics, Janssen, and ArriVent; and has received honoraria from Revolution Medicines and Natera. Dr. Cho reported employment with Yonsei University Health System; has received research support 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 BlossomPark, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebiotherapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center, and Vertical Bio AG; has served 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 Inc., Takeda, MSD, Janssen, MedPacto, Blueprint medicines, RandBio, and Hanmi; has served on advisory boards for KANAPH Therapeutic Inc, Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, and Amgen; was an invited speaker for ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, and Pfizer; owns stocks in TheraCanVac Inc [Dr. Cho: Is “TheraCanVac” the correct spelling of this organization?], Gencurix Inc, BridgeBio therapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark BioConvergence Corp., and J INTS BIO; is a member of the board of directors for J INTS BIO Royalties (PDX, PDO, PDC Licensing Contract–not patent), Champions Oncology, Crown Bioscience, Imagen, PearlRiver Bio GmbH; and Founder of DAAN Biotherapeutics. Dr. Sacher reported the following disclosures: Institutional Research & Clinical Trial PI: AstraZeneca, Amgen, Genentech, Merck, Lilly, Pfizer, BMS, Spectrum, GSK, Iovance, CRISPR Therapeutics, BridgeBio, and Hotspot Therapeutics; served on an advisory board for Genentech-Roche, Amgen, Merck, and AstraZeneca; and received travel expenses from Amgen, Genentech-Roche, and Merck. Dr. Tan served as a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Beigene, Zymeworks, Genmab, Astellas, and Takeda; received research support from ACM Biolabs, Amgen, AstraZeneca, and Pfizer; has advisor/stock options with PRISM.AI; and board/directorship with Hutchmed and Epoch Biosciences.
REFERENCES
1. Cho BC, Lu S, Li Z, et al: 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. 2026 AACR Annual Meeting. Presented April 19, 2026.
2. Riess J, Haura EB, Yaeger R, et al: Preliminary safety and clinical activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with previously treated KRAS G12D non-small cell lung cancer (NSCLC). 2026 AACR Annual Meeting. Presented April 19, 2026.
