Glecirasib plus sitneprotafib in patients with KRAS G12C -mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 1/2a trial
Published report from the Phase 1 trial registered as NCT05288205, in The Lancet. Respiratory medicine (2026), chosen as the most cited paper whose own text cites the registry id.
Overview
Background: Monotherapy with KRAS G12C (ie, KRAS Gly12Cys) inhibitors has emerged as a mainstream treatment for patients with KRAS G12C -mutated non-small-cell lung cancer (NSCLC). Synergistic effects have been observed with the combination of a KRAS G12C inhibitor and a SHP2 inhibitor in multiple xenograft models. We aimed to evaluate the safety and efficacy of the KRAS G12C inhibitor glecirasib combined with the SHP2 inhibitor sitneprotafib (JAB-3312; Jacobio Pharmaceuticals, Beijing, China) in patients with KRAS G12C -mutated solid tumours.
Methods: We conducted an open-label, multicentre, single-arm, phase 1/2a trial at 26 hospitals across China. Patients (aged ≥18 years) with locally advanced or metastatic solid tumours harbouring a KRAS G12C mutation, an Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1) were eligible for inclusion in both phases. Patients received oral glecirasib (400 mg or 800 mg once daily) in combination with oral sitneprotafib (2 mg or 3 mg once daily) in seven cohorts evaluating various dose levels and schedules of the two drugs. In phase 1, the primary endpoint was safety assessed by investigators according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) from first treatment dose to 30 days after the last dose of both agents. In phase 2a, the primary endpoint was objective response rate (ORR) between baseline and disease progression or initiation of anticancer therapy, whichever occurred first, based on the comprehensive assessment of all tumour evaluations by investigators following RECIST (version 1.1). All patients who received at least one dose of combination therapy were included in the safety and efficacy analyses. This trial is registered with ClinicalTrials.gov (NCT05288205) and is currently recruiting.
Findings: Between May 7, 2022, and Aug 20, 2024, a total of 194 patients with advanced solid tumours were enrolled, of whom 171 (88%) had NSCLC (50 [29%] in phase 1 and 121 [71%] in phase 2a). Median participant age was 65 years (IQR 59-70); 140 (82%) were men and 31 (18%) were women. At data cutoff on Aug 20, 2024, the median follow-up duration was 14·5 months (IQR 11·9-17·1), and 106 (62%) patients had discontinued treatment. Phase 1 concluded with one dose-limiting toxicity (DLT; grade 3 pneumonitis) at the highest dose level (glecirasib 800 mg plus sitneprotafib 3 mg once daily, 1 week on and 1 week off); no DLTs were observed at other dose levels. Across phase 1 and 2a, 167 patients (98%) had at least one treatment-related adverse event, which were grade 3-4 in 78 (46%) patients. The most common treatment-related adverse events (occurring in ≥20% of all 171 patients) were anaemia (105 [61%]), hypertriglyceridaemia (103 [60%]), increased aspartate aminotransferase (95 [56%]), increased alanine aminotransferase (83 [49%]), increased blood bilirubin (78 [46%]), oedema (62 [36%]), increased blood creatine phosphokinase (60 [35%]), neutropenia (54 [32%]), decreased white blood cell count (50 [29%]), and increased bodyweight (44 [26%]). Three (2%) patients discontinued glecirasib and sitneprotafib due to treatment-related adverse events. No grade 5 treatment-related adverse event was reported. The ORR was 71% (72 patients [95% CI 61-79]) in the subgroup of 102 patients with previously untreated NSCLC; 49% (19 patients [32-65]) in the 39 patients previously treated with systemic therapy but naive to KRAS G12C inhibitors; and 10% (three patients [2-27]) in the 30 patients previously treated with KRAS G12C inhibitor therapy.
Interpretation: Glecirasib combined with sitneprotafib showed promising efficacy and manageable safety in patients with advanced KRAS G12C -mutated NSCLC, particularly among those who had not received previous treatment. These findings support the evaluation of this combination in a phase 3 trial comparing this chemotherapy-free regimen to current standard of care in this patient group.
Funding: Jacobio Pharmaceuticals.
Translation: For the Chinese translation of the abstract see Supplementary Materials section.
Indexed on Europe PMC as PubMed record 41325755 (DOI 10.1016/s2213-2600(25)00258-9). Its abstract cites the registry id NCT05288205, which is how it was matched to this trial; no figure has been checked by an editor.
This is the paper Europe PMC returns for registry id NCT05288205 with the most citations, so it is the natural first reading for anyone following the Phase 1 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
- Matched to the trial by the registry id cited in the Europe PMC record; the summary reproduces the record's abstract and no figure has been verified against the full paper.