Initial results from a phase I study of the SHP2 inhibitor GH21 as monotherapy in patients with advanced solid tumors.

e15140 Background: GH21 is a selective, orally bioavailable allosteric inhibitor of SHP2, an oncogenic phosphatase that plays a crucial role in the RAS-MAPK and immune suppression pathways. This phase I study (NCT05183243) assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of GH21 in patients with advanced solid tumors. Methods: This open-label, multicenter study comprised an accelerated titration and “3+3” dose escalation part followed by dose expansion. Two dose regimens, QD and BIW D1D2 (twice weekly, day 1 and 2 schedule), were explored in dose escalation part with a starting dose of 3 mg QD and 18 mg BIW D1D2, 5 cohorts and 3 cohorts were explored respectively. Patients were administrated with GH21 multiple doses, 7 days after initially receiving GH21 single dose, with a 21-day cycle in dose escalation part. Two cohorts described above were explored with a 28-day cycle in dose expansion part. GH21 was administered until unacceptable toxicity or disease progression. Key endpoints included safety, PK, PD, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Results: As of December 31, 2024, 70 patients were enrolled, mainly including non-small cell lung cancer (NSCLC), colorectal cancer, head and neck squamous cell carcinoma (HNSCC) and esophageal squamous carcinoma (ESC). 66 patients (94.3%) reported treatment-related adverse events (TRAEs) with 24 patients experiencing grade 3 or higher events (34.3%). The common grade 3 or higher TRAEs included thrombocytopenia (14.3%), anemia (8.6%), creatine kinase increase (4.3%). Among 60 patients assessable for efficacy analysis, 1 patient of NSCLC with KRAS p.G12C mutation had confirmed partial response and 24 had stable disease, and DCR was 41.7%. Among 22 patients assessable for response at the dose level of 9mg QD in expansion part, stable disease occurred in 15 patients (DCR, 68.2%) and the median PFS was 3.48 months. No grade 4/5 TRAEs were observed at 9mg QD cohort and the most common grade 3 TRAEs (≥5%) were thrombocytopenia (14.3%), anemia (14.3%), creatine kinase increase (10.7%) and oedema peripheral (7.1%), 9 mg QD was determined to be the RP2D for GH21 monotherapy. Stable disease was achieved as the best observed response in all (8/8, 100%) heavily treated HNSCC and ESC. PK of GH21 was linear and dose-independent with mean half-life in the range of 37.0 h-51.4 h. Accumulation in PK exposure was observed post multiple dosing with QD. PD analysis indicated a significant decrease in the levels of pERK in peripheral blood monocytes 3 hours after first dosing and sustained inhibition of pERK with QD dosing. Conclusions: GH21 was generally well tolerated while providing benefits to heavily treated NSCLC, HNSCC and EC, who has a favorable pharmacokinetic property as monotherapy. The combination therapy studies in which GH21 can exert synergistic effects will be anticipated. Clinical trial information: NCT05183243 .