653O - Glecirasib (KRAS G12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) in patients with KRAS p.G12C mutated solid tumors

Background

Glecirasib is a direct oral KRAS G12C inhibitor (KRAS G12Ci) with favorable tolerability and promising efficacy. JAB-3312 is a potent oral SHP2 inhibitor that may overcome KRAS G12Ci resistance. Together these compounds were shown to exert synergistic anti-tumor effect when combined with glecirasib in multiple animal models. Here we present the preliminary clinical data from the dose escalation phase.

Methods

The phase 1/2a study [NCT05288205] evaluated glecirasib plus JAB-3312 in patients (pts) with KRAS p.G12C mutated solid tumors. The primary endpoint of the dose escalation part was safety and tolerability. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) per RECIST 1.1 and pharmacokinetics (PK) profile. Glecirasib 400 mg or 800 mg daily was combined with various JAB-3312 doses and schedules.

Results

As of April 7^th, 2023, 60 pts (50 non-small cell lung cancer [NSCLC], 9 colorectal cancer, and 1 pancreatic cancer) were enrolled in six dose levels. About 40% had ≥ 2 prior lines of therapy, and 26.7% had received prior KRAS G12Ci treatment. Dose escalation concluded with one dose-limiting toxicity (grade 3 pneumonitis) at a higher dose level. The most common (>20%) treatment-related adverse events (TRAE) included anemia, ALT/AST increased, hypertriglyceridemia, bilirubin increased, neutropenia/leukopenia, creatine kinase increased, and edema. TRAE ≥ grade 3 occurred in 36.7% of pts. No TRAE led to discontinuation of both glecirasib and JAB-3312. PK of JAB-3312 of the combination was generally comparable with historical monotherapy, suggesting low risk of drug-drug interaction. Amongst the 50 pts with NSCLC, 35 were efficacy evaluable, 14 have not reached the first scan and one withdrew due to COVID-19. Out of 28 evaluable pts with KRAS G12Ci naïve NSCLC, ORR was 50% (14/28) and DCR was 100%. In pts with KRAS G12Ci treated NSCLC, ORR was 14.3% (1/7), and DCR was 57.1%. Additional safety, efficacy and PK data will be presented at this meeting.

Conclusions

Glecirasib plus JAB-3312 was well tolerated with promising efficacy in KRAS p.G12C NSCLC. Currently, dose expansion is underway to further evaluate efficacy and safety.

Clinical trial identification

NCT05288205.

Editorial acknowledgement

Legal entity responsible for the study

Jacobio Pharmaceuticals Group Co., Ltd.

Funding

Jacobio Pharmaceuticals Group Co., Ltd.

Disclosure

A. Wang-Gillam, Y. Ding, Z. Rao, C. Bi: Financial Interests, Personal, Full or part-time Employment: Jacobio Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.