Glecirasib, an investigational small molecule inhibitor of KRAS G12C mutations developed by Jacobio Pharmaceuticals, is emerging as a promising therapeutic option for various solid tumors. This selective and covalent KRAS G12C inhibitor targets one of the most common and challenging oncogenic drivers in cancer. Glecirasib is currently undergoing an NDA review at the China CDE and has received Breakthrough Therapy Designation from China’s Center for Drug Evaluation for second-line and later treatment of KRAS G12C mutant NSCLC and pancreatic cancer, as well as Orphan Drug Designation from the U.S. FDA for pancreatic cancer.
Mechanism of Action
KRAS, a small GTPase, functions as a molecular switch regulating cell proliferation and survival. The G12C mutation, found in approximately 13% of non-small cell lung cancers (NSCLC), 3-5% of colorectal cancers, and 1-2% of pancreatic cancers, impairs GTP hydrolysis, locking KRAS in its active state and driving tumorigenesis. Glecirasib selectively and irreversibly binds to the cysteine residue of KRAS G12C in its inactive GDP-bound state, preventing its activation and blocking downstream oncogenic signaling.
Key features of Glecirasib’s mechanism include:
- High selectivity for the G12C mutant form of KRAS over wild-type KRAS, HRAS, or NRAS
- Irreversible covalent binding to Cys12, providing durable target engagement
- Binding to the GDP-bound state, trapping KRAS G12C in its inactive conformation
- Potent inhibition of MAPK pathway signaling and other KRAS-downstream oncogenic pathways
Clinical Efficacy in NSCLC
The pivotal phase 2b study in NSCLC (NCT05009329) enrolled 119 patients with KRAS G12C mutant advanced NSCLC who had progressed on prior platinum-based chemotherapy and immunotherapy. Patients received glecirasib 800 mg once daily until disease progression or unacceptable toxicity. The trial met its primary endpoint, demonstrating an objective response rate (ORR) of 47.9% (95% CI: 38.5-57.3%) by independent review.
Key efficacy results included:
- Median progression-free survival (PFS) per IRC was 8.2 months (95% CI: 5.5-13.1 months)
- Median overall survival (OS) of 13.6 months (95% CI: 10.9 months – NE)
- Disease control rate of 86.3% (95% CI: 78.7-92.0%)
The majority of CR/PR patients are ongoing. The median duration of response has not been reached; 6-month and 12-month rDoR rates were 73.6% and 56.6%, respectively
Clinical Activity in Pancreatic Cancer and Other Solid Tumors
In 48 evaluable patients with previously treated advanced pancreatic cancer or other solid tumors, glecirasib demonstrated a confirmed ORR of 50% and a disease control rate of 93.8%. In the pancreatic cancer cohort specifically (n=31), the confirmed ORR was 41.9% with a median PFS of 5.6 months and median OS of 10.7 months. These results are particularly encouraging given the historically poor outcomes in pancreatic cancer and the limited efficacy of other KRAS G12C inhibitors in this indication.
Safety and Tolerability
Glecirasib demonstrated a favorable safety and tolerability profile. Treatment-related adverse events (TRAEs) occurred in 97.5% of patients; grade ≥3 TRAEs in 38.7%. No grade 5 (fatal) TRAE occurred. Most common TRAEs included anemia, blood bilirubin increased, and alanine aminotransferase increased/ aspartate aminotransferase increased. Notably, there were low rates of gastrointestinal toxicities compared to other KRAS G12C inhibitors (nausea 7%, vomiting 7.6%, diarrhea 3.4%). Treatment discontinuation due to TRAEs occurred in 5.0% of patients.
Ongoing Clinical Trials
Several additional clinical trials of glecirasib are currently ongoing or planned:
- Phase 3 registration study of glecirasib plus the SHP2 inhibitor JAB-3312 versus tislelizumab combined with pemetrexed and carboplatin in the frontline treatment of advanced KRAS G12C mutant NSCLC (NCT06416410)
- Phase 2 single-arm pivotal study of glecirasib monotherapy in KRAS G12C mutated pancreatic cancer(NCT06008288)
- Phase 2 study of glecirasib in combination with cetuximab in KRAS G12C mutant colorectal cancer (NCT05194995)
- Phase 2 single-arm pivotal study of glecirasib monotherapy in KRAS G12C mutated pan-tumor basket patients (biliary tract cancer, gastric cancer, small bowel cancer, etc.)
Future Directions
Future development plans for glecirasib include expansion into earlier lines of therapy, evaluation in additional tumor types harboring KRAS G12C mutations, and development of combination strategies to enhance efficacy and overcome resistance mechanisms. With its promising clinical data and favorable safety profile, glecirasib has the potential to significantly impact the treatment landscape for patients with KRAS G12C mutant cancers.
