Glecirasib is a KRAS G12C inhibitor currently being developed by Jacobio. Several Phase I/II clinical trials of the drug are currently ongoing in China, the United States, and Europe for patients with advanced solid tumors harboring KRAS G12C mutation. This includes a pivotal clinical trial in NSCLC in China; a monotherapy study for STK11 co-mutated NSCLC in the front-line setting, and combination therapy trials with SHP2 inhibitor JAB-3312 in NSCLC and with Cetuximab in colorectal cancer.

Jacobio presented findings from a Phase I/IIa clinical study involving glecirasib in combination with JAB-3312. The trial included seven dose groups, incorporating different combinations and dosing intervals of glecirasib at 400 mg and 800 mg with JAB-3312. Its primary objective was to assess the safety, effectiveness, and tolerance across these dose groups, laying the groundwork for a future registrational clinical trial.

As of August 4, 2023, the study had enrolled a total of 144 patients with KRAS G12C mutations, comprising 129 individuals with non-small cell lung cancer, 14 with colorectal cancer, and one with pancreatic cancer.

Glecirasib plus JAB-3312 has demonstrated promising efficacy in KRAS G12C NSCLC.

The objective response rate (ORR) was 86.7% (13/15) in the dose group of 800 mg glecirasib in combination with 2 mg JAB-3312, in the front-line setting. The mPFS (median progression-free survival) and duration of response are still under observation as the patients are still undergoing treatment. In the dose of 400 mg glecirasib, the ORR was 55.6% (with 2mg JAB-3312) and 50% (with 4mg JAB-3312). Median PFS and DOR have not been reached.

Glecirasib plus JAB-3312 has a manageable safety profile. The incidence of Grades 3 and 4 TRAEs (treatment-related adverse events) was 39.6% across all the dose groups, whereas the incidence of Grades 3 and 4 TRAEs was 36.7% in the dose group of 800 mg glecirasib in combination with 2 mg JAB-3312. No Grade 5 TRAE was seen. No new safety signals were identified compared to glecirasib and JAB-3312 as monotherapy.

The data indicates that the SHP2 inhibitor is one of the most promising potential companion drugs for the KRAS G12C inhibitor in the treatment of NSCLC.

KOL insights

“In KRAS G12C mutant NSCLC patients, the combination therapy of glecirasib with JAB-3312 has shown positive efficacy signals. Compared with monotherapy, combination therapy can synergistically inhibit tumor growth. In addition, both drugs are administered orally, so patients do not need to be hospitalized, which is more convenient for patients. We look forward to further validating the clinical efficacy of the combination therapy through follow-up studies. ” – Professor, Cancer Hospital, Chinese Academy of Medical Sciences, China

Conclusion: DelveInsight estimated that the United States had the highest number of KRAS mutation cases in NSCLC among the 7MM. In the United States, KRAS G12C is present in ~37% of NSCLC cases. The most frequent KRAS variant observed in NSCLC is G12C.

 

The results from Jacobio's Phase I/IIa clinical study on the combination of glecirasib and JAB-3312 present a significant advancement in the treatment of KRAS G12C mutant non-small cell lung cancer (NSCLC). The remarkable 100% disease control rate and the substantial 86.7% objective response rate in the 800 mg glecirasib and 2 mg JAB-3312 dose group are highly promising findings. Importantly, this combination therapy has shown a manageable safety profile, with no Grade 5 treatment-related adverse events and no new safety signals, making it a compelling treatment option for patients. These results highlight the potential of SHP2 inhibitors as valuable companion drugs to KRAS G12C inhibitors in the management of NSCLC. The convenience of oral administration adds to the appeal of this approach, reducing the need for hospitalization and improving the quality of life for patients. With ongoing studies and further validation, it is evident that glecirasib and JAB-3312 could potentially redefine the landscape of KRAS G12C NSCLC therapy, offering new hope to patients facing this challenging condition.

Note: The therapeutics segment is experiencing significant NSCLC clinical trial activity, which is further expected to drive Non-Small Cell Lung Caner market growth in the coming years.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the KRAS Inhibitors Market Insights and Market Forecast and Non-Small Cell Lung Cancer Market Report