KRAS G12C–mutated CRC|
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The KRAS G12C inhibitor fulzerasib (IBI351; GFH925) demonstrated promising activity and a manageable safety profile in KRAS G12C inhibitor–naive patients with KRAS G12C–mutated metastatic colorectal cancer (mCRC), according to data from a pooled analysis of a phase 1 (NCT05005234) and a phase 1b study (NCT05497336) published in Signal Transduction and Targeted Therapy.1
At the December 13, 2023, data cutoff, patients who received fulzerasib monotherapy (n = 56) achieved a confirmed overall response rate (ORR) of 44.6% (95% CI, 31.3%-58.5%) and a disease control rate (DCR) of 87.5% (95% CI, 75.9%-94.8%). The median duration of response (DOR) was 12.6 months (95% CI, 12.6-13.9). At a median follow-up of 13.8 months (95% CI, 11.1-13.8), the median progression-free survival (PFS) was 8.1 months (95% CI, 5.5-13.8) and the median overall survival (OS) was 17.0 months (95% CI, 12.6-not reached [NR]).
“These findings warrant further clinical development of fulzerasib monotherapy or combination therapy as a potential treatment option for patients with KRAS G12C–mutated mCRC,” Ying Yuan, MD, chief physician, Department of Medical Oncology, at the Second Affiliated Hospital, Zhejiang University School of Medicine, in China, and his coauthors wrote. “A phase 3 study is planned to evaluate fulzerasib combined with cetuximab (Erbitux) in [patients with] mCRC, with results to be reported in due course.”
In May 2023, fulzerasib was granted breakthrough therapy designation by China’s National Medical Products Administration for the treatment of patients with pretreated advanced CRC with a KRAS G12C mutation.2
The pooled analysis included adult Chinese patients with histologically confirmed KRAS G12C–mutated mCRC.1 Patients were required to have an ECOG performance status of 0 or 1 and have received at least 1 dose of fulzerasib in either of the trials from which the data were pooled.
In the phase 1 study, patients received fulzerasib at 700 mg daily (n = 3), 450 mg twice daily (n = 4), 600 mg twice daily (n = 40), or 750 mg (n = 1) twice daily. All eligible patients in the phase 1b trial (n = 8) received fulzerasib at 600 mg twice daily.
The primary end point was ORR. Secondary end points included DCR, PFS, OS, DOR, and time to response, all per RECIST 1.1 criteria.
At baseline, the median age of the pooled population was 58 years (range, 32-76). Most patients were less than 60 years old (57.1%), male (60.7%), had an ECOG performance status of 1 (73.2%), were never smokers (66.1%), and received prior therapy with 5-fluorouracil (98.2%). All patients had stage IV disease; the number of prior lines of treatment was 0 (1.8%), 1 (37.5%), 2 (26.8%), and at least 3 (33.9%).
Additional findings from the pooled analysis revealed that patients who received fulzerasib at the recommended phase 2 dose (RP2D) of 600 mg twice daily (n = 48) achieved a confirmed ORR of 45.8% (95% CI, 31.4%-60.8%) and a DCR of 89.6% (95% CI, 77.3%-96.5%). The median DOR was NR (95% CI, 4.8-NR). The median PFS and OS were 8.2 months (95% CI, 5.6-13.8) and 17.0 (95% CI, 14.4-17.0), respectively.
Moreover, patients who received fulzerasib at the RP2D who received at least 2 prior lines of therapy (n = 27) experienced a confirmed ORR of 63.0% (95% CI, 42.4%-80.6%) and a DCR of 88.9% (95% CI, 70.8%-97.6%). The median DOR was NR (95% CI, 4.1-NR). The median PFS was 8.2 months (95% CI, 5.6-NR) and the median OS was 17.0 months (95% CI, 12.0-17.0).
No new safety signals were reported during the pooled analysis. Any-grade treatment-emergent adverse effects and treatment-related adverse effects (TRAEs) occurred at rates of 98.2% and 94.6%, respectively. The most common any-grade TRAEs included anemia (50.0%), decreased white blood cell count (32.1%), increased blood bilirubin (30.4%), and pruritus (26.8%). The only serious adverse effect was grade 3 anemia, which occurred in 5.4% of patients. No patients discontinued treatment due to a TRAE.
“Given the low incidence of gastrointestinal events observed with fulzerasib, its combination with anti-EGFR antibody and fluoropyrimidine-based chemotherapy presents a promising treatment approach,” study authors wrote. “However, due to the relatively high incidence of anemia associated with fulzerasib, special attention should be paid to potential myelosuppression when it is used in combination with chemotherapy.”
References
- Yuan Y, Deng Y, Jin Y, et al. Efficacy and safety of IBI351 (fulzerasib) monotherapy in KRASG12C inhibitor-naïve Chinese patients with KRASG12C-mutated metastatic colorectal cancer: a pooled analysis from phase I part of two studies. Signal Transduct Target Ther. 2025;10(1):241. doi:10.1038/s41392-025-02315-7
- Innovent receives NMPA breakthrough designation for IBI351 (KRASG12C inhibitor) as monotherapy for previously treated advanced colorectal carcinoma. News release. Innovent. May 15, 2023. Accessed August 8, 2025. https://www.innoventbio.com/InvestorsAndMedia/PressReleaseDetail?key=390