China’s National Medical Products Administration has granted a breakthrough therapy designation to the KRAS G12C inhibitor IBI351 as monotherapy for previously treated patients with advanced colorectal carcinoma harboring a KRAS G12C mutation.
China’s National Medical Products Administration (NMPA) has granted a breakthrough therapy designation to the KRAS G12C inhibitor IBI351 (GFH925) as monotherapy for previously treated patients with advanced colorectal carcinoma (CRC) harboring a KRAS G12C mutation.1
The designation was supported by data from a pooled analysis of a phase 1/2 trial (NCT05005234) and a phase 1 trial (NCT05497336), which collectively included 54 patients with CRC who received IBI351 monotherapy. Data from the pooled analysis showed that the KRAS G12C inhibitor displayed safety and tolerability with promising antitumor activity. Full data will be presented at the 2023 ASCO Annual Meeting.
“We are glad to see the NMPA [grant] another breakthrough therapy designation based on the preliminary results of IBI351 monotherapy in advanced CRC," Hui Zhou, PhD, senior vice president of Innovent, stated in a news release. “The prognosis of [patients with] advanced CRC with [a] KRAS G12C mutation is worse than KRAS wild-type patients with limited therapeutic options. Currently, there are no approved drugs targeting KRAS G12C available on the market in China. The preliminary data of IBI351 monotherapy has shown outstanding efficacy and favorable safety in previously treated advanced CRC. We look forward to obtaining more data from the ongoing clinical trials, and further validating the clinical benefits of IBI351 as monotherapy or combination therapy in patients with advanced CRC."
IBI351 is a novel, orally active, potent KRAS G12C inhibitor developed to target the GTP/GDP exchange, which is an essential step in pathway activation, by modifying the cysteine residue of the KRAS G12C protein covalently and irreversibly. The agent previously received a breakthrough therapy designation from the NMPA for the treatment of patients with advanced non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation who have received at least 1 systemic therapy.
In the phase 1 dose-escalation portion of the phase 1/2 trial, patients with advanced NSCLC and gastrointestinal tumors, including CRC, are receiving IBI351 monotherapy. Patients are required to be at least 18 years of age with pathologically diagnosed, previously treated, advanced tumors harboring a KRAS G12C mutation. They also need to have adequate organ function and measurable disease per RECIST v1.1 criteria.2
Key exclusion criteria include significant concomitant diseases, active brain metastases, or previous treatment with a KRAS G12C inhibitor.
The primary end point of the study is the incidence of dose-limiting toxicities (DLTs). Objective response rate (ORR) serves as a secondary end point.
The other phase 1 study is investigating IBI351 monotherapy and in combination with cetuximab (Erbitux) in patients between 18 and 75 years of age with KRAS G12C–mutated metastatic CRC. Patients are required to have at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and a life expectancy of more than 12 weeks.3
Patients are excluded if they have a history of deep venous thrombosis or any other serious thromboembolism within 3 months prior to enrollment; a history of radiation-induced pneumonitis, idiopathic pneumonia, active pneumonia, pulmonary fibrosis, diffuse pulmonary interstitial disease, or organizing pneumonia; undergo a surgical procedure within 28 days prior to enrollment that may affect dosing or study assessments; or received therapeutic or palliative radiation therapy within 14 days prior to enrollment.
Incidence of DLTs and ORR are the study’s co-primary end points. Incidence of serious adverse effects is a key secondary end point.