IBI351 Gets Breakthrough Therapy Designation for KRAS G12C–Mutated NSCLC in China

The Center for Drug Evaluation of China's National Medical Products Administration (NMPA) has granted a breakthrough therapy designation to IBI351 (GFH925) for the treatment of patients with advanced non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation who have received at least 1 prior line of systemic therapy.¹

The designation was based on data from a phase 1/2 trial (CTR20211933) that showed 55 patients with NSCLC treated with IBI351 monotherapy experienced an objective response rate (ORR) of 50.9% and a disease control rate (DCR) of 92.7%. Additionally, 21 patients treated at the recommended phase 2 dose of 600 mg of IBI351 twice daily achieved an ORR of 61.9% and a DCR of 100%. The median duration of response (DOR) and median progression-free survival (PFS) were not reached yet.

Updated study results will be published at an upcoming medical conference in 2023.

"We are glad to see the NMPA grant breakthrough therapy designation based on the results of phase 1 data of IBI351," Hui Zhou, PhD, senior vice president of Innovent, stated in a news release. "[Patients with] KRAS G12C–mutated NSCLC have limited treatment options. IBI351 demonstrated encouraging efficacy and safety data in phase 1 study. A single-arm registrational trial of IBI351 monotherapy in previously-treated advanced NSCLC is ongoing. We are working to advance into late-stage clinical development to explore the potential of IBI351 as monotherapy and in [combination] therapy."

IBI351 is a novel, orally active, potent KRAS G12C inhibitor designed to effectively target the GTP/GDP exchange by modifying the cysteine residue of the KRAS G12C protein covalently and irreversibly. Preclinical cysteine selectivity studies showed high selectivity of IBI351 toward KRAS G12C, and IBI351 effectively inhibits the downstream signal pathway to induce apoptosis and cell cycle arrest of tumor cells.

The phase 1/2 trial is evaluating the safety, tolerability, and efficacy of IBI351 monotherapy in patients with advanced solid tumors who failed or were intolerant to standard of care treatment.

Safety data showed that IBI351 was well tolerated. No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. Additionally, 92.5% of patients (n = 67) experienced any-grade treatment-related adverse effects (TRAEs). The most common TRAEs included anemia, increased transferase, increased bilirubin, pruritus, and fatigue.

Grade 3 or higher TRAEs occurred in 19.4% of patients; however, no grade 5 TRAEs or TRAEs leading to treatment discontinuation were reported.

The single-arm registrational trial of IBI351 monotherapy in patients with previously treated advanced NSCLC harboring KRAS G12C mutations is ongoing.

A planned phase 1 trial (NCT05504278) will also investigate the combination of IBI351 plus sintilimab with or without chemotherapy in patients with advanced nonsquamous NSCLC harboring a KRAS G12C mutation.²

References

1. Innovent announces NMPA's breakthrough therapy designation for IBI351 (KRAS G12C inhibitor) as monotherapy for previous treated advanced non-small cell lung cancer. News release. Innovent. January 4, 2023. Accessed January 10, 2023. https://bit.ly/3GxeQbG
2. Efficacy and safety of IBI351 in combination with sintilimab ± chemotherapy in advanced non-squamous non-small cell lung cancer subjects with KRAS G12C mutation. ClinicalTrials.gov. Updated August 17, 2022. Accessed January 10, 2023. https://clinicaltrials.gov/ct2/show/NCT05504278