IBI351 NDA Under NMPA Review in Advanced KRAS G12C–Mutant NSCLC

November 28, 2023

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The Center for Drug Evaluation of China’s National Medical Products Administration has accepted and granted priority review to the new drug application for IBI351 in the treatment of patients with advanced, KRAS G12C–mutant NSCLC who have received at least 1 prior systemic therapy.

Yu Wang, MD, PhD

The Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has accepted and granted priority review to the new drug application (NDA) for IBI351 (GFH925) in the treatment of patients with advanced, KRAS G12C–mutant non–small cell lung cancer (NSCLC) who have received at least 1 prior systemic therapy.¹

The designation was supported by results from a phase 1/2 study (NCT05005234) of IBI351 monotherapy.¹

Preliminary efficacy data from the phase 1 dose-escalation portion of this study were reported during the 2023 AACR Annual Meeting. At the February 10, 2023, data cutoff, 41 of the 67 evaluable patients achieved a partial response with the agent. The investigator-assessed objective response rate (ORR) in this population was 61.2%, with a disease control rate (DCR) of 92.5%. Moreover, patients treated with the recommended phase 2 dose (RP2D) of 600 mg twice daily (n = 30) experienced higher responses, with an investigator-assessed ORR of 66.7% and a confirmed ORR (cORR) of 53.3%. The DCR in this cohort was 96.7%.

Full results from the phase 2 trial will be presented at the 2023 ESMO Asia Congress, taking place from December 1 to 3, 2023.

"GFH925 is GenFleet's first NDA-stage product and becomes China's first KRAS G12C inhibitor that receives NDA acceptance and priority review designation. That demonstrates GFH925's encouraging safety and efficacy in treating advanced NSCLC, and its potential in commercialization in the future,” Yu Wang, MD, PhD, chief medical officer of GenFleet, stated in a press release.

The novel, oral KRAS G12C inhibitor was designed to covalently and irreversibly modify the cysteine residue of the KRAS G12C protein, thereby preventing GTP/GDP exchange during normal pathway activation.

The single-arm, registrational study included 74 patients with advanced solid tumors harboring a KRAS G12C mutation who had progressed on, or were intolerant to, standard-of-care treatment in China. Patients in the dose escalation phase started at 250 mg escalating to 900 mg given once a day or starting at 450 mg escalating to 750 mg given twice a day.²

The coprimary end points of the phase 1a portion of the study were safety, tolerability, and finding the maximum tolerated dose and recommended phase 2 dose of the KRAS inhibitor. The primary end point in both the phase 1b and 2 portion of the study was ORR. Secondary end points included pharmacokinetics and antitumor activity as defined by RECIST v1.1.²

In January 2023, IBI351 monotherapy obtained breakthrough therapy designation from China’s NMPA for patients with advanced KRAS G12C–mutant NSCLC who received at least 1 systemic therapy.³ Findings from a phase 1/2 trial (CTR20211933) supported this decision, and demonstrated that IBI351 monotherapy produced an ORR of 50.9% and a DCR of 92.7% in patients with NSCLC (n = 55). Moreover, patients treated with the RP2D of IBI351 achieved an ORR of 61.9% and a DCR of 100%.

“[A] KRAS mutation as the 'undruggable' target for decades has become one of the most popular directions for clinical development recently. IBI351 is a novel, irreversible covalent inhibitor of [the] KRAS G12C mutation," Professor Yi-Long Wu from Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, stated in the release. “IBI351 monotherapy demonstrated favorable safety and promising activity in KRAS G12C–mutated advanced NSCLC. We look forward to the NDA approval of this novel drug to benefit more NSCLC patients with [a] KRAS G12C mutation soon.”

IBI351 also received breakthrough therapy designation from the CDE in May, 2023, for previously treated patients with advanced KRAS G12C–mutant CRC.⁴ This decision was supported by data from a pooled analysis of 54 patients in a phase 1/2 trial (NCT05005234) and a phase 1 trial (NCT05497336). Among the 42 patients with metastatic CRC who received IBI351 monotherapy at the RP2D, the ORR was 42.9%, the confirmed ORR was 31.0%, and the DCR was 88.1%. The data cutoff for this analysis was February 16, 2023.^1,4

In China, 2 phase 1b studies of IBI351 in combination with cetuximab (Erbitux) and the PD-1 inhibitor sintilimab (Tyvyt), respectively, are ongoing in previously untreated patients with advanced NSCLC and KRAS G12C mutations.¹