Fulzerasib Receives Approval in China for Advanced KRAS G12C+ NSCLC

Supporting data for the approval came from a phase 2 study (NCT05005234) assessing the safety and efficacy of fulzerasib for patients with advanced NSCLC harboring KRAS G12C mutations following disease progression on standard therapy.

China’s National Medical Products Administration (NMPA) has approved fulzerasib (Dupert) as a treatment for adults with advanced KRAS G12C–mutated non–small cell lung cancer (NSCLC) following at least 1 prior line of systemic therapy, according to a press release from the developer, Innovent Biologics, Inc.¹

Fulzerasib—an investigational, orally active KRAS G12C inhibitor—was designed to covalently and irreversibly alter the cysteine residue of the KRAS G12C protein, which helps with targeting the GTP/GDP exchange involved in pathway activation. Based on results from prior preclinical cysteine selectivity studies, investigators hypothesized that treatment with fulzerasib may impede downstream signal pathways, consequently yielding tumor cell apoptosis and cell cycle arrest.

Supporting data for the approval came from a phase 2 study (NCT05005234) assessing the safety and efficacy of fulzerasib for patients with advanced NSCLC harboring KRAS G12C mutations following disease progression on standard therapy.

As of the data cutoff date of December 13, 2023, treatment with fulzerasib appeared to be tolerable while eliciting antitumor activity among 116 patients with NSCLC. Based on an independent radiology review committee (IRRC) assessment, the confirmed objective response rate (ORR) was 49.1% (95% CI, 39.7%-58.6%). Additionally, study treatment conferred a disease control rate (DCR) of 90.5% (95% CI, 83.7%-95.2%), while the median duration of response (DOR) was not reached. Data showed that the median progression-free survival (PFS) was 9.7 months (95% CI, 5.6-11.0) and that the median overall survival (OS) was not reached.

“KRAS has long been considered an 'undruggable' target despite being a common oncogenic driver mutation. The advent of KRAS G12C inhibitors has opened new avenues for precision medicine in cancers harboring this mutation,” Yi-Long Wu, MD, a professor from Guangdong Lung Cancer Institute of Guangdong Provincial People's Hospital, said in the press release.¹ “We are proud to be part of the clinical research and development of [fulzerasib], the first KRAS G12C inhibitor approved in China. We hope that [fulzerasib] will soon benefit more patients with advanced lung cancer harboring KRAS G12C mutations, driving the progress of precision treatment for lung cancer.”

In the phase 2 portion of this open-label, multi-center study, investigators assessed the efficacy of fulzerasib in patients with advanced NSCLC harboring KRAS G12C mutations.² Those with KRAS G12C–mutated colorectal cancer (CRC) and other tumors were also assessed during the phase 1b portion of the study. Patients received fulzerasib as an oral tablet formulation.

The trial’s primary end points included adverse effect (AEs) and dose-limiting toxicities in phase 1a, ORR per RECIST v1.1 criteria in phase 1b, and ORR per IRRC evaluation in phase 2. Secondary end points across all phases of the study included pharmacokinetics, DCR, DOR, time to response, PFS, and OS.

Patients 18 years and older with at least 1 measurable lesion per RECIST v1.1 guidelines and an ECOG performance status of 0 or 1 were eligible for enrollment on the trial. Having a minimum life expectancy of 12 weeks was another requirement for study entry.

Those with significant cardiovascular system disease, unstable brain metastases, or the presence of serious acute or chronic infections were ineligible for enrollment. Additionally, having significant gastrointestinal diseases such as intractable hiccups, nausea, vomiting, or cirrhosis was also grounds for exclusion from the trial.

“Patients with advanced NSCLC harboring KRAS G12C mutations have limited treatment options, with traditional chemotherapy offering minimal benefits. We are excited that [fulzerasib] has become the first KRAS G12C inhibitor approved in China, marking the beginning of a new era in targeted therapy for KRAS mutations,” Hui Zhou, PhD, senior vice president at Innovent, concluded.¹

References

1. China's first approved KRAS G12C inhibitor: Innovent announces the approval of Dupert® (fulzerasib) by the National Medical Products Administration of China. News release. Innovent Biologics, Inc. August 22, 2024. Accessed August 22, 2024. https://tinyurl.com/2tszfzvu
2. A study of GFH925 in patients with advanced solid tumors with KRAS G12C mutations. ClinicalTrials.gov. Updated August 16, 2023. Accessed August 22, 2024. https://tinyurl.com/mryc79r2