Fulzerasib Approved in China for KRAS G12C–Mutant Advanced NSCLC

China’s National Medical Products Administration has approved fulzerasib (Dupert; formerly IBI351) for the treatment of adult patients with advanced non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation who have received at least 1 prior systemic therapy.¹ 

This regulatory decision was supported by findings from a registrational, single-arm, phase 2 trial (NCT05005234) that evaluated the efficacy and safety of fulzerasib monotherapy in patients with advanced solid tumors harboring a KRAS G12C mutation who had progressed on or were intolerant to standard treatment in China. At a data cutoff date of December 13, 2023, among 116 evaluable patients with NSCLC, fulzerasib elicited an overall response rate (ORR) of 49.1% (95% CI, 39.7%-58.6%), as confirmed by the independent radiology review committee (IRRC). The disease control rate (DCR) was 90.5% (95% CI, 83.7%-95.2%), and the median duration of response (DOR) was not yet reached (NR). Furthermore, the median progression-free survival (PFS) was 9.7 months (95% CI, 5.6-11.0), and the median overall survival (OS) was NR.

Investigators noted that the agent was generally well tolerated. The most common treatment-related adverse effects (TRAEs) included anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%), and the presence of protein urine (25.0%).2 In total, 7.8% of patients had TRAEs leading to treatment discontinuation.

“KRAS has long been considered an ‘undruggable’ target despite being a common oncogenic driver mutation,” Yi-Long Wu, MD, professor at the Guangdong Lung Cancer Institute at Guangdong Provincial People’s Hospital in China, stated in a news release.¹ “The advent of KRAS G12C inhibitors has opened new avenues for precision medicine in cancers harboring this mutation. 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.”

Recapping the Registrational Phase 2 Trial

Among the 116 patients with NSCLC enrolled in the phase 2 trial, 91.4% had an ECOG performance status of 1, 30.2% had brain metastases, and 84.5% had received prior treatment with both platinum-based chemotherapy and PD-1/PD-L1 inhibitors.²

Patients received oral fulzerasib at 600 mg twice daily. The trial’s primary end point was confirmed ORR per IRRC assessment and by RECIST 1.1 criteria. Key secondary end points included safety, IRRC-confirmed DCR, DOR, PFS, and OS.

All 95 of the biomarker-evaluable patients had positive KRAS G12C expression per tissue biopsy, and 72 of these patients had positive KRAS G12C expression per liquid biopsy. Patients with positive KRAS G12C expression in both tissue and liquid biopsy had a higher baseline tumor burden (P < .05) and worse PFS outcomes (P < .05) compared with those who only had positive KRAS G12C expression in tissue biopsy.

The most common genes that were commutated with KRAS G12C were TP53 (45.3%), STK11 (30.5%), and KEAP1 (21.1%). Mutations in KEAP1, STK11, POLE, PIK3CG, BRINP3, and SMAD4 were significantly associated with worse PFS outcomes (P < .05). STK11 mutations were also significantly associated with higher baseline tumor burden and lower response rate (P < .05).

A New Era

“Patients with advanced NSCLC harboring KRAS G12C mutations have limited treatment options, with traditional chemotherapy offering minimal benefits,” Hui Zhou, PhD, senior vice president of Innovent, added in the news release. “[This approval marks] the beginning of a new era in targeted therapy for KRAS mutations. As Innovent's eleventh drug, [fulzerasib] further strengthens our robust oncology portfolio. Innovent will continue to leverage its leadership and expertise in oncology to drive innovation in cancer treatment and serve more patients in need.”

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 21, 2024. Accessed August 22, 2024. https://www.innoventbio.com/InvestorsAndMedia/PressReleaseDetail?key=473
2. Zhou Q, Meng X, Sun L, et al. Efficacy and safety of KRAS G12C inhibitor IBI351 monotherapy in patients with advanced non-small cell lung cancer: results from a phase 2 pivotal study. J Thorac Oncol. Published online August 8, 2024. doi:10.1016/j.jtho.2024.08.005