GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, announced US Food and Drug Administration (FDA) has granted the clinical trial approval for GFH925 (KRAS G12C inhibitor) in a multi-center, open-label, randomized and controlled phase III study treating refractory metastatic colorectal cancer (CRC) patients.

It is the first phase III trial of KRAS G12C inhibitor monotherapy targeting CRC patients worldwide, with GFH925 being the first G12C inhibitor that received Breakthrough Therapy Designation (BTD) from China's National Medical Products Administration (NMPA) for previously treated advanced CRC. GFH925 was also granted BTD and New Drug Application acceptance with Priority Review Designation by NMPA for previously treated advanced non-small cell lung cancer（NSCLC）patients with G12C mutation.

The trial (GFH925X0301) will enroll refractory metastatic CRC patients harboring KRAS G12C mutation who have progressed or experienced disease recurrence on or after at least two prior lines of therapies, or intolerant to the last treatment. The primary objective is to compare the efficacy of GFH925 versus the current standard of care.

A pooled analysis from the two phase I studies was published at ESMO Asia 2023: GFH925 monotherapy for CRC demonstrated efficacy (including objective response rate and median progression-free survival) superior to other single-agent KRAS G12C inhibitors and comparable to the combination regimens of other G12C inhibitors with anti-EGFR antibodies.

"We appreciate the FDA's recognition of GFH925' efficacy and safety profile, as this is our first global phase III monotherapy study in treating advanced stage CRC. We believe the approval of our proposed trial design highlights the potential of GFH925 monotherapy in this indication, thus bringing more therapeutic options and clinical benefits to the patients. This is a significant step forward in the development of GFH925, paving the way for its potential future use as a front-line treatment for CRC. "stated Yu Wang, Ph.D/M.D., Chief Medical Official of GenFleet. "Additionally, the study of GFH925 in combination with cetuximab is ongoing in Europe treating advanced NSCLC in the first-line setting and the phase II trial has completed the enrollment; the preliminary data analysis of this combination study, accepted as a late breaking abstract, has been selected for oral presentation during the 2024 ASCO annual meeting. GFH925's global development reflects GenFleet's forward-thinking strategy, the expertise of our clinical team and the deep understanding of biology for our RAS-targeted pipeline."

According to GLOBOCAN 2022 report, there were over 1.9 million new CRC cases and over 900,000 deaths worldwide, both accounting for over 9% in all cancer types. Approximately 40% of CRC patients carry KRAS mutations, with the prevalence of mutated G12C allele in CRC being only next to NSCLC. Standard first- and second-line treatments are based on combination of fluoropirimidines plus oxaliplatin or irinotecan, associated to an anti-EGFR (RAS wild type) or anti-VEGF antibody.

Among the patients that eventually develop metastases to liver, lung and/or peritoneum, KRAS mutation in CRC is a prognostic factor associated with advanced disease status, poor tumor differentiation, distant metastasis, and inferior survival. On the other hand, a limited number of CRC patients receive checkpoint inhibiting therapies, especially when compared with patients of other hot tumors such as lung cancer; more targeted agents with a safety profile are called for those patients. Moreover, prior-line EGFR inhibitors may lead to secondary KRAS mutations. There is consequently a substantial unmet clinical need, coupled with vast market potential, for developing innovative KRAS inhibitors.

GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, announced US Food and Drug Administration (FDA) has granted the clinical trial approval for GFH925 (KRAS G12C inhibitor) in a multi-center, open-label, randomized and controlled phase III study treating refractory metastatic colorectal cancer (CRC) patients.

It is the first phase III trial of KRAS G12C inhibitor monotherapy targeting CRC patients worldwide, with GFH925 being the first G12C inhibitor that received Breakthrough Therapy Designation (BTD) from China's National Medical Products Administration (NMPA) for previously treated advanced CRC. GFH925 was also granted BTD and New Drug Application acceptance with Priority Review Designation by NMPA for previously treated advanced non-small cell lung cancer（NSCLC）patients with G12C mutation.

The trial (GFH925X0301) will enroll refractory metastatic CRC patients harboring KRAS G12C mutation who have progressed or experienced disease recurrence on or after at least two prior lines of therapies, or intolerant to the last treatment. The primary objective is to compare the efficacy of GFH925 versus the current standard of care.

A pooled analysis from the two phase I studies was published at ESMO Asia 2023: GFH925 monotherapy for CRC demonstrated efficacy (including objective response rate and median progression-free survival) superior to other single-agent KRAS G12C inhibitors and comparable to the combination regimens of other G12C inhibitors with anti-EGFR antibodies.

"We appreciate the FDA's recognition of GFH925' efficacy and safety profile, as this is our first global phase III monotherapy study in treating advanced stage CRC. We believe the approval of our proposed trial design highlights the potential of GFH925 monotherapy in this indication, thus bringing more therapeutic options and clinical benefits to the patients. This is a significant step forward in the development of GFH925, paving the way for its potential future use as a front-line treatment for CRC. "stated Yu Wang, Ph.D/M.D., Chief Medical Official of GenFleet. "Additionally, the study of GFH925 in combination with cetuximab is ongoing in Europe treating advanced NSCLC in the first-line setting and the phase II trial has completed the enrollment; the preliminary data analysis of this combination study, accepted as a late breaking abstract, has been selected for oral presentation during the 2024 ASCO annual meeting. GFH925's global development reflects GenFleet's forward-thinking strategy, the expertise of our clinical team and the deep understanding of biology for our RAS-targeted pipeline."

According to GLOBOCAN 2022 report, there were over 1.9 million new CRC cases and over 900,000 deaths worldwide, both accounting for over 9% in all cancer types. Approximately 40% of CRC patients carry KRAS mutations, with the prevalence of mutated G12C allele in CRC being only next to NSCLC. Standard first- and second-line treatments are based on combination of fluoropirimidines plus oxaliplatin or irinotecan, associated to an anti-EGFR (RAS wild type) or anti-VEGF antibody.

Among the patients that eventually develop metastases to liver, lung and/or peritoneum, KRAS mutation in CRC is a prognostic factor associated with advanced disease status, poor tumor differentiation, distant metastasis, and inferior survival. On the other hand, a limited number of CRC patients receive checkpoint inhibiting therapies, especially when compared with patients of other hot tumors such as lung cancer; more targeted agents with a safety profile are called for those patients. Moreover, prior-line EGFR inhibitors may lead to secondary KRAS mutations. There is consequently a substantial unmet clinical need, coupled with vast market potential, for developing innovative KRAS inhibitors.