SHANGHAI, April 19,
2024 /PRNewswire/ -- 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.
References:
1. Global cancer statistics 2022: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in
185 countries, CA: A Cancer Journal for Clinicians,
Apr. 2024
2. Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New
Arrows in the Quiver, International Journal of Molecular
Science, Mar. 2024
3. Disease Burden of Total and Early-Onset Colorectal Cancer in
China from 1990 to 2019 and
Predictions of Cancer Incidence and Mortality, Clinical
Epidemiology, Feb. 2023
4. Comprehensive pan-cancer genomic landscape of KRAS altered
cancers and real-world outcomes in solid tumors, Precision
Oncology, Dec. 2022
About GFH925 and RAS
The clinical data of two phase I
studies of GFH925 monotherapy for CRC treatment were posted at 2023
ESMO Asia. For 600mg BID patients (n=48), confirmed ORR and DCR
were of 45.8% and 89.6% respectively; median PFS was 7.6 months.
GFH925 the first China-developed
KRAS G12C inhibitor that has its NDA submission accepted and
granted with Priority Review Designation by NMPA. GFH925 also
received Breakthrough Therapy Designations this year for treating
advanced KRAS G12C-mutant NSCLC patients that have received at
least one systemic therapy and CRC patients who have received at
least two systemic therapies.
RAS protein family can be divided into KRAS, HRAS and NRAS
categories. KRAS mutations are detected in nearly 90% of pancreatic
cancer, 30-40% of colon cancer, and 15-20% lung cancer patients.
The occurrence of KRAS G12C mutation subset is more frequently
observed than those with ALK, ROS1, RET and TRK 1/2/3 mutations
combined. GFH925 is a novel, orally active, potent KRAS G12C
inhibitor designed to effectively target the GTP/GDP exchange, an
essential step in pathway activation, by modifying the cysteine
residue of KRAS G12C protein covalently and irreversibly.
Preclinical cysteine selectivity studies demonstrated high
selectivity of GFH925 towards G12C. Subsequently, GFH925
effectively inhibits the downstream signal pathway to induce tumor
cells' apoptosis and cell cycle arrest.
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