GenFleet Therapeutics Announces Efficacy & Safety Result from Phase II Trial for First-line NSCLC Treatment in KROCUS Study, fulzerasib (KRAS G12C Inhibitor) in Combination with cetuximab, in a Late-breaking Abstract at the Oral Presentation of 2024 ASCO Annual Meeting

SHANGHAI and CHICAGO, June 2, 2024 /PRNewswire/ — GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, today announced the phase II trial data of KROCUS Study, fulzerasib (GFH925, KRAS G12C inhibitor) in combination with cetuximab for first-line non-small cell lung cancer (NSCLC) treatment,at the 2024 American Society of Clinical Oncology (ASCO) annual meeting.

The preliminary result of the trial was accepted as a late-breaking abstract and selected for oral presentation at the clinical science symposium of lung cancer treatment, highlighting the combination therapy’s promising efficacy and its excellent safety/tolerability profile. Notably, this marks the first time that a KRAS G12C inhibitor is combined with an EGFR inhibitor as a first-line NSCLC treatment with its data presented at a global academic event.

The KROCUS Study, led by renowned lung cancer expert Dr. Rafael Rosell, is a European multi-center phase Ib/II study initiated in March 2023. As of April 19 this year, a total of 40 subjects were enrolled and 33 of them received at least one available post-treatment tumor assessment: the objective response rate (ORR) reached 81.8% and the disease control rate (DCR) reached 100%. The post-treatment evaluation revealed that most patients (27/33) exhibited tumor response: one patient achieved complete response; the other two achieved partial response with a shrinkage in their tumor size by 100%.

Additionally, the combination therapy demonstrated a favorable safety/tolerability profile, with both treatment-related adverse events (TRAEs) and TRAEs above grade 3 occurring at a lower rate than those in the fulzerasib monotherapy study in second line and above NSCLC. The data was presented by Dr. Vanesa Gregorc from Italy’s Candiolo Cancer Institute, Italy.

The new drug application for fulzerasib monotherapy in treating advanced KRAS G12C-mutant NSCLC has been accepted and granted priority review designation by China’s National Medical Products Administration (NMPA). Based on the data presented at 2023 ESMO Asia, the registrational phase II study of GFH925 monotherapy for NSCLC showed an ORR of 46.6% and a DCR of 90.5%; the median progression-free survival (mPFS) was 8.3 months. In addition, fulzerasib monotherapy received two breakthrough designations for advanced G12C-mutant NSCLC and metastatic colorectal cancer (CRC) patients.

“I am delighted that the preliminary data of this phase II trial was selected for oral presentation at ASCO, an acknowledgement of this innovative combination therapy’s potential in treating NSCLC patient in a of first-line setting. Currently, there are multiple global trials exploring the combination of KRAS G12C and EGFR inhibitors for later-line CRC. However, GenFleet is propelling the validation of this synergistic mechanism further into first-line treatment for NSCLC, the cancer type with the largest G12C-mutant patient population. We eagerly anticipate the trial’s continued progress, aiming to offer more frontline options for patients worldwide. “said Dr. Rafael Rosell, the principal investigator of KROCUS study.

“The design of the KROCUS Study is based on deep research into synergistic mechanisms, animal models validation, as well as clinical data generated from the fulzerasib monotherapy in the second-line setting. We are excited to see that the preliminary data from our first-line combination study exceeding our expectation. Furthermore, this chemo- and immuno-free combination could potentially mitigate overlapped toxicities and delay drug resistance, leaving space to allow later-line immunotherapy to extend the patients’ overall survival.” stated by Yu Wang, M.D.,Ph.D., Chief Medical Officer of GenFleet.

KROCUS: a Phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC
Presenter: Dr. Vanesa Gregorc
Abstract No. : LBA8511

A total of 40 treatment naïve advanced KRAS G12C positive NSCLC patients were treated with GFH925 in combination with cetuximab (fulzerasib 600mg BID + cetuximab 500 mg/m2 Q2W) as of April 19, 2024. Most patients (95%) were diagnosed with stage IV disease and 13 (32.5%) patients with brain metastases.

Efficacy: As of cutoff date, of the 33 patients who received at least one post-treatment tumor assessment, investigator-assessed ORR was 81.8% (95% CI: 64.5, 93.0) and DCR was 100% (95% CI: 89.4, 100); ORR among patients with brain metastasis was 70%. The median duration of response (DoR) was not reached yet and 88% of patients were still on treatment with a median follow-up of 5.1 months.

Safety: As of cutoff date, the combination therapy was well tolerated. Treatment-related adverse events (TRAEs) occurred in 87.5% of subjects and the majority of the TRAEs were grade 1-2. About 17.5% of subjects reported grade 3 TRAEs. There were no grade 4-5 TRAEs, and no TRAEs led to treatment discontinuation. No new safety signals were identified compared with fulzerasib or cetuximab as single agent.

About KROCUS Study and fulzerasib (GFH925)
The multi-center study of fulzerasib in combination with cetuximab started in scores of clinical research centers worldwide from March 2023 and sets its objectives to evaluate the safety/tolerance, efficacy and the pharmacokinetic characteristics of the combination in advanced NSCLC patients harboring KRAS G12C mutation.

Fulzerasib the first China-developed KRAS G12C inhibitor that has its NDA submission accepted and granted with Priority Review Designation by NMPA. Fulzerasib 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 fulzerasib towards G12C. Subsequently, fulzerasib effectively inhibits the downstream signal pathway to induce tumor cells’apoptosis and cell cycle arrest.

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