Fulzerasib emerges as a game-changer for KRAS G12C-mutated NSCLC with promising preliminary efficacy and an excellent safety profile in Phase II KROCUS Study!
Sotorasib and adagrasib have both been approved for use in pretreated KRAS G12C-mutated NSCLC patients, demonstrating ORR of 37.1% and 42.9%, and mPFS of 6.8 and 6.5 months, respectively. However, a new contender in this space, fulzerasib (also known as GFH925 or IBI351), has shown even more compelling efficacy in previously treated advanced KRAS G12C-mutated NSCLC patients in China.
In the first-line setting for advanced KRAS G12C-mutated NSCLC patients, fulzerasib combined with cetuximab showed promising efficacy and a very favorable safety profile. Investigator-assessed data revealed an ORR of 81.8% and a DCR of 100%. In addition, 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. As of the cutoff date, the combination therapy was well tolerated. The most treatment-related adverse events (TRAEs) being mild or moderate and no new safety signals observed.
These encouraging results have led to the planning of a Phase III trial to confirm the efficacy and safety of this combination therapy in a larger first-line population.
KOL insights
“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. 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.” – Expert Opinion.
“These results, especially in CNS cases, mark a major step forward with a controlled safety profile.” – Expert Opinion.
Conclusion
NSCLC accounts for approximately 85% of all newly diagnosed lung cancers. Data shows that western nations have a higher incidence of KRAS mutations than Asian nations. The KRAS mutation rate in NSCLC varies from 20–40% in the USA, EU4, and the UK. In Japan, it is less than 20%. A number of Chinese biotechs are active in the KRAS Space. Companies like GenFleet Therapeutics (fulzerasib), InventisBio (garsorasib), JacoBio (glecirasib), and others are currently investigating KRAS inhibitors in NSCLC. In China, there are currently no commercially available KRAS-targeted therapies.
The new drug application (NDA) 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). With its NDA for priority review by China's NMPA, along with breakthrough therapy designations, underscores the potential of fulzerasib. Additionally, fulzerasib monotherapy has received two breakthrough therapy designations for advanced G12C-mutant NSCLC and metastatic colorectal cancer (mCRC) patients. Combining fulzerasib with cetuximab has shown enhanced anti-tumor activity, particularly in first-line treatment, with promising results that warrant further validation in a Phase III trial. This positions fulzerasib as a promising new option for patients with KRAS G12C-mutated cancers.
