First-in-human dose-expansion study of NBF-006, a novel investigational siRNA targeting GSTP, in patients with KRAS-mutated non-small cell lung cancer

Glutathione S‑transferase Pi (GSTP) has a role in detoxification and anti‑oxidative damage response. Additionally, GSTP has a chaperone function that regulates key oncogenic pathways such as the KRAS and JNK. Since redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pathways may lead to more effective therapy. NBF-006 is a novel drug product comprised of GSTP siRNA encapsulated within a proprietary lipid nanoparticle. It is designed to deliver siRNA to localized and metastatic lung tumors. As per the results presented at the AACR 2024 conference, around Thirty-eight patients with NSCLC, with or without KRAS mutation underwent treatment at varying doses of NBF-006. The drug was well tolerated with no treatment-related grade 4-5 AEs, SAEs, or DLTs. Two grade 3 events were assessed as possibly related to study treatment, anemia, and bilateral pleural effusions (both at 0.6 mg/kg). 

The most common NBF-006-related AEs were Grade 1 or 2 infusion-related reactions (IRRs) (18 %) and nausea (11 %). IRRs (n=8 in seven patients), occurred in the first cycle and were well-managed. One patient discontinued due to recurring IRR. Cytokine elevation was only noted in this patient. No clinically meaningful complement activation nor ADA response has been observed. Apart from that, two patients (1.2 and 1.6 mg/kg) experienced a durable PR, and 17 patients experienced SD. The disease control rate achieved was 19/38 (59%). Patient enrichment strategies were evaluated with interesting trends observed.

Conclusion

NBF-006 shows long-term tolerability and promising efficacy in heavily treated pan-KRAS mutant NSCLC patients, warranting further clinical exploration alone or in combination with standard therapy.