Abstract CT040: 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
Authors: Bazhenova Lyudmila , Mamdani Hirva , Chiappori Alberto , Spira Alexander , Iams Wade , Tolcher Anthony , Barve Minal , Gabayan Afshin , Vandross Andrae , Cina Cima , Cohen-Arazi Yael , Albaugh Zachary , Huynh Annie , Gullbo Joachim , Zabludoff Sonya 
Published: April 2024

Abstract
Background
Glutathione S-transferase Pi (GSTP) has a role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function which 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 GSTP downregulation leads to inhibition of KRAS signaling through modulation of both MAPK and PI3K pathways, NBF-006 is being developed to treat KRAS mutant tumors. NBF-006-001 is a first-in-human dose escalation and expansion study evaluating safety, tolerability, PK, and preliminary efficacy of NBF-006 administered intravenously. The dose escalation phase enrolled 21 patients with advanced non-small cell lung cancer (NSCLC), pancreatic, or colorectal cancer. No DLTs or treatment-related SAEs were observed. NSCLC disease control rate of 55% (6/11) was observed in heavily pre-treated patient population, warranting further investigations. Final results from the dose escalation and expansion of NBF-006-001 are reported here.
Results
Thirty-eight NSCLC patients, with or without KRAS mutation, received treatment at 0.3 mg/kg [n=1], 0.6 mg/kg [n=12], 1.2 mg/kg [n=14], or 1.6 mg/kg [n=11]. NBF-006 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. Linear PK (t1/2 ~41 hrs) was observed with dose proportional increases up to 1.6 mg/kg without exposure accumulation or reduction after repeat doses. GSTP mRNA knock-down in PBMCs was statistically significant at 1.2 and 1.6 mg/kg dose levels. Patients had received 1-7 prior lines of therapy (1 line [n=10], 2 lines [n=10], and ≥ 3 lines [n=16] respectively). Two patients (1.2 and 1.6 mg/kg) experienced a durable PR, 17 patients experienced SD. The disease control rate is 19/38 (59%). Patient enrichment strategies were evaluated with interesting trends observed.
Conclusion
NBF-006 is well tolerated up to 1.6 mg/kg dose level for over a year with early signs of efficacy in heavily pre-treated pan-KRAS mutant NSCLC patients. The results suggest that further clinical development of NBF-006, alone or in combination with standard therapy, is warranted.
Citation Format: Lyudmila Bazhenova, Hirva Mamdani, Alberto Chiappori, Alexander Spira, Wade Iams, Anthony Tolcher, Minal Barve, Afshin Gabayan, Andrae Vandross, Cima Cina, Yael Cohen-Arazi, Zachary Albaugh, Annie Huynh, Joachim Gullbo, Sonya Zabludoff. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT040.