A phase 2 multi-center pharmacodynamic study of the fatty acid synthase (FASN) inhibitor TVB-2640 in advanced <i>KRAS</i> -mutant non–small cell lung cancer.

3079 Background: Preclinical and translational studies demonstrate that KRAS-mutant NSCLC has a unique metabolic dependence on de novo fatty acid synthesis, mediated by fatty acid synthase (FASN) and downstream lipid metabolism pathways that support saturated fatty acid production, enabling rapid tumor growth, survival, and resistance to lipid peroxidation. TVB-2640 is an orally bioavailable and selective FASN inhibitor that blocks the β-ketoacyl reductase step of fatty acid synthesis and has demonstrated antitumor activity in KRAS mutant NSCLC models. Methods: This single-arm trial (NCT03808558) enrolled patients with previously treated, advanced KRAS mutant NSCLC. Eligible patients had progressed on prior platinum-based chemotherapy (100%) and immune checkpoint inhibition (95%), had measurable disease by RECIST v1.1, ECOG performance status 0–1, and adequate organ function. One patient had received prior KRAS directed therapy. TVB-2640 100 mg/m 2 (equivalent to two to four 50-mg tablets) was administered orally once daily in continuous 28-day cycles. Exploratory correlative analyses included 11 C-acetate PET, plasma lipidomics, sebaceous lipid profiling, and quality-of-life measures. Results: Among 18 enrolled patients, the median age was 69 years, 12 (67%) were male, 14 (78%) were white and 13 (72%) had a history of smoking. Median number of prior lines of therapy was 4. The most common KRAS mutations were G12V (44%), G12C (17%), and G12D (17%). No patients had a radiographic response, 7 (39%) had stable disease, 9 (50%) had disease progression, and 2 (11%) were non-evaluable. Five patients (28%) had radiographic shrinkage of target lesions but did not achieve partial response due to the magnitude of decrease (n = 3) or progression of non-target lesions (n = 2). Median progression-free survival was 1.8 months (95% CI, 1.7-1.8 months). Overall, 84% of patients had adverse events (AE). Most common AEs were xerostomia (50%), dry skin (44%), and fatigue (39%). Most common grade ≥ 3 AEs (44%) were fatigue, dermatological toxicities, xerostomia, ocular toxicities and anemia (11% each). Conclusions: Single-agent FASN inhibition with TVB-2640 in heavily pretreated KRAS mutant NSCLC did not meet the primary endpoint of response. Since FASN is a downstream effector of mutant KRAS, combination regimens with KRAS inhibitors can be considered as a future approach in NSCLC. Ongoing correlative studies may further inform the use of this agent. Despite not meeting its primary endpoint, this clinical trial highlights a novel therapy targeting energy metabolism in lung cancer. Clinical trial information: NCT03808558 .