Abstract CT153: First in human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640

Abstract

Introduction FASN inhibition causes selective disruption of palmitate biosynthesis that, in tumor cells, leads to apoptosis. TVB-2640 is an oral, first-in-class, small molecule reversible inhibitor of FASN that demonstrated in vivo antitumor effects. We previously reported the results of dose escalation and now present evidence of activity in patients (pts) treated in the dose expansion cohorts. Methods This fully enrolled multicenter phase I trial included pts with advanced solid tumors. TVB-2640 was given PO once daily at the MTD (100 mg/m2) as monotherapy (mono) or in combination (combo) with weekly IV paclitaxel (80 mg/m2). Results The most common related AEs observed in both groups (mono, N=44, combo, N=43) included alopecia (41%), palmar-plantar erythrodysesthesia (PPE) (47%), and decreased appetite (13%). Additional common AEs in the mono group included dry skin (19%) and in the combo group included nausea (28%). Gr3 related AEs included decreased appetite (8%) and PPE (9%); all other related AEs were ≤ Gr2. All related AEs were reversible on dose interruption. No enhancement of paclitaxel toxicity was observed with TVB-2640. Pneumonitis in the combo arm was observed uncommonly (9%), but the contribution of TVB-2640 to this effect is uncertain. Pharmacokinetic analyses showed that TVB-2640 had a similar half-life whether given alone or in combo with paclitaxel. Clearance rates were similar on days 1 and 8 (or day 15 for combo). Multiple pharmacodynamic markers demonstrated potent inhibition of FASN and lipogenesis in pts. With respect to clinical activity, overall, 5 confirmed RECIST partial responses (cPR) were seen. Among pts with NSCLC, 18 of 31 were KRASmut, and KRASmut pts achieved longer progression-free survival on TVB-2640 monotherapy, with 60% of KRASmut pts vs. 0% of KRASwt pts on study > 12 wks. Among 18 KRASmut pts, 11 achieved prolonged SD (≥16 wks), including 6 mono pts (SD=19-46 wks) and 5 combo pts (SD=23-54 wks), whereas no KRASwt pts achieved prolonged SD. One NSCLC combo pt achieved cPR at wk 12 and remained on study for 39 wks. Of 14 breast cancer pts, 3 pts achieved cPR and 8 pts achieved prolonged SD (≥16 wks), despite extensive previous treatment, including taxane resistance. One ongoing breast cancer pt with SD, entering her 78th wk of treatment, discontinued paclitaxel at wk 35 and remains on monotherapy . One pt with peritoneal carcinoma (combo) achieved cPR and a 58% decrease in CA125. Reductions in CA125 were seen in 5 out of 12 ovarian cancer pts, who were typically heavily pretreated and taxane-resistant. Summary TVB-2640 demonstrated antitumor activity, including objective responses when combined with weekly paclitaxel, as well as prolonged SD as monotherapy or in combination with paclitaxel. Further studies are planned to evaluate the efficacy of TVB-2640 in NSCLC and breast cancer pts. Citation Format: Gerald Falchook, Manish Patel, Jeffrey Infante, Hendrik-Tobias Arkenau, Emma Dean, Andrew Brenner, Erkut Borazanci, Juanita Lopez, Kathleen Moore, Peter Schmid, Arthur Frankel, Suzanne Jones, William McCulloch, George Kemble, Howard Burris. First in human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT153. doi:10.1158/1538-7445.AM2017-CT153

Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat

“…Its monotherapy and in combination with paclitaxel have entered the clinical trial stage. 113 Lovastatin, simvastatin, and atorvastatin are specific HMGCR inhibitors that have been FDA approved to lower cholesterol. 114,115 Targeting these enzymes may be a therapeutic alternative for MYC-driven cancers.…”

Aberrant lipid metabolism as a therapeutic target in liver cancer

“…To date, TVB-2640 is the only FASN inhibitor to have moved into a phase 1 human clinical trial. This study was initiated to investigate safety and to determine the recommended phase II dose of TVB-2640 as monotherapy and in combination with paclitaxel or docetaxel in patients with advanced or metastatic solid tumor cancers [73]. The trial enrolled 17 patients with non-small cell lung cancer on the monotherapy arm.…”

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…Its antitumor activity was demonstrated in monotherapy and co-treatment with paclitaxel. 117 Some common negative side effects were observed including alopecia, palmar-plantar erythrodysesthesia, and decreased appetite, among others. Now, phase 2 of clinical trials of TVB-2640 (monotherapy and/or co-treatment) is underway, and includes the treatment of lung, colon, breast, and astrocytoma cancer (NCT03808558, NCT02980029, NCT03179904, and NCT03032484).…”