Preliminary activity in the first in human study of the first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640.

2512 Background: FASN inhibition is a novel approach to cancer treatment involving 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 demonstrates in vivo antitumor effects. We previously reported the results of dose escalation and now present evidence of preliminary activity from the dose expansion. Methods: This ongoing multicenter Phase I trial enrolled patients (pts) with advanced solid tumors with adequate organ function. TVB-2640 was given orally 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 AE’s seen in both groups [mono, N=53; combo, N=47] were: alopecia (57%), palmar-plantar erythrodysesthesia (PPE) (36%), dry eye (13%), and increased lacrimation (11%). Gr 3 AE's include corneal edema (3%) and PPE (10%). Other toxicities were ≤ Gr 2 and only minor GI symptoms occurred. All toxicities were reversible on dose interruption and no enhancement of paclitaxel toxicity was observed when given with TVB-2640. 3 confirmed RECIST partial responses (cPR) all in combo, and multiple cases of prolonged stable disease (SD) (>16 wks) in both arms was seen. 16 NSCLC pts were accrued: 6 were KRAS Mut and, of those, 3 achieved SD with monotherapy for 17, 24 and 38 wks. 2 pts treated in combo had SD for 24 and 21 wks. One combo NSCLC pt (no prior taxane) was a cPR at week 8 and continues on study at wk 22. 3/12 breast cancer pts treated in combo had SD for 20 (TNBC), 24 and 25 wks. One combo breast cancer pt achieved a cPR at wk 12 and continues on study at wk 24. One cPR was seen in a combo treated pt with peritoneal carcinoma, along with a 58% reduction in CA-125 levels. Further reductions in CA-125 ranging from 58-98%, were seen in 5 of 12 ovarian pts. All ovarian pts had received prior taxanes and most, if not all, were taxane resistant upon study entry. Conclusions: TVB-2640 demonstrated prolonged SD when given in monotherapy and cPR when combined with weekly paclitaxel. Responses were seen across multiple tumor types, including KRASmut NSCLC, ovarian and breast cancer. Further exploration in specific tumor types is ongoing. Clinical trial information: NCT02223247.