Abstract P6-11-09: Heavily pre-treated breast cancer patients show promising responses in the first in human study of the first-In-class fatty acid synthase (FASN) inhibitor, TVB-2640 in combination with paclitaxel

Abstract

Introduction 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 in breast cancer patients treated in the dose expansion cohort. Methods This ongoing international, multicenter Phase I trial enrolls patients (pts) with advanced solid tumors with adequate organ function. TVB-2640 is 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 observed [mono, N=53; combo, N=47] were: alopecia (57%), palmar-plantar erythrodysesthesia (PPE) (36%), dry eye (13%) and increased lacrimation (11%). Gr. 3 toxicities 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 common paclitaxel toxicity was observed when given with TVB-2640. Rare cases of pneumonitis in combination have been observed but the contribution of TVB-2640 to this effect is uncertain. 14 breast cancer patients were enrolled and treated in combination with weekly paclitaxel while 3 breast patients were given monotherapy (during the dose escalation phase). Among patients treated in combination, three (3) confirmed RECIST partial responses (cPR) were seen and multiple cases of prolonged stable disease (SD) (≥16 wks) despite heavy pre-treatment and taxane resistance in all but 2 cases. One ER+, PR+, Her2+ patient achieved a cPR and was on study for 26 weeks. One ER-/PR-/Her2+ patient whose previous best response to paclitaxel treatment was SD for 24 weeks, reached a cPR at week 12, discontinued paclitaxel at week 21 and remains on monotherapy TVB-2640 with a sustained cPR at week 29. The third responder with cPR is an ER+, PR+, HER2- patient whose previous taxane treatment lasted 15 weeks (response unknown) and she remains on study at week 24. Of the remaining 11 patients, 10 achieved SD > 12 weeks and 8 of the 10 maintained that response for 16-45 weeks. The ongoing SD patient at week 45, discontinued paclitaxel at week 35 and remains on monotherapy TVB-2640. Summary TVB-2640 demonstrated multiple cPRs and prolonged SD when combined with weekly paclitaxel in 93% of patients treated. Further exploration of response in patients recently progressed on a taxane (progression within the prior 6 months) and safety with TVB-2640 in combination with docetaxel is being explored. Citation Format: Brenner AJ, Falchook G, Patel M, Infante JR, Arkenau H-T, Dean EM, Borazanci E, Lopez JS, Moore K, Schmid P, Frankel AE, Jones S, McCulloch W, Kemble G, Grimmer K, Burris H. Heavily pre-treated breast cancer patients show promising responses in the first in human study of the first-In-class fatty acid synthase (FASN) inhibitor, TVB-2640 in combination with paclitaxel [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-09.

Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer

“…A modified, orally available version of TVB-3166, TVB-2640, is currently in phase-I clinical trials in patients with advanced solid malignancies (NCT02223247). Combined with paclitaxel, TVB-2640 proved beneficial in heavily pretreated breast cancer patients (38, 39). New trials are now investigating TVB-2640 in different stages of astrocytomas, breast, and colon cancers (NCT03032484, NCT03179904, and NCT02980029).…”

Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism

“…We screened a FASN mutant query cell line multiple times and identified highly confident negative GIs, many of which were involved in lipid metabolism. Perturbation of de novo fatty acid synthesis has been suggested as a prominent cancer therapeutic approach and multiple compounds targeting FASN are currently being tested in clinical trials; for example, TVB-2640 is a FASN inhibitor that is being tested in solid tumors in phase 2 trials, while both Fatostatin and Betulin are inhibitors of the SREBP-SCAP interaction in pre-clinical development 6 , 49 . Since single agent therapies often lead to emergence of resistance and tumor relapse, it makes sense to pursue therapeutic targets that are synergistic with FASN inhibition.…”

Targeting Metabolism for Cancer Therapy

“…Targeting FASN has been found to reduce palmitoylation of tubulin and disrupt microtubule organization, inhibiting tumor cell growth (Heuer et al, 2017). The compound TVB-2640 is the first compound targeting FASN to enter clinical trials (Table 1), and when combined with paclitaxel, can cause partial responses or prolonged stable disease (Brenner et al, 2017). …”