Preliminary activity in the first in human study of the first-in-class fatty acid synthase (fasn) inhibitor, tvb-2640


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Sreeja Aruketty1,Gerald Falchook2,Manish Patel3,Andrew Brenner4,Jeffrey Infante5,Erkut Borazanci6,Juanita Lopez7,Kathleen Moore8,Peter Schmid9,Arthur Frankel10,Emma Dean11,John Sarantopoulos4,Suzanne Jones5,Mariane Sousa Fontes12,Louise Lim9,Todd M Bauer5,Judy Wang3,William McCulloch13,George Kemble13,Marie O'Farrell13,Katharine Grimmer13,Howard Burris5,Hendrik-Tobias Arkenau14
1Experimental Cancer Medicine Team, The Christie NHS Trust,2Sarah Cannon Research Institute at HealthONE, Denver, CO, USA,3Sarah Cannon Research Institute/Florida Cancer Specialists, FL, USA,4Cancer Therapy & Research Center, San Antonio, TX, USA,5Sarah Cannon Research Institute/Tennessee Oncology, TN, USA,6HonorHealth Research Institute/Translational Genomics Research Institute, AZ, USA,7The Royal Marsden/Institute of Cancer Research, Sutton, UK,8Sarah Cannon Research Institute University of Oklahoma, OK, USA,9Barts Cancer Institute, London, UK,10University of Texas Southwestern Medical Center, Dallas, TX, USA,11Experimental Cancer Medicine Team, The Christie NHS Trust, Manchester, UK,12The Royal Marsden NHS Foundation Trust, Sutton, UK,133-V Biosciences, Menlo Park, CA, USA,14Sarah Cannon Research Institute, London, UK

Abstract

Background

FASN inhibition is a novel investigational treatment approach that selectively disrupts palmitate biosynthesis, leading to apoptosis in cancer cells. TVB-2640 is an oral, first-in-class, reversible inhibitor of FASN which has demonstrated anti-tumour activity in vivo. Here we present evidence of preliminary efficacy in this first-in-human trial.  

Method

In this ongoing multicentre Phase I trial, patients with advanced solid tumours receive oral TVB-2640 (100 mg/m2) once daily as monotherapy, or in combination with weekly IV paclitaxel (80 mg/m2).

Results

The most common AE’s [monotherapy, N=53; combination, N=47] were alopecia (57%), palmar-plantar erythrodysesthesia (PPE) (36%) and dry eye (13%). Gr 3 toxicities included PPE (10%) and corneal oedema (3%); other toxicities were ≤ Gr 2. Toxicities were reversible on dose interruption and TVB-2640 did not enhance paclitaxel toxicity. Five confirmed RECIST partial responses (cPR) and multiple cases of prolonged stable disease (SD) (≥16 weeks) were reported in the combination and monotherapy arms respectively.

Of 21 NSCLC patients, 10 were KRASmut and 8 of these achieved prolonged SD; 3 patients receiving monotherapy (17, 24 and 42 weeks) and 5 patients in the combination arm (23, 30, 83, 95 and 97 weeks). One NSCLC patient (combination) had a cPR at week 12 (remains on study [week 36]).

3/12 breast cancer patients (combination) achieved a cPR; (16 weeks, 2 patients remain on study [week 16 and 24]) and 5 achieved SD (16, 24 weeks, 3 patients remain on study [week 16, 24 and 32]). A patient with peritoneal carcinoma (combination) experienced cPR with a 58% reduction in CA125 levels. Further reductions in CA125 were seen in 5/12 ovarian patients (pre-treated with taxanes and mostly taxane resistant).

Conclusion

TVB-2640 demonstrated prolonged SD in monotherapy and cPR in combination with weekly paclitaxel.  Responses were seen in a range of tumour types including KRASmut NSCLC, ovarian and breast cancer.