First Human Study Taking Place With Fatty Acid Synthase Inhibitor
First Human Study Taking Place With Fatty Acid Synthase Inhibitor
As part of the our coverage of the American Association for Cancer Research annual meeting, being held April 1st to April 5th in Washington, DC, we are speaking with Gerald Falchook, MD, who is the director of drug development at the Sarah Cannon Research Institute at HealthONE in Denver, Colorado. Dr. Falchook presented (abstract CT153) data on the first human study of a first-in-class molecule, a fatty acid synthase or FASN inhibitor that is called TVB-2640.
—Interviewed by Anna Azvolinsky, PhD
OncoTherapy Network: First, can you describe the drug and what fatty acid synthase is and how it may be important in cancer?
Dr. Falchook: Thank you, I’d be happy to. TVB-2640 is fatty acid synthase inhibitor, the first drug in this class to enter a clinical trial for patients. Fatty acid synthase also known as FASN has an important role in cancer biology. FASN is the only enzyme known to catalyze synthesis of palmitate, and cancer cells become dependent on palmitate for several processes. Palmitate is converted into complex lipids, which contribute to membrane structures. Lipid rafts form abundantly in the membranes of cancer cells, which are used to assemble signaling complexes. Also, FASN facilitates the palmitoylation of several critical proteins including Wnt, tubulin, and Ras. Inhibition of FASN with a drug like TVB-2640 prevents palmitoylation and lack of this modification alters subcellular protein localization and function.
In addition, inhibition of FASN can shut down signaling pathways such as PI3 kinase and protein kinase C. FASN is known to be widely expressed in multiple tumor types and cancer cell metabolism is much more dependent on FASN than normal cells are. The preclinical xenograft studies with TVB-2640 demonstrated that the drug was able to inhibit tumor growth and achieve progression. Because of the promising preclinical findings, a phase I trial 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. TVB-2640 is given as an oral capsule, taken once a day. This trial was designed with standard eligibility criteria for patients with advanced or metastatic solid tumor cancers.
OncoTherapy Network: Could you talk a bit about whether there is any evidence that this drug may be particularly useful as a therapy in certain tumor types?
Dr. Falchook: Yes. At the recommended phase II dose, expansion cohorts were enrolled into select tumor types with a special interest in patients with non-small cell lung cancer, breast cancer, and ovarian cancer. Previously published data showed that FASN tumor expression may be a marker for prognosis as patients with FASN overexpression in these tumor types had worse overall survival or relapse-free survival. Among these three tumor types, I will start by discussing the results of the patients with non-small cell lung cancer.
The trial enrolled 17 patients with non-small cell lung cancer on the monotherapy arm. Although no objective responses were observed, an interesting trend of longer median time to progression was observed among patients with KRAS-mutant non-small cell lung cancer compared to wild-type, of 19 weeks compared to 5 weeks which would be consistent with what we know to be the effect of FASN inhibition on Ras pathway signaling.
Next, a total of 14 patients with non-small cell lung cancer were treated in the combination arm with paclitaxel. We observed one patient with a confirmed partial response and five patients with stable disease lasting longer than 6 months. Again, we observed a very interesting trend that longer median time to progression in KRAS-mutant patients compared to wild-type, of 28 weeks versus 14 weeks.
Next, I will talk about the patients with breast cancer. A total of 15 patients with breast cancer were treated on the combination with paclitaxel. All of these patients had received prior taxanes and 13 of 15 patients had taxane resistance. These patients were heavily pretreated with an average of 7 prior systemic regimens. Despite prior taxane therapy and many prior treatments, we observed three confirmed partial responses and three patients with stable disease lasting longer than 6 months. Among the patients with HER2-positive breast cancer, responses were achieved in two of the three patients treated and this is a subset of breast cancer that is known to have the highest expression of FASN.
Lastly, I’ll talk about the patients with ovarian cancer. A total of 17 patients with ovarian cancer were treated on a taxane combination. Similar to the breast cancer patients, all of these patients had received prior taxane therapy. We observed two confirmed partial responses and two patients with stable disease lasting longer than 6 months.
OncoTherapy Network: Okay. Can you talk about some more of the details of the overall efficacy and safety results and also the number of patients on this trial in total?
Dr. Falchook: I’d be happy to. A total of 136 patients were treated on the trial with TVB-2640 including 76 patients with monotherapy and 60 patients in combination with either paclitaxel or docetaxel. This is a heavily pretreated population with most patients having received at least 3 prior regimens. The dose-limiting side effects observed included palmar-plantar erythrodysesthesia also known as hand-foot syndrome, as well as eye toxicity including iritis, corneal edema, and keratitis. These dose-limiting toxicities were considered on-target effects of inhibiting lipogenesis. Fortunately, these side effects were reversible. The recommended phase II dose of TVB-2640 was determined to be 100 mg/m2. Once patients were treated at the phase II dose, skin and eye toxicities were grade 2 or less and have been manageable in most patients with supportive measures.
Pharmacodynamic correlates were also investigated during this trial. Serum measurement of malonyl carnitine, demonstrated a 3.8-fold increase and serum tripalmitin showed a 13% decrease, which is consistent with target engagement and inhibition of FASN. In addition, sebum-specific fatty acids were collected from the skin and measured showing a greater than 90% reduction by day 15, consistent with inhibition of lipogenesis.
OncoTherapy Network: So, following these results, what are the next questions and next steps in the development of this drug?
Dr. Falchook: Well, because of these promising early results, a phase II trial of TVB-2640 in combination with trastuzumab and paclitaxel will open later this year for patients with HER2-positive breast cancer that has progressed from prior trastuzumab and taxane treatment. I suspect that you will be hearing more about TVB-2640 in the future.
OncoTherapy Network: Thank you so much for joining us today, Dr. Falchook.
Dr. Falchook: Thank you.