Phase 2 Study of Denifanstat Looks to Add First-in-Class Agent to HER2+Breast Cancer Treatment Armamentarium

Karthik V. Giridhar, MD

As trastuzumab (Herceptin)-based regimens have solidified their place in the HER2- positive breast cancer treatment paradigm, an unmet need for additional therapeutic options has emerged among patients who have developed resistance to these agents. With the development of the first-in-class fatty acid synthase (FASN) inhibitor denifanstat (TVB- 2640), which is being evaluated in a phase 2 trial (NCT03179904), investigators are hoping that the agent can be a key component in restoring sensitivity to standard treatments for patients with HER2- positive metastatic breast cancer, in addition to its antitumor properties.

“[In] HER2-positive breast cancers, it’s generally anticipated that patients are going to develop resistance to trastuzumab-based therapy,” Karthik V. Giridhar, MD, chair of the Breast Tumor Group in the Division of Medical Oncology, Department of Oncology, and a medical oncologist at Mayo Clinic in Rochester, Minnesota, said in an interview with OncologyLive. “We are trying to better understand each mechanism of resistance. We know a portion of these resistance mechanisms may be through this cancer metabolic activity that FASN inhibitors may help address. Restoring sensitivity to trastuzumab and other HER2-targeted therapies is still a key need in the clinic.”

The FASN protein is overexpressed in a variety of hematologic and solid malignancies, including non–small cell lung cancer lung cancer (NSCLC); breast, ovarian, prostate, pancreatic, and colon cancers; and lymphoma. The increase of FASN expression has been correlated with tumor stage and is associated with decreased survival. Preclinical findings have demonstrated that inhibition of FASN can restore sensitivity to chemotherapeutics. FASN inhibition may remodel the plasma membrane, leading to restored sensitivity to standard therapies.¹

Denifanstat is the first highly selective FASN inhibitor to enter clinical study. The agent is a small molecule FASN inhibitor; preclinical studies have shown that FASN inhibition with short-interfering RNAs and other small molecules has led to tumor cell apoptosis, increased sensitivity of chemotherapy- resistant tumor cells to agent activity, and inhibition of tumor growth in mouse xenograft models.¹

“FASN is highly expressed in HER2-positive breast cancers. In HER2-positive breast cancer and breast cancer in general, higher expression is associated with poor progression-free survival. [Denifanstat] is a first-in-class drug that disrupts cancer metabolism, and it helps address HER2- resistance to trastuzumab and resensitize [cancer cells] to trastuzumab,” Giridhar explained.

Early-Phase Efficacy Seen in Advanced Solid Tumors

In March 2021, investigators published findings from the first-in-human, phase 1 study (NCT02223247) of denifanstat in patients with advanced solid tumors. The trial enrolled adult patients with previously treated advanced metastatic solid tumors who received up to 4 prior cytotoxic chemotherapy regimens for metastatic disease, prior endocrine and/ or nonmyelosuppressive therapy; had an ECOG performance status of 1 or 0; and had adequate renal, hepatic, and bone marrow function.¹

Patients received denifanstat monotherapy (n = 78), denifanstat plus paclitaxel (n = 58), or denifanstat plus docetaxel (n = 6). In all cohorts, the initial dose of denifanstat was 60 mg/m² orally once daily with the dose being escalated in 100% increments until a toxicity of grade 2 or higher severity was reported. Then investigators employed a classic 3 + 3 design until the maximum tolerated dose (MTD) was reached; the 3 + 3 design was also used to determine the MTD in the combination cohorts. Paclitaxel and docetaxel were given intravenously according to the dosing schedule indicated in the prescribing information.¹

The coprimary end points were the determination of the MTD of denifanstat and the incidence of dose-limiting toxicities (DLTs). Secondary end points included tumor response per RECIST 1.1, pharmacokinetics, and safety.²

At baseline, most patients had stage IV disease (90%), were women (57%), were White (95%), and had known metastatic disease (97%). The mean number of prior treatment regimens in the monotherapy, paclitaxel, and docetaxel arms was 4, 4.6, and 5.5, respectively. The median time since diagnosis was 32 months (range, 8-119), 21 months (range, 6-262), and 71 months (range, 30-131), respectively.¹

Findings from the study demonstrated that 6 DLTs occurred in the denifanstat monotherapy arm (n = 76), including grade 3 corneal edema (n = 1), keratitis (n = 1), iritis (n = 1), and palmar-plantar erythrodysesthesia syndrome (n = 3). The MTD and recommended phase 2 dose (RP2D) of denifanstat monotherapy was determined to be 100 mg/m², which is generally equivalent to a flat dose of 150 mg to 200 mg, depending on the patient’s body surface area.¹

In the paclitaxel arm (n = 55), there were 2 DLTs reported at the 200-mg flat dose; the MTD and RP2D both were determined to be 100 mg/m². All 5 patients who received denifanstat plus docetaxel developed hematologic toxicity of grade 3 or greater severity, and as a result the combination was not further explored in the study.¹

No partial responses (PRs) or complete responses were observed among 69 efficacy-evaluable patients in the monotherapy arm, but 42% experienced stable disease. In the denifanstat plus paclitaxel arm (n = 53), the confirmed PR rate was 11% and the disease control rate (DCR) was 70%; notable disease control was observed in patients with breast cancer (100%), NSCLC (82%), and gynecologic cancers (ovarian and cervical; 53%). In a subgroup of patients with breast cancer in the paclitaxel arm (n = 15), all of whom had received prior taxanes, the confirmed PR rate was 20% and the median time to progression was 24 weeks.¹

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in the denifanstat monotherapy and paclitaxel combination arm at a rate of 98.7% and 100%, respectively. Most patients in both arms also experienced a grade 3 or higher TEAE (57.9% vs 70.9%).¹

The most common any-grade TEAEs in the monotherapy arm included skin and subcutaneous tissue disorders (82.9%), gastrointestinal disorders (68.4%), general disorders and administration site conditions (63.2%), and eye disorders (50%). Common grade 3 or greater TEAEs included general disorders and administration site conditions (17.1%), skin and subcutaneous tissue disorders (10.5%), and infections and infestations (6.6%).¹

In the paclitaxel arm, the most common any-grade TEAEs were skin and subcutaneous tissue disorders (85.5%), gastrointestinal disorders (81.8%), general disorders and administration site conditions (72.7%). Grade 3 or higher TEAEs included gastrointestinal disorders (21.8%), blood and lymphatic system disorders (16.4%), and skin and subcutaneous tissue disorders (18.2%).¹

Investigators concluded that denifanstat displayed potent FASN inhibition with clinical activity and an emergent favorable safety profile. Further investigation of denifanstat at the RP2D of 100 mg/m² in patients with KRASmutated NSCLC, breast cancer, and ovarian cancer in larger clinical studies is warranted, they wrote.¹

In light of the positive phase 1 findings, denifanstat is being evaluated in multiple solid tumor types outside of metastatic breast cancer. Specifically, the agent is being examined as monotherapy for the treatment of patients with KRAS-mutated NSCLC in a singlearm phase 2 study (NCT03808558) and a phase 1 window trial (NCT02980029) in patients with resectable colon cancer and other solid tumors.^3,4

Phase 2 Trial Design

The phase 2 trial of denifanstat in HER2-positive metastatic breast cancer will enroll adult patients with measurable disease per RECIST 1.1 criteria who have received up to 6 prior chemotherapy regimens in the metastatic setting and an ECOG performance status of 1 or 0 into cohort A or B. In cohort A, patients must have either distant disease progression during combination therapy with taxane-based chemotherapy and anti-HER2 therapy for the treatment of metastatic disease, during or within 180 days after discontinuation of taxane-based chemotherapy and anti-HER2 therapy in the adjuvant setting, or distant disease progression during or within 180 days after discontinuation of anti- HER2 therapy in the adjuvant setting following surgical resection. In cohort B, patients must have distant disease progression following endocrine therapy and anti-HER2 therapy for the treatment of metastatic disease or in the adjuvant setting. (Figure).⁵

Patients in cohort A will receive oral denifanstat daily on days 1 to 28; intravenous paclitaxel on days 1, 8, and 15; and intravenous trastuzumab on days 1, 8, 15, and 22. In cohort B, patients will be treated with the same regimen as cohort A and continue endocrine therapy with oral anastrozole daily, oral exemestane daily, intramuscular fulvestrant on days 1 and 14 of cycle 1 and day 1 of subsequent cycles, or oral daily letrozole. Optional trastuzumab will be allowed in both arms every 21 days after 3 cycles and discontinuation of paclitaxel. Cycles will last 28 days and repeat until disease progression or unexpected toxicity.⁵

The primary end point is objective response rate. Secondary end points are duration of response, clinical benefit rate, and progression- free survival. Changes in biomarker expression represent an exploratory end point.⁵

“The primary goal is seeing if adding [denifanstat] for patients who have already received and progressed on trastuzumab can restore sensitivity to trastuzumab, in combination either with paclitaxel or endocrine therapy,” Giridhar said.

The trial is active and is recruiting patients. The estimated enrollment is approximately 80 patients, and the estimated primary completion date is July 2024.⁵

References

1. Falchook G, Infante J, Arkenau HT, et al. First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors. EClinicalMedicine. 2021;34:100797. doi:10.1016/j.eclinm.2021.100797
2. A phase 1, first-in-human study of escalating doses of oral TVB-2640 in patients with solid tumors. ClinicalTrials.gov. Updated August 14, 2017. Accessed December 13, 2023. https://clinicaltrials.gov/study/NCT02223247
3. Phase 2 study of TVB-2640 in KRAS non-small cell lung carcinomas. ClinicalTrials.gov. Updated August 28, 2023. Accessed December 13, 2023. https://clinicaltrials.gov/study/NCT03808558
4. TVB 2640 for resectable colon cancer other resectable cancers; a window trial. ClinicalTrials.gov. Updated January 20, 2023. Accessed December 13, 2023. https://clinicaltrials.gov/study/NCT02980029
5. FASN inhibitor TVB-2640 and trastuzumab in combination with paclitaxel or endocrine therapy for the treatment of HER2 positive metastatic breast cancer. ClinicalTrials.gov. Updated December 15, 2023. Accessed December 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03179904