Early Clinical Activity Observed With TAC01-HER2 in HER2-Positive Solid Tumors

The ongoing phase 1/2 TACTIC‑2 trial (NCT04727151) revealed TAC01-HER2 to be well tolerated and show early signals of clinical activity in patients with HER2-positive solid tumors, according to Triumvira Immunologics.¹

TAC01-HER2 showed encouraging safety data in both dosing cohorts with no dose limiting toxicities, cytokine release syndrome, or immune effector cell-associated neurotoxicity observed. All serious adverse events were confirmed to be unrelated to TAC01-HER2.

Additionally, early signals of clinical activity were observed in the higher of the 2 dosing cohorts with a 75% disease control rate, including 1 partial response.

“Gastric adenocarcinoma remains a deadly disease with poor outcomes. The safety profile of TAC01-HER2 has been well differentiated compared to other approved CAR T-cell therapies. Additionally, the partial response in the study in a patient with metastatic gastric cancer is promising and underscores the potential of this novel cell therapy to treat patients who need it most,” concluded Benjamin L. Schlechter, MD, Dana-Farber Cancer Institute and an investigator on the TACTIC-2 study, in the press release.

The open-label, multicenter, phase 1/2 TACTIC-2 trial aims to determine the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of TAC01-HER2 in patients with HER2-positive solid tumors, including breast cancer, lung cancer, colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, and more which have progressed on prior anticancer therapies.^2,3

Enrollment was open to patients aged 18 years and older with a recent tumor sample to confirm HER2-protein expression on tumor cell surface, relapsed or refractory disease after at least 2 prior lines of therapy, measurable disease per RECIST v1.1 criteria, a life expectancy of at least 12 weeks, adequate organ function, and an ECOG performance status of 0 or 1.

After the collection of T cells and before the administration of TAC01-HER2, patients underwent lymphodepletion, consisting of 3 consecutive days of intravenous (IV) fludarabine at 30 mg/m² and IV cyclophosphamide at 300 mg/m2 with or without mesna IV. Four patients were treated with dose level 1 of 1.3 x 10⁵ cells/kg, 4 patients had received dose level 2 of 6.8 x 10⁵ cells/kg. There are also patients enrolled to receive the third dose level of 1.3 x 10⁶ cells/kg of TAC01-HER2, and the trial is enrolling patients to receive dose level 4 of 6.8 x 10⁶ cells/kg.

Primary end points of the trial included dose-limiting toxicities and establishing the MTD with the secondary end points of overall response rate, duration of response, overall survival, establishing the recommended phase 2 dose, and safety.

In cohorts 1 and 2 of the trial, the median age of patients was 65.5 years (range, 42-70), 62.5% of patients were male, and 87.5% were White. Half of the enrolled patients had an ECOG performance status of 0 while the other half had a status of 1. A HER2 expression of 3+ was found in 87.5% of patients while the other 12.5% had a HER2 expression of 2+/ISH+.

In regard to tumor type, 2 patients had gastric cancer, 2 patients had CRC, and 1 patient each had gastroesophageal junction cancer, gallbladder cancer, esophageal cancer, and rectosigmoid cancer.Patients had a median of 4.5 prior lines of therapy (range, 2-12), and the median number of prior lines of HER2-targeted therapy was 2 (range, 0-9). Moreover, previous HER2 therapies given to patients included trastuzumab (Herceptin; n = 5), fam-trastuzumab deruxtecan-nxki (Enhertu; n = 3), and investigative agents (n = 5).

Findings revealed that there were early signals of clinical activity observed in the second dosing cohort with a disease control rate of 75%. A patient with stage IVb metastatic gastric cancer who was heavily pre-treated and defined as 3+ HER2 by immunohistochemistry had achieved a partial response.

CT scans which were taken 29-days after dosing revealed a 36.5% reduction in tumor size in target lesions vs baseline. Further, the size of numerous metabolically active lymph nodes which were associated with the mass decreased and 2 patients in the second cohort had a significant disease burden which has been observed with stable disease with no change in tumor measurements compared to baseline.

Regarding safety, there were no dose-limiting toxicities reported in cohorts 1 and 2 and no patients experienced any grade cytokine release syndrome or immune effector cell–associated neurotoxicity.

The most common adverse effect (AE) was any grade anemia and occurred in all 8 patients. Additional any-grade AEs were decreased white blood cell count (n = 6), decreased neutrophil count (n = 6), increased alanine transaminase (n = 3), decreased platelet count (n = 2), and decreased lymphocyte count (n = 2). All serious AEs were confirmed to have been attributed to causes unrelated to TAC01-HER2 infusions.

The enrollment of the phase 1 portion of the study is expected to be completed by the end of 2022. Once the optimal dose is identified, the phase 2 registration component of the trial will be initiated in the start of 2023. The first patient in the phase 1 dose level 3 of 1-3 x 10⁶ cells/kg has already been treated.

“These initial data encourage us as HER2 is a well-validated target with growing clinical significance. There remains a large treatable patient population beyond breast and gastric cancers with tremendous unmet need across the spectrum of HER2 expression, especially low and intermediate, and we believe TAC-T-cell therapies can be an effective way of treating these patients,” said Deyaa Adib, MD, chief medical officer of Triumvira Immunologics, in the press release.

References:

1. Triumvira immunologics presents initial HER2-positive solid tumor clinical data at ESMO. News release. Triumvira Immunologics. September 12, 2022. Accessed October 20, 2022. https://bwnews.pr/3gs75tW

2. Schlechter BL, Olson D, Saibil S, et al. A phase I/II trial investigating safety and efficacy of autologous T cell antigen-coupler (TAC) T cells targeting HER2 in relapsed or refractory solid tumors (TACTIC-2). Poster presented at: European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France.

3. TAC T-cells for the treatment of HER2-positive solid tumors (TACTIC-2). ClinicalTrials.gov. Updated April 29, 2022. Accessed October 20, 2022. https://clinicaltrials.gov/ct2/show/NCT04727151