Background: IFN-γ, a cytokine that plays diverse roles in innate and adaptive immunity, has been shown to be essential in anti-tumor immune response. In vitro and in vivo studies have shown the synergistic effect of IFN-γ in combination with HER2-targeting monoclonal antibodies with or without taxane chemotherapy. We previously conducted a phase I trial of IFN-γ in combination with paclitaxel, trastuzumab and pertuzumab (IPTP) in metastatic HER2-positive breast cancer (HER2+BC) based on which we initiated a phase II neoadjuvant study with this combination. Methods: Early stage HER2+BC patients were eligible. Treatment included 12 weeks of weekly paclitaxel 80 mg/m2 IV, trastuzumab IV every 3 weeks x 4 (8 mg/kg loading dose, then 6 mg/m2) and pertuzumab IV every 3 weeks x 4 (840 mg loading dose, then 420 mg) in combination with IFN-γ 50 mcg/m2 subcutaneous injection three times weekly starting on day 1. The primary objective was to evaluate the pathologic complete response rate (pCR) in breast and nodes. This study had a planned interim analysis after 23 patients were evaluable for pCR based on a Simon's two stage design with 90% power and a type I error rate of 0.1. The final proportion of hormone receptor (HR) status among accrued patients will be used for comparison to historical control because pCR is expected to be lower for HR+HER2+BC compared to HR-HER2+BC subtype (25% vs 50% respectively). Here we are reporting the planned interim analysis results. Results: Twenty three patients were enrolled between 1/2018 and 7/2019. Most patients had clinical stage II/III (86%) and 43% were clinically and pathologically node positive. Nineteen out of 23 (82%) had HR+ and 3 had invasive lobular carcinoma. The pCR for all patients was 52% (12/23). The pCR for HR+HER2+ and HR-HER2+ BC subgroup was 57% (11/19) and 25% (1/4) respectively. Further evaluation using RCB (residual cancer burden) showed 12 pts RCB-0, 5 RCB-I, 5 RCB-II, and 1 RCB-III. Two SAE included pneumonitis/heart failure and hematochezia. The most frequently observed grade 1 and 2 AEs were fatigue (69%), diarrhea (59%), rash (41%) and nausea (41%). Grade 3 toxicities (4% or higher) included diarrhea (n=3) and no grade 4 AE was noted.

Conclusion: The addition of IFN-γ to neoadjuvant chemotherapy using paclitaxel, trastuzumab and pertuzumab was well tolerated with manageable toxicities. This study evaluated de-escalated treatments only 12 weeks duration and the anthracycline-free regimen which was highly effective with pCR of 52%. The pCR for HR+HER2+BC subtype was 57% which compares favorably to the expected pCR of 25% with neoadjuvant chemotherapy alone in HR+HER2+ patients. This regimen met the criteria to proceed to the second stage of the phase II trial and appears promising especially in HR+HER2+BC. Updated results will be presented at the meeting including correlative studies.

Citation Format: Hyo S. Han, Dawn Goodridge, Avan Armaghani, Ricardo Costa, Aixa Soyano Muller, Loretta Loftus, Hatem Soliman, Brooke Fridley, Laila Khazai, Aiana Cerezo, Jesse Hevia, Marilin Rosa, Hung Khong, Brian Czerniecki. A phase II neoadjuvant trial of Interferon-gamma plus weekly paclitaxel, trastuzumab and pertuzumab in patients with HER-2 positive breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT185.