Résumé
Treatment with Tucatinib in addition to Pertuzumab and Trastuzumab in patients with HER2-positive metastatic breast cancer (HER2+ MBC) after local therapy of isolated brain progression: InTTercePT, a UCBG/GINECO study. Background HER2+ MBC patient on first line treatment with pertuzumab and trastuzumab have a 13% risk of developing brain metastasis (BM) as the first site of progression. For such patient with isolated brain progression, guidelines recommend to use central nervous system (CNS) directed therapy whenever possible (stereotactic radiosurgery or surgery or both). These patients will have a higher risk of subsequent brain and systemic progression after local treatment. Therefore, whether systemic treatment should be continued or changed remains an open question. The tyrosine kinase inhibitor tucatinib is an orally bioavailable HER2 inhibitor with validated antineoplastic activity and the ability to cross the blood brain barrier. The randomized HER2CLIMB study, demonstrated that adding tucatinib to trastuzumab/capecitabine improved both progression-free survival (PFS) and overall survival (OS) among HER2+ MBC patients previously treated with trastuzumab, pertuzumab and T-DM1. Particularly, this regimen demonstrated improved antitumor activity in patients with BM, in terms of CNS-PFS and OS. Exploratory analysis of HER2CLIMB and in a phase 1b study, showed patients who continued systemic treatment with tucatinib (in combination either with trastuzumab/capecitabine or TDM-1) after CNS-directed treatment had a better outcome compared with those that discontinued systemic tucatinib-based treatment. These results suggest that for patient in the first line metastatic setting who experience isolated brain progression, adding tucatinib to the trastuzumab/pertuzumab regimen could help control BM, improve PFS, OS and patients’ quality of life. Trial design InTTercePT is an open-label, single-arm, national, multicentric, phase II trial assessing the combination of tucatinib, pertuzumab and trastuzumab. Tucatinib will be administered orally twice daily at 300 mg. Pertuzumab and trastuzumab will be administered at the initial dose of 840 mg and 8 mg/kg respectively following by a maintenance dose of 420 mg and 6mg/kg respectively, 3-weekly. If indicated, hormone therapy is allowed in combination with HER2-directed therapy. Eligibility criteria include HER2+ MBC with isolated brain progression (new or progressive BM with stable or responding systemic disease) under pertuzumab/trastuzumab treatment (± taxane) after complete local treatment (surgery and/or radiation therapy). There is no limit to the number and size of BM. Specific aims To evaluate the efficacy, in terms of PFS rate (RECIST v1.1) of tucatinib in combination with pertuzumab/trastuzumab. Secondary endpoints include OS, brain PFS (RECIST v1.1) and BM response in patient not in complete remission at the brain level after local treatment and safety (NCI-CTCAE v5.0). Statistical methods Given the lack of safety data from this association, two interim safety analysis are planned: after 10 and 20 patients having received at least one dose of the treatments combination during at least one cycle. The number of patients to be included was calculated using Fleming’s single-stage procedure for phase II trials. The sample size calculation was based on a minimum success (non-progression rate at 6 months) considered of interest of p1 = 75% and an uninteresting rate of p0 = 60%. Assuming a unilateral type I error alpha of 10% and a power of 85%, 52 patients are needed. Considering 5% of the patients may be non-evaluable, 55 patients will be included. At the time of analysis, if at least 37 successes are observed, the treatment will be considered as interesting for further investigation. The study is recruiting. By July 1, 2022, 10 patients have been screened and 8 treated (NCT05041842). Funding SeaGen Contact information thomas.bachelot@lyon.unicancer.fr
Citation Format: Thomas Bachelot, Christelle Jouannaud, Benjamin Verret, Sylvie Chabaud, Camille Petrau, Laetitia Stefani, Mony Ung, Isabelle Desmoulins, William Jacot, Caroline Bailleux, Sandrine Marques, Jérôme Lemonnier, Anne-Claire Hardy-Bessard. Treatment with Tucatinib in addition to Pertuzumab and Trastuzumab in patients with HER2-positive metastatic breast cancer (HER2+ MBC) after local therapy of isolated brain progression: InTTercePT, a UCBG/GINECO study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-10-01.