Abstract OT-28-02: Phase II Randomized Trial of Neoadjuvant Trastuzumab and Pertuzumab with Either Palbociclib Plus Letrozole or Paclitaxel for Postmenopausal Women with Estrogen Receptor-Positive / HER2-positive Breast Cancer - the TOUCH Trial

Abstract Background: HER2 blockade in combination with chemotherapy (CT) remains the treatment of choice for patients with HER2+ early breast cancer (BC), irrespective of estrogen receptor (ER) status. Patients with ER+/HER2+ early BC may benefit from HER2 blockade in combination with endocrine therapy (ET) and potentially also new targeted agents. Recent data have elucidated cyclin-dependent kinases 4 and 6 (CDK4/6) as key therapeutic targets acting downstream of both ER and HER2 pathways suggesting CDK4/6 inhibitors like palbociclib may be ideal partners for ET in this context. Pre-clinical and clinical data suggest that a gene signature of functional loss of retinoblastoma (RBsig) might predict sensitivity to CT versus CDK4/6 inhibition in ER+/HER2+ early BC. The TOUCH hypothesis is that neoadjuvant therapy with palbociclib + ET + dual HER2 blockade with trastuzumab and pertuzumab may be more active in postmenopausal patients with ER+/HER2+ RBsig LOW early BC while those with RBsig HIGH may require CT. This will be formally tested in the primary objective, exploring the interaction between the RBsig status (HIG or LOW) and treatment activity, assessed by pathological complete response (pCR), of palbociclib+letrozole versus paclitaxel when given with trastuzumab+pertuzumab for ER+/HER2+ primary breast cancer. The study was initially targeting older patients due to the particular appealing of CT de-escalation in this population. Due to the increasing interest for CT de-escalation and the mounting evidence of the potential benefit of such ET combination optimization, TOUCH has been recently amended to extend accrual to postmenopausal women. Trial design: TOUCH is an open-label, multicenter, randomized phase II neoadjuvant trial in postmenopausal patients with ER+/HER2+ primary BC. Eligible patients will be randomized (1:1) to dual HER2 blockade (5 doses trastuzumab + pertuzumab) plus either palbociclib (125 mg/d po; 21 of 28d x 4 cycles) and letrozole (daily x 16 weeks), or paclitaxel (80 mg/m2 iv, d1,8,15 q28 days x 4 cycles), before surgery. RBsig (HIGH vs LOW) will be determined centrally on mandatory pre-treatment biopsies. Patients ≥65 years will receive a baseline geriatric assessment including G8, Instrumental Activity of Daily Living (IADL) and Charlson Comorbidity Index. The primary objective is to explore the interaction between RBsig and treatment activity assessed by pathological complete response (pCR) at time of surgery. Exact logistic regression will test RBsig by treatment interaction (2-sided a=.05) and estimate odds ratios (OR) for treatment effect on pCR according to RBsig status. The sample size provides 86% power, assuming an overall pCR rate of 26%, 50% RBsig LOW, and OR=2.4 vs OR=0.11 for RBsig LOW vs HIGH. Accrual: The trial will recruit 144 patients from approximately 45 Centers in Belgium, France, Italy and Switzerland. The first patient was enrolled in April 2019. Accrual as of mid-June 2020 was 25 patients. The TOUCH trial (IBCSG 55-17) is sponsored and coordinated by IBCSG with financial support from Pfizer and Roche. The trial is conducted in collaboration with Unicancer GERICO and SAKK. NCT03644186 Citation Format: Laura Biganzoli, Etienne Brain, Luca Malorni, Andrea Gombos, Ursula Hasler-Strub, Claudio Zamagni, Camille Chakiba, Heidi Roschitzki-Voser, Meredith M Regan. Phase II randomized trial of neoadjuvant trastuzumab and pertuzumab with either palbociclib plus letrozole or paclitaxel for postmenopausal women with estrogen receptor-positive / HER2-positive breast cancer - The TOUCH trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-28-02.