Abstract RF1-02: Palbociclib plus letrozole versus weekly paclitaxel, both in combination w/ trastuzumab plus pertuzumab, as neoadjuvant treatment for patients w/ HR+/HER2+ early breast cancer: primary results from the randomized phase II TOUCH trial (IBCSG 55-17)

Abstract Background: HR+/HER2+ breast cancer (BC) is a biologically heterogeneous group characterized by low pathological complete response (pCR) to chemotherapy combined with anti-HER2 therapy and relative endocrine resistance in the neoadjuvant setting. CDK4/6 inhibitors (CDK4/6i) have recently shown potential for chemotherapy de-escalation when combined with endocrine and anti-HER2 therapy. Methods: TOUCH is an international, open-label, phase II trial for post-menopausal patients (pts) with cT>1 cm, cN0 or cN1, HR+/HER2+ BC, randomized 1:1 to Paclitaxel (T) 80 mg/m2 iv on day 1,8,15 q28d for 4 cycles (arm A) or Palbociclib (Pal) standard dose/schedule for 4 cycles plus Letrozole (L) 2.5 mg/day for 16 weeks (arm B). All received 5 cycles of trastuzumab sc + pertuzumab iv (HP) standard dose q3w. Randomization was stratified by: a) age and G8 geriatric score (<65 y vs ≥65 y and G8 >14 vs ≥65 y and G8 ≤14); b) cN0 vs cN1. The primary objective was the interaction between a gene-signature of E2F pathway activity (RBsig) and pCR (ypT0/ypTis ypN0), hypothesizing higher pCR for tumors with RBsig high in T+HP, and for tumors with RBsig low in Pal+L+HP. RNA-sequencing was performed from pre-treatment FFPE biopsies (NEBNext® UltraTM II Directional RNA Library Prep Kit with the Twist Human Core Exome + Custom IntegraGen Enrichment V2 capture System, Paired End 100b reads). RBSig score was calculated by first standardizing each normalized gene measurement across all sequenced specimens and adding up standardized values for each gene. RbSig was dichotomized at the median. Treatment-by-RBSig interaction was estimated using logistic regression. Results: From October 2018 to July 2022, 145 pts were randomized (73 in arm A, 72 in arm B) in 37 centers from 4 countries. Median age was 69 years (IQR 63,73), with 99 pts (68%) being ≥65y of age (65 with G8 score >14, 34 with G8 ≤14); 132 pts (91%) had a ECOG PS 0; at diagnosis 109 pts (75%) were cN0 with a median cT of 30 mm (IQR 20-40); 76 pts (56%) had G3 tumors. More pts completed Pal vs T (94.4% vs 79.5%) and >95% completed 5 cycles of HP. Surgery was performed in 98.6% of the pts, BCS being more frequent in arm B vs A (82% vs 67%). pCR and other secondary efficacy endpoints were similar between arms. Overall, pCR was 32.9% (95%CI: 22.3-44.9) in arm A vs 33.3% (95% CI: 25.5-41.4) in arm B. RBsig was successfully determined in 115 pts who completed at least one full dose of treatment. Median RBsig was lower in arm B. There was no interaction between pCR and RBsig (p=0.18): pCR in RBsig high vs low was 31% (95%CI: 16.1-50) vs 42% (95%CI: 23.3-63.1) in Arm A, and 38% (95%CI: 20.2-59.4) vs 26% (95%CI: 11.9-44.6) in Arm B. No new safety signal was observed. Grade 3-4 adverse events were seen in 31.5% vs 54.1% of pts in arm A vs Arm B (mainly diarrhea in Arm A and asymptomatic neutropenia in Arm B). Conclusions: Although the primary hypothesis was not supported, TOUCH shows for the first time that, when combined with dual anti-HER2 blockade, a de-escalated chemo-free backbone of Pal+L yields pCR rates similar to weekly T. The lack of clinical impact of the increased rate of neutropenia of Pal+L suggests it might represent an attractive alternative for postmenopausal pts with HR+/HER2+ BC, especially older ones. Translational studies are ongoing to uncover potential gene-signatures with prognostic/predictive significance. Citation Format: Luca Malorni, S. Tyekucheva, C. Zamagni, U. Hasler-Strub, A. Gombos, C. Chakiba-Brugère, M. Colleoni, A. Mueller, A.M. Minisini, D. Taylor, J.P. Salmon, E. Gallerani, A. Cariello, A. Fontana, H. Roschitzki-Voser, R. Kammler, B. Ruepp, S. Loi, G. Viale, M.M. Regan, E. Brain, L. Biganzoli. Palbociclib plus letrozole versus weekly paclitaxel, both in combination w/ trastuzumab plus pertuzumab, as neoadjuvant treatment for patients w/ HR+/HER2+ early breast cancer: primary results from the randomized phase II TOUCH trial (IBCSG 55-17) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF1-02.