Jacot, William

1005 Background: In the phase 3 HER2CLIMB-05 study (NCT05132582), TUC + maintenance HP demonstrated a statistically significant improvement in progression-free survival (PFS) vs control treatment (Tx) (hazard ratio: 0.641, P < 0.0001) in patients (pts) with HER2+ locally advanced or metastatic breast cancer (MBC). Here we report additional efficacy and safety outcomes by stratified subgroups. Methods: Pts with centrally confirmed HER2+ MBC without evidence of progression following chemotherapy-based induction Tx (taxane + HP) were randomly assigned 1:1 to TUC (300 mg) or PBO BID + HP. Randomization was stratified by diagnosis ( de novo /recurrent), hormone receptor (HR) status (positive/negative), and presence or history of brain metastases (BM; yes/no). Endocrine therapy (ET) is permitted for pts with HR+ disease. The primary endpoint is investigator-assessed PFS. Confirmed objective response rate (cORR), duration of response (DOR), and safety were evaluated in stratified subgroups. Results: Among pts assigned to TUC + HP (n = 326) or PBO + HP (n = 328), ∼69% had de novo MBC, ∼53% had HR+ status with ∼45% having received concurrent ET, and ∼12% had baseline BM. At data cutoff (Sep 5, 2025), median PFS was longer with TUC than PBO + HP in all stratified subgroups; TUC + HP consistently improved cORR vs PBO + HP (Table). Safety outcomes in subgroups aligned with the overall population. Conclusions: TUC + HP demonstrated clinically meaningful efficacy vs PBO + HP in pts with de novo or recurrent disease, HR+ or HR− disease, and baseline BM or not, with no new safety signals identified. Results were consistent with the overall population and support TUC + HP as a potential new maintenance therapy across pts with HER2+ MBC. Clinical trial information: NCT05132582 . Efficacy outcomes. Overall De novo Recurrent HR+ (± ET) † HR− BM (yes) BM (no) TUC+HP(n=326) PBO+HP(n=328) TUC+HP(n=227) PBO+HP(n=226) TUC+HP(n=99) PBO+HP(n=102) TUC+HP(n=168) PBO+HP(n=176) TUC+HP(n=158) PBO+HP(n=152) TUC+HP(n=41) PBO+HP(n=40) TUC+HP(n=285) PBO+HP(n=288) Median PFS, mos (95% CI) 24.9(21.3−NE) 16.3(12.6−18.7) 28.9(22.7−NE) 16.8(12.9−19.2) 21.3(15.6−27.2) 12.7(8.3−18.1) 25.0(16.5−NE) 18.1(13.0−20.8) 24.9(19.4−NE) 12.6(9.4−16.8) 8.5(4.2−16.5) 4.2(2.2−8.1) 27.2(24.3−NE) 18.1(14.8−20.7) cORR*, % (95% CI) 22.6(18.0−27.8) 15.2(11.3−19.7) 26.1(20.2−32.7) 18.5(13.5−24.4) 15.1(8.5−24.0) 7.0(2.6−14.6) 20.1(14.0−27.5) 12.9(8.2−19.0) 25.2(18.4−33.0) 17.9(11.8−25.5) 15.0(5.7−29.8) 8.3(1.8−22.5) 23.8(18.7−29.5) 16.1(11.9−12.1) Median DOR*, mos (95% CI) 20.9(16.4−NE) 16.9(12.3−NE) NR(16.4−NE) 16.3(10.4−NE) 17.9(8.3−NE) NR(7.2−NE) 20.9(12.6−NE) 18.7(7.8−NE) NR(8.6−NE) 14.5(10.4−NE) 12.6(8.1−NE) 16.3(12.5−NE) 20.9(16.4−NE) 18.7(10.4−NE) *ORR and DOR were assessed in patients with target or non-target lesions at baseline. † Data on HR+ w/ ET will be presented.

Abstract Background: The current standard of care for first-line (1L) treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) consists of induction chemotherapy combined with trastuzumab (TRAS) and pertuzumab (PERT) followed by maintenance therapy with TRAS + PERT. Although this regimen has been associated with sustained disease control, most patients eventually experience disease progression. The HER2CLIMB-05(NCT05132582) study is investigating the efficacy and safety of adding tucatinib to TRAS + PERT as maintenance therapy in patients with HER2+ MBC after completion of 1L chemotherapy-based induction therapy. Methods: Patients with centrally confirmed HER2+MBC without evidence of progression after 1L induction therapy with 4 to 8cycles of a taxane combined with TRAS + PERT, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and no or asymptomatic brain metastases (BM) were enrolled in HER2CLIMB-05. Contrast-enhanced brain magnetic resonance imaging was performed at screening and regular intervals during the study. Patients were randomly assigned 1:1 to receive either tucatinib 300 mg or placebo twice daily, in combination with either TRAS (6 mg/kg IV or 600 mg SC) plus PERT (420 mg/kg IV) or a SC fixed-dose combination of TRAS, PERT, and hyaluronidase administered every 21 days. Endocrine therapy was permitted for patients with hormone receptor-positive tumors. The primary endpoint is investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints include overall survival (OS), PFS by blinded independent central review, investigator-assessed central nervous system (CNS)-PFS, and safety. Results: Between March 2022 and July 2024, 654 patients were randomly assigned to receive tucatinib (n = 326) or placebo (n = 328) with1L maintenance therapy. All patients were female (median age: 54 years [range, 24-83]);45.0% were White, 35.2% were Asian, 2.9% were Black/African American, and 19.3%were Hispanic/Latino(a)/Spanish origin. Most patients had ECOG PS of 0 (64.1%)and de novo metastatic disease (69.3%). At baseline, 12.4% of patients had presence or history of BM and 52.6% had hormone receptor-positive MBC. As of September5, 2025, PFS was statistically significantly improved with the addition of tucatinib versus placebo to 1L maintenance therapy (hazard ratio [HR] = 0.641 [95%confidence interval (CI), 0.514-0.799]; 2-sided P &lt; 0.0001). All prespecified patient subgroups demonstrated a PFS benefit with tucatinib combination 1L maintenance therapy consistent with the overall population and regardless of presence or absence of BM at baseline or hormone-receptor status. OS is still immature (observed number of deaths = 51;tucatinib arm versus control arm HR = 0.539 [95% CI, 0.303-0.957; 2-sided P= 0.032]). In the safety analysis set, the most common treatment-emergent adverse events (TEAEs) in the tucatinib arm (n = 326) were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (alanine aminotransferase: 28.2%; aspartate aminotransferase:25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1% were, respectively, grade ≥ 3. In the tucatinib arm, 13.5% of patients discontinued tucatinib due to TEAEs. Conclusions: In the HER2CLIMB-05 trial, the addition of tucatinib to TRAS + PERT as 1L maintenance therapy demonstrated a statistically significant and clinically meaningful improvement in PFS with a manageable safety profile in patients with HER2+ MBC. Citation Format: E. Hamilton, G. Curigliano, M. Martin, F. Lerebours, J. Tsurutani, M. Savard, K. Jerzak, X. Hu, L. Martins de Aquino Pimentel, C. O'Sullivan, E. Tokunaga, A. Okines, C. Huang, W. Jacot, J. Sohn, E. Cronemberger Silva, V. Mueller, S. Yang, G. Granata, Q. Shen, L. Santarpia, V. Dieras Her2climb-05: a randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for her2+ metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS1-01.

PURPOSE The HER2CLIMB-05 study (ClinicalTrials.gov identifier: NCT05132582 ) is investigating the efficacy and safety of adding tucatinib to trastuzumab and pertuzumab as first-line (1L) maintenance therapy in patients with human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer (MBC). METHODS Patients with centrally confirmed HER2+ MBC without evidence of progression post induction therapy and no or asymptomatic brain metastases (BM) were enrolled. Patients were randomly assigned 1:1 to tucatinib (300 mg) or placebo twice a day combined with trastuzumab/pertuzumab. The primary end point is investigator-assessed progression-free survival (PFS); secondary end points include overall survival (OS), PFS per blinded independent central review, CNS-PFS, and safety. RESULTS Between March 2022 and July 2024, 654 patients were randomly assigned to tucatinib (n = 326) and placebo (n = 328) arms. All patients were female (median age, 54 years), 69.3% had de novo MBC, 52.6% were hormone receptor–positive, and 12.4% had presence/history of baseline BM. In this primary analysis, PFS was statistically significantly improved with addition of tucatinib versus placebo (hazard ratio, 0.641 [95% CI, 0.514 to 0.799]; P < .0001; median PFS: 24.9 v 16.3 months); a PFS benefit was seen regardless of the presence/absence of BM or hormone receptor status. OS data remain immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (ALT: 28.2%; AST: 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥3. In the tucatinib arm, 13.5% discontinued tucatinib because of TEAEs. CONCLUSION Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC.

Abstract Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in patients with metastatic breast cancer, focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental Design: In total, 4,436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg) and 325 (7.3%) and 1,189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), whereas 2,009 (45.3%) patients had at least one CTC at both time points (pos/pos). The median OS for the neg/neg, neg/pos, pos/neg, and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P &lt; 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared with CTC nonresponders (pos/pos; HR, 0.48; 95% confidence interval, 0.44–0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in metastatic breast cancer are urgently needed.

Abstract Background: Several studies suggest clinical utility of serial circulating tumor cell (CTC) enumeration as a means of assessing response status in metastatic breast cancer (MBC). The aim of this study is to conduct a comprehensive pooled analysis comprising globally available data to further define and explore the role of CTC enumeration as a tool for early treatment monitoring in patients with MBC with a focus on the predictive power in different breast cancer subtypes and clinical settings. Methods: In a global effort, peer-reviewed published studies with data on repeated CTC assessments (CellSearch® technology; Menarini Silicon Biosystems; Bologna, Italy) in MBC patients were screened and investigators were asked to provide individual patient data for this pooled analysis. 2761 cases from 32 data sets with data on both baseline and one follow up CTC assessments were included in the analysis (median time interval between the two CTC assessments 35 days). Data were analyzed using log rank tests and Cox regressions to evaluate the association between serial CTC enumeration results and overall survival (OS) in the full patient cohort and defined subgroups. Results: 588 (21.3%) patients had no CTCs at both time points (neg/neg), 236 (8.5%) patients were CTC negative at baseline and CTC positive at follow up (neg/pos), 712 (25.8%) patients converted from CTC positive at baseline to CTC negative (pos/neg), and 1225 (44.4%) patients had at least one CTC at both time points (pos/pos). Log rank tests showed significant differences in OS between these four CTC change groups (p &lt; 0.0001 for all pairwise comparisons except for the comparison between neg/pos and pos/neg, p = 0.015). Median OS for the neg/neg, neg/pos, pos/neg and pos/pos group was 45.6, 26.1, 34.6, and 17.6 months, respectively. Hazard ratios (HR) (reference group neg/neg) were 1.38 (95% CI 1.16 - 1.64) for the pos/neg group, 1.78 (95% CI 1.43 - 2.22) for the neg/pos group, and 3.06 (95% CI 2.63 - 3.56) for the pos/pos group. Results were similar if a cutoff of 5 CTCs was used for CTC positivity (pos/neg group: HR 1.43, 95% CI 1.25 - 1.63; neg/pos group: HR 2.39, 95% CI 1.91 - 2.99; pos/pos group: HR 3.54, 95% CI 3.12 - 4.02). In total, 2586 patients could be assigned to different tumor subtypes based on known hormone receptor (ER) and HER2 status of the primary tumor: 1513 (58.5%) patients had a luminal-like tumor (ER positive, HER2 negative), 682 (26.4%) patients had a HER2-positive tumor, and 391 (15.1%) patients had a triple-negative tumor. In patients with luminal-like tumors, the hazard ratios were 1.67 (95% CI 1.29 - 2.17), 2.01 (95% CI 1.45 - 2.77), and 3.87 (95% CI 3.09 - 4.83) for the pos/neg, neg/pos, and pos/pos group, respectively. In patients with HER2-positive tumors, the neg/pos group (HR 1.68, 95% CI 1.12 - 2.53) and the pos/pos group (HR 2.11, 95% CI 1.58 - 2.83) showed significantly worse OS compared to the neg/neg group, while in triple-negative patients, the pos/pos group had a significantly shorter OS compared to the neg/neg group (HR 2.99, 95% CI 2.11 - 4.24). The results will be up-dated by inclusion of additional large data sets (CALGB 40502, CALGB 40503, COMET, SWOG S0500, TBCRC 001) for the analysis to be presented at SABCS 2020. Conclusion: This large pooled analysis confirms that at a median of 35 days after treatment initiation, follow-up CTC assessments strongly predict overall survival. These results suggest potential clinical utility of CTC monitoring as early response marker in MBC, especially in luminal-like tumors. Citation Format: Wolfgang J Janni, Tracy C. Yab, Daniel F. Hayes, Massimo Cristofanilli, Francois-Clement Bidard, Michail Ignatiadis, Meredith M. Regan, Catherine Alix-Panabières, William E. Barlow, Carlos Caldas, Lisa A. Carey, Luc Dirix, Tanja Fehm, Jose A. Garcia-Saenz, Paola Gazzaniga, Daniele Generali, Lorenzo Gerratana, Rafael Gisbert-Criado, William Jacot, Zefei Jiang, Evi Lianidou, Mark J.M. Magbanua, Luis Manso, Dimitrios Mavroudis, Volkmar Müller, Elisabetta Munzone, Klaus Pantel, Jean-Yves Pierga, Brigitte Rack, Sabine Riethdorf, Hope S. Rugo, Kostandinos Sideras, Stefan Sleijfer, Jeffrey Smerage, Justin Stebbing, Leon W.M.M. Terstappen, José Vidal-Martínez, Rita Zamarchi, Karthik Giridhar, Thomas W.P. Friedl, Minetta C. Liu. Clinical utility of repeated circulating tumor cell (CTC) enumeration as early treatment monitoring tool in metastatic breast cancer (MBC) - a global pooled analysis with individual patient data [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 GS4-08.