LBA3 Patritumab deruxtecan (HER3-DXd) in early-stage HR+/HER2- breast cancer: Final results of the SOLTI TOT-HER3 window of opportunity trial

Prat, Aleix; Falato, Claudette; Brunet, Laia Paré; Saez, O. Martinez; Andujar, J.M. Cejalvo; Vila, Mireia Margelí; Tolosa, Pablo; Bofill, F.J. Salvador; Jurado, Josefina Cruz; Gonzalez-Farre, B.; Torres, E. Sanfeliu; Ciruelos, Eva; Espinosa-Bravo, Martín; Perón, Y. Izarzugaza; Simon, S. Pernas; Esker, Stephen; Fan, P-D.; Cafiero, J.M. Ferrero; Pascual, T.; Oliveira, M.

doi:10.1016/j.annonc.2022.03.279

Cited by 14 publications

(14 citation statements)

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“…Both the window-ofopportunity SOLTI TOT-HER3 (ClinicalTrials.gov identifier: NCT04610528) study and the phase II SOLTI-2103 VALEN-TINE (ClinicalTrials.gov identifier: NCT05569811) study are investigating the efficacy of neoadjuvant HER3-DXd and its biological effects on the tumor microenvironment. 19 In conclusion, HER3-DXd showed clinically meaningful and durable antitumor activity in heavily pretreated patients, across major breast cancer subtypes with high or low HER3 expression. A manageable and acceptable safety profile was observed in this population with adverse prognostic features.…”

Section: Discussionmentioning

confidence: 81%

Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3–Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3–Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial

Krop,

Masuda,

Mukohara

et al. 2023

JCO

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PURPOSE Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study. METHODS Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion. RESULTS One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; mPFS, 11.0 months). Objective responses were observed in cancers with HER3-high and HER3-low membrane expression. Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, GI and hematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred. CONCLUSION HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.

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Section: Discussionmentioning

confidence: 81%

Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3–Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3–Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial

Krop,

Masuda,

Mukohara

et al. 2023

JCO

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“…While e cacy of rst generation ADCs like T-DM1 was associated with target expression 10 , this could not be found in last generation ADCs. Indeed, TROP2 expression was not predictive of Sacituzumab Govitecan e cacy in the ASCENT trial 11 and the e cacy of patritumab deruxtecan was observed across patients with mBC and a broad spectrum of HER3 expression 12,13 . Nevertheless, most of the patients included in the phase I/II trial testing patritumab deruxtecan in mBC presented high levels of HER3 tumor expression.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of action and resistance to Trastuzumab Deruxtecan in patients with metastatic breast cancer: the DAISY trial

Varga

Mosele

Deluche

et al. 2022

Preprint

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Trastuzumab deruxtecan (T-DXd) is an anti-HER2 (human epidermal growth factor receptor 2) antibody-drug conjugate which has previously shown efficacy in patients with HER2-overexpressing and HER2-low metastatic breast cancer (mBC). However, the mechanisms of action and resistance of this drug remain partially unclear. DAISY (NCT04132960) is a phase II, open-label study that included patients with mBC whose disease progressed after at least one line of chemotherapy in the metastatic setting. Patients were enrolled in three cohorts according to HER2 expression determined by immunohistochemistry (IHC); cohort 1: HER2-overexpressing (HER2 IHC 3 + or HER2 IHC 2+/ISH+, n = 72), cohort 2: HER2-low (HER2 IHC2+/ISH- or HER2 IHC 1+, n = 74), and cohort 3: HER2 IHC 0 mBC (n = 40). Patients were treated with T-DXd 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. In the full analysis set population (n = 177), the confirmed objective response rate (ORR) was of 70.6% (95% CI: 58.3–81) in cohort 1, 37.5% (95% CI: 26.4–49.7) in cohort 2, and 29.7% (95% CI: 15.9–47) in cohort 3 (p < 0.0001). The median progression-free survival (PFS) was 11.1 months (95% CI: 8.5–14.4) in cohort 1, 6.7 months (95% CI: 4.4–8.3) in cohort 2, and 4.2 months (95% CI: 2-5.7); in cohort 3. Cohort 1 was significantly associated with longer PFS (adjusted HR: 0.53, 95% IC: 0.34–0.84, p = 0.007), and cohort 3 with shorter PFS (adjusted HR: 1.96, 95% IC: 1.21–3.15, p = 0.006) as compared to cohort 2. Exploratory analyses showed that HER2 spatial distribution predicted T-DXd response in patients with HER2-overexpressing mBC and that the transcriptomic response to T-DXd was different according to HER2 expression. No quantitative modulation of tumor microenvironment was observed after 6 to 8 weeks of treatment. Finally, recurrent mutations of the DNA repair gene SLX4 were identified in 20% of samples at resistance (4/20) as compared to 2% in baseline samples (2/88), suggesting that SLX4 mutations could mediate secondary resistance to T-DXd. These data suggest that HER2 is a key determinant of T-DXd efficacy. However, an antitumor activity is also observed in a subgroup of patients without detectable HER2 expression and resistance could be partially mediated by payload sensitivity.

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“…35 At final analysis, clinical response in 45% of patients (n = 12/30) was reported, with increased immune infiltration among responders, irrespective of baseline ERBB3 expression. 36 Of note, the concordance between ERBB3 mRNA and HER3 IHC expression was weak. A single dose of HER3-DXd induced expression of immune-related genes (e.g., programmed cell death 1 [PD-1], CD8a, and CD19) and suppressed proliferation-related genes.…”

Section: Patritumab Deruxtecanmentioning

confidence: 99%

“…To overcome the limitations of IHC assay, in this trial mRNA-based ERBB3 expression assay was performed 35 . At final analysis, clinical response in 45% of patients (n = 12/30) was reported, with increased immune infiltration among responders, irrespective of baseline ERBB3 expression 36 . Of note, the concordance between ERBB3 mRNA and HER3 IHC expression was weak.…”

Section: Patritumab Deruxtecanmentioning

confidence: 99%

Antibody-Drug Conjugates in Breast Cancer: What Is Beyond HER2?

et al. 2022

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The therapeutic landscape of patients with breast cancer has changed significantly with the introduction of antibody-drug conjugates (ADCs). Although human epidermal growth factor receptor 2 (HER2) has been the centerpiece of ADC development, potentially any surface antigen with differential expression between tumor and normal cells may be suitable for targeting with ADCs. Exploration of new targets is critical to expand the fraction of patients who can benefit from ADCs. Sacituzumab govitecan, an anti–trophoblast cell surface antigen 2 ADC, is the only non–anti-HER2 ADC approved for breast cancer to date, with several novel ADCs directed against novel targets (e.g., HER3, LIV-1) at various stages of preclinical and clinical development. The aim of this review is to provide an overview of clinical trials investigating ADCs targeting novel antigens. We discuss the optimal characteristics of the target to be exploited in ADCs' design and potential future challenges in the evolving field of ADCs such as biomarker assessment, patient selection, and sequencing of ADCs.

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LBA3 Patritumab deruxtecan (HER3-DXd) in early-stage HR+/HER2- breast cancer: Final results of the SOLTI TOT-HER3 window of opportunity trial

Cited by 14 publications

References 0 publications

Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3–Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3–Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial

Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3–Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3–Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial

Mechanism of action and resistance to Trastuzumab Deruxtecan in patients with metastatic breast cancer: the DAISY trial

Antibody-Drug Conjugates in Breast Cancer: What Is Beyond HER2?

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