Current and future landscape of targeted therapy in HER2-positive advanced breast cancer: redrawing the lines

Christine Simmons; Daniel Rayson; Anil Abraham Joy; Jan-Willem Henning; Julie Lemieux; Heather McArthur; Paul B Card; Rebecca Dent; Christine Brezden-Masley

doi:10.1177/17588359211066677

Current and future landscape of targeted therapy in HER2-positive advanced breast cancer: redrawing the lines

Ther Adv Med Oncol. 2022 Jan 9:14:17588359211066677. doi: 10.1177/17588359211066677. eCollection 2022.

Authors

Christine Simmons¹, Daniel Rayson², Anil Abraham Joy³, Jan-Willem Henning⁴, Julie Lemieux⁵, Heather McArthur⁶, Paul B Card⁷, Rebecca Dent⁸, Christine Brezden-Masley⁹

Affiliations

¹ Medical Oncology, British Columbia Cancer Agency - Vancouver Centre, University of British Columbia, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
² Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, NS, Canada.
³ Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
⁴ Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada.
⁵ Centre hospitalier universitaire de Québec, Université Laval, Quebec, QC, Canada.
⁶ Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ Kaleidoscope Strategic, Inc., Toronto, ON, Canada.
⁸ National Cancer Centre Singapore, Duke-NUS Medical School, Singapore.
⁹ Sinai Health, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Abstract

Background: Evidence to date supports continued human epidermal growth factor receptor 2 (HER2) suppression beyond progression on HER2-directed therapy for advanced HER2-positive breast cancer. Data from several phase II and III trials evaluating HER2-directed therapy following second-line T-DM1 have recently become available.

Methods: We performed a systematic search of the published and presented literature to identify phase II and phase III trials assessing novel HER2-targeted agents as third-line therapy or beyond for HER2-positive advanced breast cancer using search terms 'breast cancer' AND 'HER2' AND 'advanced' AND ('phase II' OR 'phase III').

Results: Eight clinical trials reporting efficacy outcomes on third-line or greater HER2-directed therapy for HER2-positive advanced breast cancer were identified. In phase III trials, margetuximab and neratinib combinations demonstrated significant 1.3-month (hazard ratio, HR = 0.71, p < 0.001) and 0.1-month (HR = 0.76, p = 0.006) net improvements in median progression-free survival (PFS), respectively, with no significant improvements in overall survival (OS). Tucatinib added to trastuzumab and capecitabine demonstrated a significant 2.7-month improvement in median PFS (HR = 0.57, p < 0.00001) and a 5.5-month improvement in median OS (HR = 0.73, p = 0.004) in a randomized phase II trial, including significant clinical benefit for patients with brain metastases. Finally, trastuzumab-deruxtecan, zenocutuzumab, and poziotinib demonstrated benefit in phase II trials with the most robust overall response rate (62.0%) and median duration of response (18.2 months) observed for trastuzumab-deruxtecan among heavily pretreated patients.

Conclusion: Tucatinib plus trastuzumab and capecitabine significantly prolongs OS, and promising preliminary response outcomes for trastuzumab-deruxtecan suggest that sequencing of these regimens following second-line therapy is reasonable.

Keywords: HER2-positive; T-DM1; T-DXd; advanced disease; breast cancer; neratinib; pertuzumab; trastuzumab; tucatinib.

Publication types

Review