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Review
. 2022 Jan 9:14:17588359211066677.
doi: 10.1177/17588359211066677. eCollection 2022.

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

Christine Simmons  1 , Daniel Rayson  2 , Anil Abraham Joy  3 , Jan-Willem Henning  4 , Julie Lemieux  5 , Heather McArthur  6 , Paul B Card  7 , Rebecca Dent  8 , Christine Brezden-Masley  9
Affiliations
Review

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

Christine Simmons et al. Ther Adv Med Oncol. .

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.

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Conflict of interest statement

Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Christine Simmons has served in a consultancy or advisory role and received honorarium from Pfizer, Eli Lilly, Roche, and Mylan, and has received research funding from AstraZeneca Global, Roche, Knight Therapeutics, Viatris, and Pfizer. Daniel Rayson has served in a consultancy or advisory role and received honorarium from AstraZeneca, Pfizer, Eli Lilly, Merck, Gilead, Novartis, and Seagen. Anil Abraham Joy has served in a consultancy or advisory role and received honorarium from AstraZeneca, BMS, Eli Lilly, Knight Therapeutics, Gilead, Roche, Novartis, Pfizer, Mylan, and Teva. Jan-Willem Henning has served in a consultancy or advisory role and received honorarium from AstraZeneca, Pfizer, Novartis, Eli Lilly, Roche, Knight Therapeutics, Seagen, and Mylan. Julie Lemieux has served in a consultancy or advisory role and received honorarium from Novartis, Eli Lilly, Gilead, Pfizer, and AstraZeneca, and has received research funding from Celgene, Genentech, GlaxoSmithKline, Roche, Millennium, Novartis, Merck Gilead, Abbvie, Acerta, Bayer, Pfizer, BMS, Esai, Sanofi, Janssen, Ozmosys, Sierra Astrazeneca, and Takeda. Heather McArthur has served in a consultancy or advisory role and received honorarium from Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Puma Biotechnology, Daiichi-Sankyo, Seattle Genetics, Merck, and Lilly, and has received research funding from Bristol-Myers Squibb, MedImmune, LLC/AstraZenica, BTG, and Merck. Paul B. Card has nothing to declare. Rebecca Dent has served in a consultancy or advisory role and received honorarium from AstraZeneca, Viatris, Pfizer, Eisai, Merck, Eli Lilly, Novartis, and Roche, and has received research funding from AstraZeneca. Christine Brezden-Masley has served in a consultancy or advisory role and received honorarium from AstraZeneca, Eli Lilly, Knight Therapeutics, Mylan, Gilead, Roche, Amgen, Seagen, and Novartis, and has received research funding from Eli Lilly and AstraZeneca.

Figures

Figure 1.
Figure 1.
PRISMA diagram of eligible studies. ASCO, American Society of Clinical Oncology; BC, breast cancer; ESMO, European Society for Medical Oncology; HER2, human epidermal growth factor receptor 2; n, number; SABCS, San Antonio Breast Cancer Symposium; T-DM1, trastuzumab emtansine. aPrimary reports of eligible studies that were not identified through database. bIncluding current standards of treatment, trastuzumab, pertuzumab, and T-DM1.
Figure 2.
Figure 2.
Clinical trial overview for HER2-directed therapy in third-line and beyond HER2-positive advanced breast cancer. BC, breast cancer; CAP, capecitabine; CNS, central nervous system; CT, chemotherapy; LABC, locally advanced breast cancer; LAP, lapatinib; MCLA-128, zenocutuzumab; n, number of patients; NR, not reported; PER, pertuzumab; ST, systemic therapy (physician’s choice); T-DM1, trastuzumab emtansine; TRAS, trastuzumab; VIN, vinorelbine. aLength of bars give an approximation of the proportion of patients with each treatment or disease characteristic.
Figure 3.
Figure 3.
Proposed sequencing of HER2-directed therapy for HER2-positive advanced breast cancer. HER2, human epidermal growth factor 2; HER2+, HER2-positive; Pertuzumab combination, pertuzumab plus trastuzumab and a taxane; T-DM1, trastuzumab emtansine; T-Dxd, trastuzumab-deruxtecan; Tucatinib combination, tucatinib plus trastuzumab and capecitabine. *Especially if the patient has progressed on the adjuvant pertuzumab combination. If patient has progressed on adjuvant TDM-1, suggest pertuzumab combination first line.
See this image and copyright information in PMC

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