HER2-Positive Metastatic Breast Cancer Highlights 2019–2020 Almanac

Novel Targeted Agents, Immunotherapies, and Biosimilars Are Changing the Treatment Landscape

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The past 2 years have seen a dramatic change in the standard of care for patients with HER2-positive metastatic breast cancer whose disease has progressed on trastuzumab. Promising new agents and combinations for later lines of therapy may also challenge current treatment strategies, according to data from clinical trials.

Although there is currently no cure for advanced HER2-positive disease, presentations from the 2019 San Antonio Breast Cancer Symposium and the ASCO20 Virtual Scientific Program earlier this year showed improvements in progression-free and overall survival rates in patients with metastatic HER2-positive breast cancer, including those patients whose cancer has metastasized to the brain. The results from these studies prompted the National Comprehensive Cancer Network (NCCN) to update its Clinical Practice Guidelines in Oncology (NCCN Guidelines®) in the systemic treatment of metastatic breast cancer, including HER2-positive breast cancer.


Nancy U. Lin, MD

Nancy U. Lin, MD

Dr. Lin is Associate Chief in the Division of Breast Oncology and Director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute. She is also Associate Professor of Medicine at Harvard Medical School, Boston.

Clinical Trials Lead to New Standard-of-Care Options

In the international randomized HER2CLIMB study, which enrolled 612 patients with progressive HER2-positive metastatic breast cancer who had previously received trastuzumab, pertuzumab, and ado-trastuzumab emtansine, oral tucatinib, a highly selective inhibitor of the HER2 tyrosine kinase, in combination with trastuzumab and capecitabine was found to significantly improve both progression-free and overall survival in patients with and without brain metastases. Furthermore, the survival benefits of tucatinib were maintained in the subset of 291 patients with brain metastases. HER2CLIMB is the first randomized trial of a targeted agent to demonstrate improvement in survival for patients with HER2-positive breast cancer that has metastasized to the brain.1

In the population with brain metastasis, the estimated 1-year overall survival rate was 70.1% (95% confidence interval [CI] = 62.1%–76.7%) in the tucatinib arm vs 46.7% (95% CI = 33.9%–58.4%) in the control arm, corresponding to a 42% reduction in the risk of death (hazard ratio [HR] = 0.58; 95% CI = 0.40–0.85; P = .005) and a prolongation of median overall survival from 12.0 months to 18.1 months. Notably, 60% of patients with brain metastases had active, new or progressive brain metastases at study entry—a population excluded from virtually all registration trials to date. Additional analysis from this study was presented during the ASCO20 Virtual Scientific Program.2

Based on the study’s results, in April 2020, the U.S. Food and Drug Administration (FDA)  approved tucatinib in combination with trastuzumab and capecitabine for patients with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have received one or more prior anti–HER2-based regimens in the metastatic setting. The ongoing HER2CLIMB-02 study is evaluating tucatinib in an earlier-line setting, including in patients with or without brain metastases, and is comparing ado-trastuzumab emtansine alone vs in combination with tucatinib.

Also new to the treatment paradigm for advanced HER2-positive disease is the novel antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd). Results from the phase II DESTINY-Breast01 trial investigating T-DXd in heavily pretreated patients (median of six prior lines of therapy) whose cancer was resistant or refractory to the anti-HER2 monoclonal antibody trastuzumab emtansine (T-DM1) showed the measures of response were substantially higher than have been seen in other studies in this treatment setting.3 For example, the objective response rate was 60.9%, the disease control rate was 97.3%, the median duration of response was 14.8 months, the median progression-free survival was 16.4 months, and the median overall survival was not reached.

“Despite many new treatment options for patients with metastatic, HER2-positive breast cancer, therapeutic resistance remains a stubborn problem.”
— Nancy U. Lin, MD

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As historical reference, consider the phase III TH3RESA study, which compared T-DM1 vs chemotherapy of provider’s choice in the refractory HER2-positive setting.4 In this study, the objective response rate was 31% with T-DM1 and just 9% with the physician’s choice, and median progression-free survival was 6.2 months with T-DM1 vs 3.3 months with the physician’s choice.

Based on the results of the phase II DESTINY-Breast01 trial, in late 2019, the FDA granted an accelerated approval for T-DXd in the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received at least two prior lines of anti–HER2-based treatment regimens in the metastatic setting. The ongoing, randomized, phase III DESTINY-Breast03 study is evaluating T-DXd in an earlier-line setting and is comparing it with T-DM1.

Finally, the phase III NALA trial compared lapatinib/capecitabine versus the oral HER2 tyrosine kinase inhibitor, neratinib, in combination with capectibine.

Neratinib/capecitabine was associated with longer progrssion-free survival (hazard ratio [HR], 0.76; 95% conficence interval {CI], 0.63–0.93; log-rank P value = .0059). Overall survival did not significantly differ between arms (median 21 months vs 18.7 months; HR 0.88; 95% CI 0.72–1.07; P = .2086). Prior data from the phase II TBCRC 022 clinical trial also demonstrated CNS activity with the combination, with a CNS ORR of 49% in lapatinib-naive patients.

At this time, tucatinib/capecitabine/trastuzumab, T-DXd, and neratinib/capecitabine all have FDA approvals for the treatment of patients with pretreated, HER2-positive, metastatic breast cancer. In this almanac edition of The ASCO Post, you will learn about expert perspectives on options for sequencing and choosing between these regimens.

Novel Targets and Approaches

Despite many new treatment options for patients with metastatic, HER2-positive breast cancer, therapeutic resistance remains a stubborn problem. Based on preclinical observations of the Fc receptor dependence of trastuzumab activity, the phase III SOPHIA trial evaluated the novel monoclonal antibody margetuximab, which was engineered to have an Fc region that better promotes antibody-dependent cell-mediated cytotoxicity. The substitution of trastuzumab with margetuximab, when combined with chemotherapy, was associated with a modest improvement in progression-free survival, particularly in those patients carrying a CD16A-158F allele.5

Other approaches to augment the immune response to HER2-positive breast cancer include adding PD-1 or PD-L1 inhibitors to standard HER2-based therapy. In the KATE2 study, a progression-free survival benefit for the combination of T-DM1 and atezolizumab (vs T-DM1 alone) was not observed in the intent-to-treat population, but it was observed in the subset of patients with PD-L1–positive tumors.6

Finally, preclinical data support the potential role of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in combination with HER2 inhibition in HER2-positive breast cancer.7 This hypothesis has now been tested clinically in the randomized, phase II, monarcHER trial.8 In this study, median progression-free survival was longest (8.3 months, 95% CI = 5.9–12.6 months) with abemaciclib/fulvestrant/trastuzumab, vs 5.7 months (95% CI = 5.4–7.0 month) with trastuzumab/chemotherapy (HR = 0.67, P = .051). Intriguingly, median progression-free survival in the abemaciclib/trastuzumab group (without fulvestrant) was not significantly different from that in the trastuzumab/chemotherapy group.

The ongoing phase III PATINA study  (NCT02947685) is testing the value of adding the CDK4/6 inhibitor palbociclib to endocrine therapy in the trastuzumab/pertuzumab maintenance phase after first-line chemotherapy/anti-HER2 induction therapy. Although these approaches have not entered the NCCN Guidelines or other standard guidelines, they do provide intriguing insights into alternative approaches to target HER2 resistance.

“HER2CLIMB is the first randomized trial of a targeted agent to demonstrate improvement in survival for patients with HER2-positive breast cancer that has metastasized to the brain.”
— Nancy U. Lin, MD

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Changing Guidelines to Reflect New Treatment Strategies

During the 25th NCCN 2020 Annual Conference, held virtually due to the COVID-19 pandemic, key 2020 updates to its NCCN Guidelines were presented for several tumor types, including for HER2-positive metastatic breast cancer. William J. Gradishar, MD, the Betsy Bramsen Professor of Breast Oncology and Chief of Hematology/Oncology at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, presented guideline updates for biosimilars now on the market as appropriate choices as substitutes for trastuzumab. They include trastuzmab-dkst, trastuzumab-anns, trastuzumab-dttb, trastuzumab-pkrb, and trastuzumab-gyyp.9 According to the FDA’s definition, a biosimilar “is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product.”

On the following pages of this almanac, we discuss in greater detail these and other studies, which are improving the care and outcomes for patients with advanced HER2-positive breast cancer. 

DISCLOSURE: Dr. Lin has received institutional research funding from Genentech, Pfizer, Merck, and Seattle Genetics and has served as a consultant to and received honorarium from Puma, Seattle Genetics, Daiichi Sankyo, Denali Therapeutics, and the California Institute for Regenerative Medicine.


1. Murthy RK, Loi S, Okines A, et al: Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases. 2019 San Antonio Breast Cancer Symposium. Abstract GS-01. Presented December 11, 2019.

2. Lin NU, Murthy RK, Anders CK, et al: Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). ASCO20 Virtual Scientific Program. Abstract 1005. Presented May 29, 2020.

3. Krop IE, Saura C, Yamashita T, et al: [Fam-] trastuzumab deruxtecan in subject with HER2-positive metastatic breast cancer previously treated with T-DMI A phase II, multicenter, open-label study (DESTINY-Breast01). 2019 San Antonio Breast Cancer Symposium. Abstract GS1-03. Presented December 11, 2019.

4. Krop IE, Kim SB, González-Martín A, et al: Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): A randomised, open-label, phase 3 trial. Lancet Oncol 15:689-699, 2014.

5. Rugo HS, Im SA, Cardoso F, et al: Phase III SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Second interim overall survival analysis. 2019 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 11, 2019.

6. Emens LA, Esteva F, Beresford M, et al: Overall survival in KATE2, a phase II study of programmed death ligand 1 inhibitor atezolizumab plus trastuzumab emtansine (T-DM1) vs placebo plus T-DM1 in previously treated HER2-positive advanced breast cancer. ESMO Congress 2019. Abstract 305O. Presented September 28, 2019.

7. Goel S, Wang Q, Watt AC, et al: Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 29:255-269, 2016.

8. Tolaney SM, Wardley AM, Zambelli S, et al: monarcHER: A randomized phase 2 study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ advanced breast cancer. ESMO Congress 2019. Abstract 1470. Presented September 28, 2019.

9. NCCN: NCCN Flash Updates: NCCN Guidelines® and NCCN Compendium® for Breast Cancer. Available at Accessed September 21, 2020.