2018 Treatment Algorithm for Metastatic HER2-Positive Breast Cancer

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How should clinicians position anti-HER2 agents and also incorporate endocrine therapies in the treatment of metastatic HER2-positive breast cancer? At the 2018 Miami Breast Cancer Conference, this question was explored by Sunil Verma, MD, Medical Director of the Tom Baker Cancer Center and Professor and Head of Oncology at the Cumming School of Medicine, University of Calgary in Canada.1

Dr. Verma first reviewed the list of pivotal trials that have informed the treatment algorithm over the past 2 decades and then made a few new recommendations. The pivotal trials in the first-line metastatic setting, and their key findings, follow:

  • MA.31: In combination with a taxane, lapatinib (Tykerb) was inferior to trastuzumab (Herceptin).2
  • NEfERT-T: In combination with a taxane, neratinib (Nerlynx) was as effective as trastuzumab, also differentiating itself from lapatinib.3
  • BOLERO-1: Everolimus (Afinitor) combined with trastuzumab/paclitaxel showed a modest improvement in progression-free survival but significant toxicity.4
  • CLEOPATRA: Pertuzumab (Perjeta) added to trastuzumab/docetaxel showed an overall survival improvement.5
  • MARIANNE: Overall results were negative, as outcomes were similar for ado-trastuzu-mab emtansine (formerly T-DM1; Kadcyla), ado-trastuzumab emtansine plus pertuzumab, and -trastuzumab plus taxane, but informative observations were made.6

In the second-line setting and beyond, in patients with prior exposure to trastuzumab, key trials made the following findings:

  • EMILIA set ado-trastuzumab emtansine as an option for patients whose disease progresses on trastuzumab.7
  • BOLERO-3 showed the benefit of everolimus added to trastuzumab/vinorelbine, but at the cost of significant toxicity.8
  • LUX-Breast 1 showed no benefit for afatinib (Gilotrif) plus vinorelbine over trastuzumab/vinorelbine; the study was closed early.9
  • TH3RESA showed a benefit for ado-trastuzumab emtansine in more heavily pretreated patients.10
  • EGF104900, also performed in heavily pretreated patients, showed a benefit for lapatinib and trastuzumab in combination.11

Some of these studies demonstrated important benefits for the experimental drugs. In the first-line setting, docetaxel plus pertuzumab and trastuzumab showed an average gain of 15.7 months in overall survival over trastuzumab plus docetaxel, in CLEOPATRA. As second-line therapy in EMILIA, ado-trastuzumab emtansine offered a survival gain of 4 months over

Ado-trastuzumab emtansine may be an option for patients who relapse early after receiving adjuvant trastuzumab.
— Sunil Verma, MD

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capecitabine/lapatinib. In the third-line setting, ado-trastuzumab emtansine demonstrated almost a 7-month gain over treatment by physician’s choice in TH3RESA. In later lines of therapy, trastuzumab plus lapatinib improved survival by 4.5 months over lapatinib alone, the EGF104900 trial showed.

Side effects were minimally increased when either pertuzumab or lapatininb was added to trastuzumab. In the studies of ado-trastuzumab emtansine, this antibody-drug conjugate was better tolerated than the control arms.

Ado-trastuzumab Emtansine After Pertuzumab/Trastuzumab

“These improvements have been quite remarkable,” said Dr. Verma. “One of the challenges that has arisen as we have incorporated them into an algorithm is the question of the benefit of ado-trastuzumab emtansine after pertuzumab and trastuzumab.”

We still don’t have a predictive biomarker to tell us which patients are more likely to benefit from ado-trastuzumab emtansine or pertuzumab.
— Sunil Verma, MD

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Although there is a lack of prospective and long-term data to help answer this question, information can be drawn from the CLEOPATRA and PHEREXA trials,12 in which patients were allowed to receive ado-trastuzumab emtansine after trastuzumab/pertuzumab chemotherapy. Assuming the duration of treatment can be a surrogate for response and progression-free survival, ado-trastuzumab emtansine adds about 7 months’ remission time. “The evidence suggests ado-trastuzumab emtansine can be beneficial after trastuzumab/pertuzumab,” Dr. Verma concluded.

Individualizing Treatment Based on Prior Use of Trastuzumab

Patients have different sensitivities to anti-HER2 agents, depending on whether they present with de novo metastases and thus have not received trastuzumab or they developed metastatic disease after adjuvant trastuzumab. In the latter group, patients with a trastuzumab-free interval of 1 year or longer seem to be more sensitive to anti-HER2 therapies than those whose disease progressed within 1 year.

The EMILIA trial fit this description, allowing patients with prior trastuzumab exposure but whose disease-free interval was < 6 months. “What’s interesting is the progression-free survival was 10.8 months for patients receiving ado-trastuzumab emtansine alone, after relapsing within 6 months on adjuvant trastuzumab, which was much better than with capecitabine and lapatinib,” he noted.

A dual HER2-targeted approach plus an aromatase inhibitor will improve progression-free survival.
— Sunil Verma, MD

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Several other important clinical trials contained populations of patients with limited exposure to trastuzumab. The MARIANNE trial evaluated the benefit of pertuzumab added to ado-trastuzumab emtansine for first-line metastatic treatment, showing this combination was not more effective than ado-trastuzumab emtansine alone. In patients who had received adjuvant trastuzumab and then ado-trastuzumab emtansine in the first line upon relapse, the median progression-free survival was 15.2 months.

“It seems that with ado-trastuzumab emtansine, you will be able to get a similar progression-free survival as you get with taxane/trastuzumab/pertuzumab (16.9 months). So ado-trastuzumab emtansine may be an option for patients who relapse early after receiving adjuvant trastuzumab,” Dr. Verma maintained, “especially for those patients who may not want to be re-challenged with a taxane or who do not want or are unlikely to receive traditional chemotherapy.

Individualizing Treatment Based on Hormone Receptor Status

Should the crosstalk that exists between hormone receptor status and HER2 status influence the choice of treatment? At least two recent trials have suggested there may be a benefit to combining a dual-targeted approach with an aromatase inhibitor.

Several studies have suggested single-agent anti-HER2 therapy adds modestly to the effect of endocrine therapy in terms of progression-free but not overall survival. This has been shown for anastrozole plus trastuzumab or letrozole in addition to lapatinib.


First-Line Setting

  • MA.31: lapatinib + taxane vs trastuzumab + taxane
  • NEfERT-T: neratinib + paclitaxel vs trastuzumab + paclitaxel
  • BOLERO-1: everolimus + trastuzumab/paclitaxel vs trastuzumab/paclitaxel
  • CLEOPATRA: pertuzumab + trastuzumab/docetaxel vs trastuzumab/paclitaxel
  • MARIANNE: ado-trastuzumab emtansine ( pertuzumab) vs trastuzumab + taxane

Second-Line Setting

  • EMILIA: ado-trastuzumab emtansine vs capecitabine + lapatinib
  • BOLERO-3: everolimus + trastuzumab/vinorelbine vs trastuzumab/vinorelbine
  • LUX-Breast 1: afatinib + vinorelbine vs trastuzumab + vinorelbine
  • TH3RESA: ado-trastuzumab emtansine vs physician’s choice
  • EGF104900: lapatinib + trastuzumab vs lapatinib alone

Against this background, Gradishar et al recently conducted the ALTERNATIVE trial in 355 women with HER2-positive hormone receptor–positive disease.13 The patients, most of whom had been treated with adjuvant trastuzumab, were randomized to receive lapatinib/trastuzumab plus an aromatase inhibitor, trastuzumab plus an aromatase inhibitor, or lapatinib plus an aromatase inhibitor. Median progression-free survival without chemotherapy was “quite respectable” at approximately 11 months with the triplet, vs < 6 months with the single agents. Overall survival was numerically but not significantly improved (46 vs 40 months).

The PERTAIN trial asked a similar question,14 although patients could initially receive chemotherapy: Is there a benefit to adding pertuzumab to trastuzumab and an aromatase inhibitor? The study demonstrated a 3-month progression-free survival improvement with the triplet (18.9 months).

“Both of these trials suggest that a dual HER2-targeted approach plus an aromatase inhibitor will improve progression-free survival, which is now above and beyond 11 to 12 months and certainly above the 5 to 6 months we were seeing before, with the addition of trastuzumab alone to endocrine treatment,” Dr. Verma commented.

Patients who could be considered for this nonchemotherapy approach are those with minimal disease, elderly patients, and patients who have received chemotherapy and are receiving maintenance therapy with trastuzumab plus pertuzumab.

Individualizing Treatment for Brain Metastases

Up to 50% of patients with metastatic breast cancer will also have brain metastases. Should these patients be treated any differently?

Treatment options that have demonstrated some brain-specific benefit in clinical trials include capecitabine/lapatinib, the continued use of trastuzumab, ado-trastuzumab emtansine, neratinib, and the experimental agent tucatinib (ONT-380). Dr. Verma’s preferred option among them is ado-trastuzumab emtansine, based on a subset of the large EMILIA trial that achieved a doubling in overall survival. An exploratory analysis of the single-arm -KAMILLA study also found a median time to disease progression in the brain of 11.3 months with ado-trastuzumab emtansine.15

“I would consider capecitabine/lapatinib for central nervous system disease only in those patients who we are not able to control with local measures,” he said.

Individualizing Therapy With Predictive Biomarkers

There are a few prognostic biomarkers, but no predictive ones, to guide the treatment selection of metastatic HER2 therapy. High HER2 mRNA was associated with a better prognosis independently of the treatment arm in the EMILIA and CLEOPATRA studies. In CLEOPATRA, PIK3CA mutations heralded a worse prognosis, although these patients did still benefit from dual HER2 blockade. Growing evidence suggests tumor-infiltrating lymphocytes may be associated with improved prognosis in breast cancer including response to anti-HER2 therapies as well.

“We still don’t have a predictive biomarker to tell us which patients are more likely to benefit from ado-trastuzumab emtansine or pertuzumab,” Dr. Verma noted.

Putting It All Together: What’s Changed Since 2014?

In the past 3 years, since ASCO issued a treatment algorithm for HER2-positive metastatic breast cancer,16 outcomes have continued to improve. Dr. Verma said the following new approaches may be added to the standard algorithm:

  • In hormone receptor–negative or –positive patients, ado-trastuzumab emtansine can be considered a first-line treatment option for patients who are not candidates for chemotherapy or those who have had a short disease-free interval (< 6 months) after adjuvant trastuzumab.
  • With either hormone receptor status, capecitabine/trastuzumab/pertuzumab can be considered for patients who have not already received pertuzumab in the first-line setting, and this may be an option in later lines of therapy. 
  • Hormone receptor–positive patients can receive an aromatase inhibitor in combination with lapatinib/trastuzumab or trastuzu-mab/pertuzumab, especially elderly patients, patients with a low burden of disease, and patients wishing to avoid chemotherapy. ■

DISCLOSURE: Dr. Verma is on the advisory board of AstraZeneca, Amgen, Eli -Lilly, Novartis, Roche, Spectrum, and Daiichi Sankyo.


1. Verma S: Clinical algorithm for HER2-positive metastatic breast cancer. 2018 Miami Breast Cancer Conference. Invited Lecture. Presented March 9, 2018.

2. Gelmon KA, Boyle FM, Kaufman B, et al: Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results of NCIC CTG MA.31. J Clin Oncol 33:1574-1583, 2015.

3. Awada A, Colomer R, Inoue K, et al: Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: The NEfERT-T randomized clinical trial. JAMA Oncol 2:1557-1564, 2016.

4. Hurvitz SA, Andre F, Jiang Z, et al: Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): A phase 3, randomised, double-blind, multicentre trial. Lancet Oncol 16:816-829, 2015. 

5. Swain SM, Baselga J, Kim, SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-734, 2015.

6. Ellis PA, Barrios CH, Eiermann W, et al: Phase III, randomized study of trastuzumab emtansine ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study. 2015 ASCO Annual Meeting. Abstract 507. Presented June 1, 2015.

7. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.

8. Andre, F, O’Regan R, Ozguroglu M, et al: Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15:580-591, 2014.

9. Harbeck N, Huang CS, Hurvitz S, et al: Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): An open-label, randomised, phase 3 trial. Lancet Oncol 17:357-366, 2016.

10. 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.

11. Blackwell KL, Burstein HJ, Storniolo AM, et al: Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28:1124-1130, 2010.

12. Urruticoechea A, Rizwanullah M, Im SA, et al: PHEREXA: A phase III study of trastuzumab + capecitabine ± pertuzumab for patients who progressed during/after one line of trastuzumab-based therapy in the HER2-positive metastatic breast cancer setting. 2016 ASCO Annual Meeting. Abstract 504. Presented June 6, 2016.

13. Gradishar WJ, Hegg R, Im SA, et al: Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women with HER2+, HR+ metastatic breast cancer: ALTERNATIVE. 2017 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2017.

14. Arpino G, Ferrero J-M, de la Haba-Rodriguez J, et al: Primary analysis of PERTAIN: A randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer. 2016 San Antonio Breast Cancer Symposium. Abstract S3-04. Presented December 8, 2016.

15. Barrios CH, Wuerstlein R, Anton A, et al. Safety of trastuzumab emtansine in HER2-positive advanced breast cancer patients: Primary results from KAMILLA study cohort 1. 2017 ASCO Annual Meeting. Abstract 1033. Presented June 4, 2017.

16. Giordano SH, Temin S, Kirshner JJ, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32:2078-2099, 2014.