Novel Treatments Emerging in HER2+ Breast Cancer Pipeline


Aleix Prat, MD, PhD, discusses the novel treatments being developed in the paradigm of HER2-positive breast cancer.

Aleix Prat, MD, PhD

Aleix Prat, MD, PhD, head of medical oncology at August Pi i Sunyer Biomedical Research Institute in Barcelona, Spain

Aleix Prat, MD, PhD

There are a number of novel treatments being developed in the paradigm of HER2-positive breast cancer, according to Aleix Prat, MD, PhD, head of the Department of Medical Oncology at the University of Barcelona.

ABP 980

In a lecture during the 2017 San Antonio Breast Cancer Symposium, Prat highlighted some of these systemic therapies, which include biosimilars, novel chemotherapy modalities, tyrosine kinase inhibitors (TKIs), and more.A study investigating the efficacy and safety of the biosimilar ABP 980 compared with trastuzumab (Herceptin) in HER2-positive early-stage breast cancer showed clinical equivalence in the neoadjuvant setting. The results further demonstrated similarity between the drugs.

This randomized, multicenter, double-blind study compared the pathologic complete response (pCR) of ABP 980 with trastuzumab. Of the 827 patients enrolled, 725 were randomized and 696 were included in the pCR evaluation. According to the results presented at the 2017 ESMO Congress, in the APB 980 arm, 48% of patients achieved pCR compared with 40.5% in the trastuzumab arm.1 In the adjuvant part of the trial, 10 patients in each group experienced grade 3 or higher adverse events.2

Based on these results switching from trastuzumab to ABP 980 following surgery was safe for this patient population. Analytical, functional, and pharmacokinetic similarity between ABP 980 and trastuzumab has been demonstrated. Allergan and Amgen, the developers of the biosimilar, submitted a biologics license application for the agent to the FDA in July 2017 based on these data.

Subcutaneous Versus Intravenous Trastuzumab

“We can conclude that this compound is very similar in efficacy and safety compared to the trastuzumab,” said Prat.The long-term efficacy, event-free survival (EFS), and overall survival (OS) results confirmed the noninferiority of subcutaneous trastuzumab compared with intravenous trastuzumab, according to results from the randomized phase III HannaH study.

In the subcutaneous and intravenous arm, 297 and 299 patients were randomized with a median duration follow-up of 70.8 and 71.4 months, respectively. The OS was 84% in both arms (HR, 0.94; 95% CI, 0.61-1.45). EFS was 65% in both arms (HR, 0.98; 95% CI, 0.74-1.29). Patients who reached total pCR had longer EFS and OS versus those who did not.3


“One important aspect of this study is the association between pCR and outcome,” Prat said. “Back in 2016 after a median follow-up of 40 months, pCR did correlate with the outcome independently of the administration of trastuzumab. The same thing is now shown after a median follow-up of 70 months.”DS-8201 is a HER2-targeting antibody-drug conjugate. In results of a phase I trial, DS-8201 was found to be well tolerated and showed significant activity in patients with HER2-positive breast cancer who were previously treated with ado-trastuzumab emtansine (T-DM1; Kadcyla) and T-DM1 with pertuzumab (Perjeta).

In the study, 130 patients were included in the HER2-positive population. The overall response rate (ORR) was 61.4% including 1 complete response (CR).4 Duration of CR was 94.7% with a progression-free survival (PFS) of 10.4 months. Grade 3 toxicities occurred in less than 10% of patients with the most frequent grade 3 toxicity being nausea.


In August 2017, DS-8201 was granted a breakthrough therapy designation for the treatment of patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after T-DM1. According to Prat, DS-8201 is currently being evaluated in the DESTINY-Breast01 study, which aims to recruit 230 patients with a primary objective of ORR.TKIs are becoming a crowded field in metastatic HER2-positive disease, with agents such as tucatinib (ONT-380) and neratinib (Nerlynx) showing encouraging antitumor activity, explained Prat.

In patients with previously treated HER2-positive metastatic breast cancer, pyrotinib (HTI-1001), an oral, irreversible pan-ErbB receptor TKI, in combination with capecitabine yielded significantly better PFS and ORR rates when compared with lapatinib (Tykerb) and capecitabine, according to findings of a randomized phase II trial.

Metronomic Cyclophosphamide

Median follow-up time was 15 months for the 128 patients enrolled on this study. ORR was 78.5% in the pyrotinib arm and 57.1% in the lapatinib arm. Median PFS was 18.1 months compared with 7.0 months in the pyrotinib and lapatinib arms, respectively (HR, 0.363; 95% CI, 0.228-0.579; P <.0001).5Metronomic cyclophosphamide-based dual blockade seems superior to dual blockade alone in elderly and frail patients with HER2-positive metastatic breast cancer, according to phase II results from the EORTC 75111-10114 ETF/BCG study.

“These frail patients find it difficult to receive the standard-of-care treatment, which is classical pertuzumab or trastuzumab,” said Prat.

In this study, 39 and 41 patients were randomized to the dual blockade arm and metronomic cyclophosphamide-based dual blockade arm, respectively. With 20.7 months of median follow-up, 6-month and median PFS were 46.2% and 5.6 months for the dual blockade arm versus 73.4% and 12.7 months for the metronomic cyclophosphamide arm. The response rate was 53% versus 44% in the 2 arms, respectively.6

PIK3CA Alternations and Benefits From Neratinib

With an attractive safety profile, metronomic cyclophosphamide followed by T-DM1 after progression may delay or supersede taxane chemotherapy in this patient population.One year of neratinib after trastuzumab in the adjuvant setting was shown to significantly improve invasive disease-free survival (DFS) after 5 years in patients with early-stage, HER2-positive breast cancer. PIK3CA alterations may be a biomarker for differential sensitivity to neratinib after 1 year of trastuzumab, based on data from the phase III ExteNET trial.

PIK3CA mutations are important in HER2-positive disease because they are frequent, said Prat. Overall, 21.2% of primary tumors harbored PIK3CA mutations. Patients with PIK3CA alterations had fewer invasive DFS events with neratinib compared with placebo (HR, 0.41; 95% CI, 0.17-0.90; P = .028).7


  1. Minckwitz GV, Ponomarova O, Morales S, et al. Efficacy and safety of biosimilar ABP 980 compared with trastuzumab in HER2 positive early breast cancer. Ann of Oncol. 2017;28(suppl_5). doi:10.1093/annonc/mdx362.002.
  2. Minckwitz GV, Turdean M, Zhang N, et al. Safety results from a randomized, double-blind, phase 3 study of ABP 980 compared with trastuzumab in patients with breast cancer. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract PD3-10.
  3. Jackisch C, Stroyakovskiy D, Pivot X, et al. Efficacy and safety of subcutaneous or intravenous trastuzumab in patients with HER2-positive early breast cancer after 5 years’ treatment-free follow-up: Final analysis from the phase III, open-label, randomized HannaH study. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract PD3-11.
  4. Modi S, Tsurutani J, Takahashi S, et al. Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; Abstract PD3-07.
  5. Xu B, Ma F, Ouyang Q, et al. A randomized phase II trial of pyrotinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines, and/or trastuzumab. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract PD3-08.
  6. Wildiers H, Tryfonidis K, Lago LD, et al. Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer: Results from the EORTC 75111- 10114 ETF/BCG randomized phase II study. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract PD3-09.
  7. Chia SKL, Martin M, Holmes FA, et al. PIK3CA alterations and benefit with neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: Correlative analyses of the phase III ExteNET trial. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract PD3-12.
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