New Agents on Horizon for HER2-Positive Breast Cancer

Partner | Cancer Centers | <b>Sylvester Comprehensive Cancer Center</b>

There are multiple therapeutic options in development for the treatment of patients with HER2-positive breast cancer, further adding to the regimens available, explains Frances Valdes-Albini, MD.

Frances Valdes-Albini, MD

There are multiple therapeutic options in development for the treatment of patients with HER2-positive breast cancer, further adding to the regimens available, explains Frances Valdes-Albini, MD, assistant professor of clinical medicine at the University of Miami Miller School of Medicine.


In a presentation during the 2018 OncLive® State of the Science Summit™ on Breast Cancer, Albini discussed the novel treatment approaches being developed in the HER2-positive breast cancer paradigm.In the phase III randomized SOPHIA trial, margetuximab plus chemotherapy is being compared with trastuzumab (Herceptin) plus chemotherapy in the treatment of patients with HER2-positive metastatic breast cancer (NCT02492711). The purpose of this study is to determine whether patients treated with margetuximab plus chemotherapy have longer progression-free survival (PFS) and overall survival (OS) than patients treated with trastuzumab plus chemotherapy.


“Similar to trastuzumab, margetuximab blocks signaling through HER2 but also has more effective antibody-dependent cytotoxicity due to more efficient binding of the monoclonal antibody to the Fc-gamma receptor of the natural killer cell,” said Albini. This ongoing trial is estimated to enroll 530 patients with advanced HER2-positive breast cancer who have received at lease 2 prior lines of HER2-directed therapy in the metastatic setting. Patients were also eligible if they previously received neoadjuvant pertuzumab (Perjeta), at least 1 prior line of HER2- directed therapy in the metastatic setting, and at least 1 but no more than 3 lines of therapy overall in the metastatic setting. The study has an estimated completion date of March 2021.In a phase Ib study of the small-molecule tyrosine kinase inhibitor (TKI) tucatinib, previously known as ONT-380, combined with capecitabine and/or trastuzumab in HER2-positive metastatic breast cancer, the combination demonstrated an objective response rate (ORR) of 61%, with a median duration of response of 10 months (95% CI, 2.8-19.3) for patients with measureable disease.1 The median PFS was 7.8 months (95% CI, 4.1-12.4).

“This trial demonstrated encouraging antitumor activity with the triplet combination in a heavily pretreated population, including patients with brain metastases,” said Valdes-Albini.


This triplet regimen is currently being investigated in the phase II HER2CLIMB trial, which is randomizing patients with HER2- positive breast cancer with/without central nervous system metastases to the combination of tucatinib, capecitabine, and trastuzumab (NCT02614794). The primary endpoint of this trial is PFS with secondary outcomes including OS and quality of life.The oral, irreversible pan-ErbB receptor TKI pyrotinib (HTI-1001) is also being investigated in HER2-positive breast cancer. In a phase II trial, the combination of pyrotinib with capecitabine demonstrated an increased median PFS of 18.1 versus 7 months for patients receiving lapatinib (Tykerb) with capecitabine, irrespective of prior therapy with trastuzumab.2 The ORR was 78.5% in the pyrotinib arm versus 57.1% in the lapatinib arm.

However, grade 3/4 toxicities were higher in the pyrotinib arm compared with the lapatinib arm. Toxicities included hand-foot syndrome (21.5% vs 19.0%), diarrhea (13.8% vs 4.8%), decreased neutrophil count (7.7% vs 1.6%), and vomiting (4.6% vs 0%).

These data are being taken a step further in a larger phase III trial where patients will be randomized in a 2:1 ratio of pyrotinib with capecitabine or placebo with capecitabine until the occurrence of death, disease progression, or unacceptable toxicity (NCT02973737). The primary outcome of this study is PFS, with secondary outcomes of ORR, safety, duration of response, clinical benefit rate, and OS.


“There is rationale behind novel combinations, and we aim to investigate them further,” explained Valdes-Albini.DS-8201 (trastuzumab deruxtecan), a HER2-targeting antibody-drug conjugate, has demonstrated significant clinical activity in heavily pretreated patients with HER2-expressing metastatic breast cancers who previously received ado-trastuzumab emtansine (T-DM1; Kadcyla).

An ongoing 2-part phase I study showed an ORR of 61.4% in 57 evaluable patients who received DS-8201. The median PFS in 19 evaluable patients with low HER2—expressing tumors had not been reached, and the ORR was 31.6% for this patient population.3

In August 2017, DS-8201 received a breakthrough therapy designation from the FDA 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.


Daiichi Sankyo, the manufacturer of DS-8201, has initiated the pivotal phase II DESTINY-Breast01 study, which is evaluating the safety and efficacy of DS-8201 in patients with HER2-positive unresectable and/or metastatic breast cancer that is resistant or refractory to T-DM1.In the phase II PATRICIA study, researchers are investigating the CDK4/6 inhibitor palbociclib (Ibrance) plus trastuzumab with or without letrozole in postmenopausal patients with HER2- positive locally advanced or metastatic breast cancer who have received chemotherapy and treatment with trastuzumab (NCT02448420). The aim of the study is to determine whether the addition of palbociclib to standard therapy is well tolerated and can provide a PFS benefit for this patient population.

This ongoing trial aims to have an estimated enrollment of 138 patients. The primary endpoint includes PFS at 6 months, with secondary endpoints including ORR, clinical benefit rate, and safety.

“Overall, targeted therapies have changed a poor prognosis to a good one for stages I to III HER2-positive disease, and the expectation is that for the development of these agents and novel combinations, we should be able to further improve outcomes for patients with early- and advanced-stage disease,” Valdes-Albini concluded.


  1. Hamilton, E, Borges V, Conlin A, et al. Efficacy of a phase 1b study of tucatinib (ONT-380), an oral her2-specific inhibitor, in combination with capecitabine and trastuzumab in HER2+ metastatic breast cancer, including patients with brain metastases. In: Proceedings from the 2016 San Antonio Breast Cancer Symposium; December 9-12, 2016; San Antonio, Texas. Abstract P4-21-01.
  2. 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. Cancer Res. 2018;78(suppl 4). cancerres.aacrjournals. org/content/78/4_Supplement/PD3-08. Published 2018. Accessed March 27, 2018.
  3. 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; San Antonio, Texas. Abstract PD3-07.