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New Agents on Horizon for HER2-Positive Breast Cancer

Danielle Bucco
Published: Thursday, Apr 12, 2018

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.

Margetuximab

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.

Tucatinib

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.

Pyrotinib/Capecitabine

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

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.




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