Significant breakthrough for HER2+ MBC in trial with new drug tucatinib

A clinical trial shows that tucatinib, an investigative therapy used in combination with trastuzumab and capecitabine, reduces risk of death at two years by one-third in women with HER2-positive metastatic breast cancer (HER2+ MBC).

The results of the HER2CLIMB trial were presented by Rashmi K. Murthy, M.D. (pictured) at the San Antonio Breast Cancer Symposium (SABCS). Photo credit: Bruce Jancin/MDedge News. BCAC Secretary Fay Sowerby attended the presentation and said it was one of the highlights of the Symposium as Dr Murthy showed how this drug combination showed encouraging anti-tumour activity, including reducing the risk of death within two years of beginning treatment by a third and risk of disease progression or death within one year of starting treatment by half in all patients including those with brain metastases.

Tumour shrinkage was observed in nearly double the number of patients when tucatinib was administered (41% for Tras+Cap+TUC compared to 23% for Tras+Cap+placebo). The study involved women previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine (TDM-1).

Fay adds that a highlight for consumer advocates at SABCS was the fact that the HER2CLIMB study is the first randomised trial completed in patients with HER2+ metastatic breast cancer with untreated or previously treated or progressing brain metastases. Prior trials had excluded these patients on the basis the blood brain barrier would reduce the effectiveness of medicines.

Granted breakthrough therapy designation by the FDA for this therapy for locally advanced and metastatic HER2+ breast cancer, SeattleGenetics on 23 December 2019 announced they had completed a new drug application (NDA) to the US Food and Drug Administration for tucatinib. This submission is based on the results of the HER2CLIMB study. The applications as a breakthrough therapy and the NDA are for tucatinib combined with capecitabine and trastuzumab.  Until FDA approval is achieved it is not available to the US market.

During the meeting Fay spoke to representatives of SeattleGenetics and learned that tucatinib had been acquired through acquisition of Cascadian Therapeutics in early 2018, and there is now a need to develop distribution networks not just internationally but also in the US for when approval is achieved.  This means it is not currently available in the US or New Zealand and there is currently no international focus from SeattleGenetics.

There are two further breast cancer trials enrolling for tucatinib, firstly a phase three trial HER2CLIMB2 in combination with T-DM1 (Kadcyla, which PHARMAC made available in NZ on 1 December 2019). The other is a phase 2 trial I-SPY2, a neoadjuvant trial in combination with trastuzumab, pertuzumab and paclitaxel. Neither trial is enrolling in NZ.

In addition, as the drug can attack cancers that express HER2, a receptor that is very common in solid tumour cancers, it may be suitable for other cancers including colorectal, ovarian and gastric cancers along with breast.  SeattleGenetics has a phase 2 colorectal trial underway, MOUNTAINEER.

In the HER2CLIMB trial, the new drug combination was well tolerated, and side effects such as diarrhoea and reversible inflammation of the liver were low grade. Few people stopped taking part in the trial due to adverse events.

Dr Murthy said that no single regimen is currently considered the standard of care for patients with HER2-positive metastatic breast cancer who have been treated with trastuzumab, pertuzumab, and T-DM1. There are few treatment options for these circumstances.

“Additionally, up to half of patients with HER2-positive metastatic breast cancer may develop brain metastases, and effective and tolerable treatment options are needed.”

Dr Murthy told the Symposium that tucatinib in combination with trastuzumab and capecitabine has the potential to become a new standard of care in women with HER2+ MBC, with and without brain metastases.

Those who posed questions at the end of Dr Murthy’s presentation at SABCS expressed the view that it would have been interesting to see a trial arm of tucatinib in combination with trastuzumab without capecitabine, suggesting this combination may have been more tolerable and also potentially less financially demanding.


About the trial

  • The HER2CLIMB trial was a randomised phase 1b trial in patients with HER2+ metastatic breast cancer that included patients with untreated or previously treated progressing brain metastases.
  • The study involved 612 subjects, encompassing 155 sites enrolled in 15 different countries.
  • Tucatinib is an investigational, oral reversible small molecule tyrosine kinase inhibitor, TKI, that is highly selective for the kinase domain of HER2 with minimal inhibition of EGFR. EGFR has not been shown to enhance efficacy of HER2 blockade.


To see more

Rashmi K Murthy et al, 2019, ‘Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer’, The New England Journal of Medicine. DOI: 10.1056/NEJMoa1914609.



Article Type: