Murthy Shares Insight on HER2CLIMB Findings With Tucatinib in HER2+ Breast Cancer

Rashmi K. Murthy, MD

Results of the phase II HER2CLIMB trial demonstrated that the addition of tucatinib to trastuzumab (Herceptin) and capecitabine (Xeloda) reduced the risk of death by 34% compared with trastuzumab and capecitabine alone in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer.

In findings presented at the 2019 San Antonio Breast Cancer Symposium (SABCS), the tucatinib triplet showed a median overall survival (OS) of 21.9 months (95% CI, 18.3-31.0) versus 17.4 months (95% CI, 13.6-19.9) with trastuzumab and capecitabine alone (HR, 0.66; 95% CI, 0.50-0.88; P = .0048). Furthermore, the 1-year OS rate was 76% in the tucatinib arm versus 62% in the control arm. The 2-year OS rates were 45% versus 27% in the tucatinib and control arms, respectively.

The addition of tucatinib to trastuzumab/capecitabine also resulted in a 46% reduction in the risk of disease progression or death compared with trastuzumab and capecitabine alone (HR, 0.54; 95% CI, 0.42-0.71; P <.00001). The median progression-free survival (PFS) was 7.8 months (95% CI, 7.5-9.6) for the triplet arm versus 5.6 months (95% CI, 4.2-7.1) in the control arm. Moreover, the 6-month and 1-year PFS rates were 63% versus 46% and 33% versus 12%, respectively.

The HER2CLIMB trial (NCT02614794) permitted enrollment of patients with brain metastases; in this subgroup, the addition of tucatinib reduced the risk of disease progression or death by 52% (HR, 0.48; 95% CI, 0.34-0.69; P <.00001). Here, the median PFS was 7.6 months with tucatinib versus 5.4 months with trastuzumab/capecitabine alone. Additionally, the 1-year PFS rates were 25% versus 0%, respectively, and a subgroup analysis also showed an OS benefit with tucatinib in this subgroup (HR, 0.58; 95% CI, 0.40-0.85).

“Tucatinib in combination with trastuzumab and capecitabine was effective for patients with and without brain metastases,” said lead study author Rashmi K. Murthy, MD, MBE. “Furthermore, this was a very welltolerated regimen with mainly low-grade toxicities. This [approach] allows for continued treatment for patients beyond progression.”

In December 2019, the FDA granted tucatinib a breakthrough therapy designation for use in combination with trastuzumab and capecitabine to treat patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, who had prior trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla). Just a few days later, Seattle Genetics, Inc, submitted a new drug application (NDA) for tucatinib for use in combination with trastuzumab and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive disease, including those with brain metastases, following at least 3 prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant, or metastatic setting. The NDA was based on the HER2CLIMB data.

In an interview with OncLive^® during the 2019 San Antonio Breast Cancer Symposium, Murthy, an assistant professor in the Department of Breast Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the findings of the HER2CLIMB trial in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer.

OncLive^®: Could you provide an overview of the HER2CLIMB trial?

Murthy: HER2CLIMB was a pivotal study that evaluated tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2-positive metastatic breast cancer, including those with and without brain metastases. The background for this study is that [this disease] remains incurable, and we have limited treatment options after progression with the standard systemic treatments: trastuzumab, pertuzumab, and T-DM1. Additionally, up to half of patients will develop brain metastases during their disease course.

Tucatinib is an investigational oral tyrosine kinase inhibitor that is highly selective for HER2 with minimal inhibition of EGFR, so it may provide a more favorable toxicity profile. Also, in a phase Ib study, we saw that tucatinib in combination with trastuzumab and capecitabine has a safe profile with encouraging antitumor activity in heavily pretreated patients, including those with brain metastases. The efficacy in brain metastases is also supported by preclinical work.

In this study, we saw that when tucatinib was added to standard therapy of trastuzumab and capecitabine, it improved PFS in patients with and without brain metastases. Moreover, there was a significant OS benefit, notably in this heavily pretreated patient population that included patients with brain metastases. This represents a major advance in the treatment of patients with advanced HER2-positive breast cancer.

What impact will these data have on the field?

These data will support a change in the standard of care. Hopefully, this treatment will be made available to patients soon following progression on trastuzumab, pertuzumab, and T-DM1.

What factors were considered when enrolling patients for the HER2CLIMB trial?

The eligibility for the HER2CLIMB study included those who had metastatic disease and centrally confirmed HER2 positivity, and were also previously exposed to treatment with trastuzumab, pertuzumab, and T-DM1. The most unique eligibility criteria were with regard to brain metastases. The trial included patients with brain metastases who had stable disease and a history of brain metastases, but—unique to this trial—it also allowed those who had occult disease identified at screening, or those who had progressing disease in the brain following prior local therapy. These patients were enrolled as clinically appropriate, as long as they did not require urgent medical intervention and were relatively asymptomatic.

What are the next steps for this research?

Moving forward, we will be taking a deeper look at the patient population with brain metastases in this clinical trial. This presents a unique opportunity to further study this group of patients and to understand key details, such as intracranial response and progression rates, among many other things. Additionally, we have an ongoing investigator-initiated trial through the Translational Breast Cancer Research Consortium (TBCRC) to study this combination in patients with leptomeningeal disease. This trial that became activated earlier this year across multiple different sites through the TBCRC. Finally, an ongoing trial is looking at tucatinib versus placebo in combination with T-DM1. That is being done to potentially bring this drug forward into an earlier-line metastatic setting.

Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer [published online December 11, 2019. Published correction appears in N Engl J Med, published online December 27, 2019. doi: 10.1056/NEJMx190039]. N Engl J Med. doi: 10.1056/NEJMoa1914609.