Adding the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) to the HER2-targeted agent tucatinib extended progression-free survival by about 2 months vs treatment with T-DM1 alone among patients with unresectable, locally advanced or metastatic HER2-positive breast cancer, according to the results of the phase III HER2CLIMB-02 trial, presented by Sara A. Hurvitz, MD, FACP, of the University of Washington Fred Hutchinson Cancer Center, Seattle, at the 2023 San Antonio Breast Cancer Conference.¹ Of note, about 40% of patients enrolled in the trial had brain metastasis at baseline, and they had a similar progression-free survival benefit from the combination therapy as the overall study population.

After a median follow-up of 24.4 months, the median time to disease progression or death was 9.5 months with tucatinib plus T-DM1 vs 7.4 months with T-DM1 alone, reflecting a 24% likelihood of reducing disease progression or death with the combination. Among patients with brain metastasis at baseline, the median time to disease progression or death was 7.8 months with the combination of tucatinib plus T-DM1 vs 5.7 months with T-DM1 alone, for a 36.1% risk reduction of disease progression or death favoring the combination. Overall survival data were immature.

“The HER2CLIMB-02 and HER2CLIMB studies provide level 1 evidence for the use of tucatinib in patients with active or progressing brain metastasis.”

— Sara A. Hurvitz, MD, FACP

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“The HER2CLIMB-02 and HER2-CLIMB studies provide level 1 evidence for the use of tucatinib in patients with active or progressing brain metastasis. I would use tucatinib [in that setting] over standard second-line therapy with fam-trastuzumab deruxtecan-nxki [T-DXd]. For patients without active brain metastasis, T-DXd remains the standard of care after trastuzumab and taxane,” said Dr. Hurvitz.

Dr. Hurvitz noted that HER2-positive breast cancer has a propensity to metastasize to the brain. Up to 50% of patients will develop brain metastasis, she said.

Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor, which is approved in combination with trastuzumab and capecitabine for the treatment of previously treated, HER2-positive, locally advanced or metastatic breast cancer, based on the results of the previous HER2CLIMB trial; this study showed improved overall and progression-free survival with the addition of tucatinib, including in patients with HER2-positive breast cancer who had brain metastasis.² T-DM1 is a HER2-directed antibody-drug conjugate approved as monotherapy for patients with HER2-positive breast cancer.

Advances in HER2-targeted therapy, including antibody-drug conjugates, prompted the current study designed to evaluate whether the addition of T-DM1 would boost the efficacy of tucatinib demonstrated in HER2CLIMB.

“This study is one of very few large breast cancer studies prospectively designed to evaluate novel systemic therapies in patients with brain metastases,” Dr. Hurvitz said. “While there is much interest in improving outcomes for patients with HER2-positive breast cancer brain metastases, most studies evaluating systemic agents have been limited by a small size, a retrospective design, or an exploratory analysis of a larger study.”

Study Details

The randomized, double-blind, placebo-controlled phase III HER2CLIMB-02 trial enrolled 463 patients with unresectable locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane in any setting. The entry criteria allowed enrollment of previously treated, stable, progressing, or untreated brain metastases not requiring immediate local therapy, and it is the second large trial to do so.

Participants were randomly assigned in a 1:1 ratio to receive either 21-day cycles of either tucatinib at 300 mg orally twice a day and T-DM1 at 3.6 mg/kg intravenously every 3 weeks or T-DM1 and placebo.

Demographic and disease characteristics were well balanced between the two arms at baseline. A total of 44.1% of all patients had baseline active or stable brain metastasis. Median patient age was about 55 years. Median duration of follow-up was 24.4 months.

Results and Toxicity

In addition to extended progression-free survival, patients treated with the combination of tucatinib plus T-DM1 had a higher objective response rate: 42% vs 36.1% in the control arm.

The most common treatment-emergent adverse events more frequently reported in the experimental arm vs the control arm included nausea (65.4% vs 49.4%), diarrhea (56.7% vs 26.6%), and fatigue (48.9% vs 37.3%). The most common grade 3 and higher treatment-emergent adverse events reported with the combination were liver function abnormalities: elevated alanine and aspartate aminotransferase levels (16.5%, each event) vs 2.6% in the control arm. Treatment discontinuations associated with treatment-emergent adverse events were reported in 22.1% of the experimental arm and 11.6% of the control arm. Deaths attributed to treatment-emergent adverse events were reported in three patients and two patients, respectively.

Although more dose adjustments and treatment discontinuations occurred in the combination arm, Dr. Hurvitz noted they were mainly manageable with monitoring and clinical intervention. There were no new safety signals related to the combination therapy reported in the trial.

One potential limitation to this study is that it was not designed to compare the effect of the experimental regimen with tucatinib plus trastuzumab and capecitabine (the regimen used in HER2CLIMB) or with regimens containing T-DXd, another HER2-directed antibody-drug conjugate approved as second-line therapy.

Brain Imaging

During the discussion at a press conference where these data were presented, Dr. Hurvitz pointed out that it is not standard practice to perform brain imaging in asymptomatic patients who experience disease progression on treatment for HER2-positive breast cancer. Imaging was used in this study to identify patients with active and asymptomatic brain metastasis and to make sure both arms were well balanced for this factor.

“Perhaps we should look again at the imaging guidelines now that we have better drugs for these patients [with brain metastases],” she suggested. 

DISCLOSURE: Dr. Hurvitz has received research funding from Ambrx, Arvinas, AstraZeneca, Bayer Celcuity, CytomX Therapeutics, Daiichi Sankyo, Dantari, Dignitana, Genentech, G1 Therapeutics, Gilead Sciences, Greenwich Life Sciences, GSL Immunomedics, Eli Lilly, Loxo Oncology, MacroGenics, Novartis, OBI Pharma, Orinove, Orum Therapeutics, Pfizer, Pheonix Molecular Designs, Peiris Pharmaceuticals, Puma Biotechnology, Radius Health, Sanofi, Seagen, and Zymeworks; has received royalties from McGraw-Hill, Sage Publications, Wiley, and Wolters Kluwer; and has received honoraria from the Vaniam Group and OncLive.

REFERENCES

1. Hurvitz S, Loi S, O’Shaughnessy J, et al. HER2-CLIMB-02: Randomized, double-blind, phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. 2023 San Antonio Breast Cancer Symposium. Abstract GS01-10. Presented December 6, 2023.

2. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382:597-609, 2020.