Tucatinib-T-DM1 combo improves PFS in patients with metastatic breast cancer

Treatment with trastuzumab emtansine (T-DM1) plus tucatinib safely prolongs progression-free survival (PFS) in patients with previously treated HER2-positive locally advanced (LA) or metastatic breast cancer (MBC), including those with brain metastases, reports a study.

“For patients who previously received trastuzumab and a taxane (∼80 percent of whom had prior pertuzumab treatment), the combination of tucatinib and T-DM1 improved PFS relative to T-DM1 alone, with a manageable safety profile, including for patients with brain metastases,” the investigators said.

A total of 463 patients with HER2-positive LA/MBC met the eligibility criteria and were randomized 1:1 to receive T-DM1 (3.6 mg/kg intravenously every 21 days) combined with either tucatinib (300 mg orally twice daily) or placebo (control arm).

The median PFS over a median follow-up duration of 24.4 months was 9.5 months in the tucatinib arm and 7.4 months in the control arm (hazard ratio [HR], 0.76, 95 percent confidence interval [CI], 0.61‒0.95; p=0.0163). All prespecified subgroups, including those with brain metastases, achieved a PFS benefit. [Ann Oncol 2026;37:341-352]

Results from the interim overall survival (OS) analysis were immature. The median OS was not reached in the tucatinib arm vs 38.0 months in the control arm (HR, 1.23, 95 percent CI, 0.87‒1.74).

Safety profile

The tucatinib arm showed higher incidences of treatment-emergent adverse events (TEAEs) associated with treatment discontinuation (22.1 percent vs 11.6 percent) and of grade 3 and above (68.8 percent vs 41.2 percent). The most common grade ≥3 TEAEs in tucatinib-treated patients were elevated levels of alanine aminotransferase (16.5 percent) and aspartate aminotransferase (16.5 percent).

One patient in the tucatinib arm died, but it was ruled to be unrelated to the study drug and resulted from progression of hepatic metastases.

“Nevertheless, proactive monitoring and timely dose modifications may mitigate the risk of hepatotoxicity associated with tucatinib and T-DM1,” the investigators said.

“Overall, the types of TEAEs observed in [this study] were expected for the tucatinib arm, were consistent with previously reported phase Ib results of tucatinib in combination with T-DM1, and were similar to the types of TEAEs seen in the tucatinib arm of the registrational HER2CLIMB study,” they added. [N Engl J Med 2020;382:597-609; JAMA Oncol 2018;4:1214-1220]

Treatment setting

Trastuzumab deruxtecan has already replaced T-DM1 monotherapy as a standard-of-care treatment in the second-line setting, but the latter remains a practical option for patients with HER2-positive LA/MBC in the third- or later-line setting. [https://www.esmo.org/living-guidelines/esmo-metastatic-breast-cancer-living-guideline/her2-positive-breast-cancer/her2-positive-breast-cancer/third-line-and-beyond]

“In second- or later-line settings, tucatinib in combination with T-DM1 may become a future treatment option for patients who are not eligible for, have safety concerns with, or are unable to access T-DXd,” the investigators said.

“Furthermore, the data reported here add to existing evidence of tucatinib and T-DM1 efficacy for patients with brain metastasis, and combination treatment may represent a viable option for this vulnerable population,” they added. [Lancet Oncol 2017;18:743-754; Ann Oncol 2020;31:1350-1358]