February 12, 2021 - The European Commission has granted marketing authorization to tucatinib for use in combination with trastuzumab and capecitabine in the treatment of adult patients with HER2-positive, locally advanced or metastatic breast cancer who have previously received at least 2 HER2-targeted regimens
The European Commission has granted marketing authorization to tucatinib (Tukysa) for use in combination with trastuzumab (Herceptin) and capecitabine in the treatment of adult patients with HER2-positive, locally advanced or metastatic breast cancer who have previously received at least 2 HER2-targeted regimens.1
The regulatory decision was based on data from the phase 2 HER2CLIMB trial (NCT02614794), which showed that tucatinib reduced the risk of progression or death by 46% (HR, 0.54; 95% CI, 0.42-0.71; P <.00001) and reduced the risk of death by 34% (95% CI, 0.50-0.87; P = .0048) compared with trastuzumab/capecitabine alone.2,3
“The approval is a significant advancement for patients in Europe, who will for the first time have an approved medicine demonstrating a survival benefit for HER2-positive metastatic breast cancer after disease progression following 2 standard anti-HER2 treatment regimens,” Professor Volkmar Mueller, deputy director at the University Medical Center Hamburg-Eppendorf, stated in a press release. “In the HER2CLIMB pivotal trial, the tucatinib combination regimen improved overall and progression-free survival [PFS] compared to trastuzumab and capecitabine alone, including in patients with active, untreated, or progressing brain metastases, a population with significant unmet need.”
The double-blind, phase 2 HER2CLIMB trial enrolled patients with HER2-positive metastatic breast cancer who had previously received trastuzumab, pertuzumab (Perjeta), and trastuzumab emtansine (T-DM1; Kadcyla). To be eligible for enrollment, patients had to have an ECOG performance status of 0 or 1 and have a brain MRI done at baseline.
Participants were randomized 2:1 to receive either oral tucatinib at a twice-daily dose of 300 mg or placebo in combination with trastuzumab at a dose of 6 mg/kg every 3 weeks and capecitabine at a dose of 100 mg/m2 on days 1 through 14 for a 21-day treatment cycle. Patients were stratified by presence of brain metastases (yes vs no), performance status (0 vs 1), and region (United States or Canada or rest of the world).
The primary end point of the trial was PFS, and key secondary end points comprised overall survival (OS), PFS in patients with brain metastases, as well as confirmed objective response rate (ORR).
Baseline characteristics were well balanced between the 2 arms. The median age of participants was 55 years, 99% were female, and about 50% had an ECOG performance status of 0. Approximately two-thirds of patients in each arm had estrogen receptor– and/or progesterone receptor–positive disease. In both arms, patients had received a median of 4 prior lines of therapy overall and a median of 3 prior lines in the metastatic setting. Forty-eight percent of patients in the tucatinib arm had brain metastases at baseline versus 46% of those in the placebo arm.
Additional data from an analysis of patients with brain metastases were presented during the 2020 ASCO Virtual Scientific Program. Of 291 patients with brain metastases, 174 had active brain metastases; 108 of these patients had received treatment but were progressing, while 66 of these patients were untreated. A total of 117 patients had treated, stable brain metastases.
The median age of this subgroup was 52.5 years, 99.2% were female, 56.33% had an ECOG performance status of 1, and 58.7% of patients had ER- and/or PR-positive disease. Approximately 97% of patients had non–central nervous system (CNS) metastatic disease. The majority of patients, or 69.75%, had previously received radiotherapy for their brain metastases, 43.65% had prior whole brain radiation, and 40.45% had prior targeted radiation. About 15% of patients had previously undergone surgery.
Results showed that the tucatinib regimen resulted in improved PFS in patients with brain metastases(n = 291) at median PFS of 7.6 months versus 5.4 months with trastuzumab/capecitabine alone; this translated to a 52% reduction in the risk of progression or death (HR, 0.48; 95% CI, 0.34-0.69; P <.00001).4 The 1-year PFS rates were 25% (95% CI, 17%-34%) in the tucatinib arm versus 0% in the placebo arm.
Moreover, the tucatinib regimen also improved CNS-PFS over trastuzumab/capecitabine alone in this subgroup, at 9.9 months versus 4.2 months, respectively; this translated to a 68% reduction in the risk of CNS progression or death (HR, 0.32; 95% CI, 0.22-0.48; P <.00001). The 1-year CNS-PFS rates in the investigational and control arms were 40.2% (95% CI, 29.5%-50.6%) and 0%, respectively.
The tucatinib regimen also reduced the risk of death by 42% in this patient subgroup over trastuzumab/capecitabine (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS with the tucatinib triplet was 18.1 months versus 12.0 months with the doublet. The OS rates at 1 year were 70.1% (95% CI, 62.1%-76.7%) and 46.7% (95% CI, 33.9%-58.4%), respectively.
Regarding safety, the most frequently reported toxicity that occurred in 20% or more of patients who received tucatinib included diarrhea, nausea, vomiting, stomatitis, increased aspartate aminotransferase, increased alanine aminotransferase, and rash.
In April 2020, the FDA approved tucatinib for use in combination with trastuzumab and capecitabinefor the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, following at least 1 prior anti-HER2–based treatment in the metastatic setting. The decision was based on data from HER2CLIMB.