December 11, 2020 - The European Medicines Agency’s Committee for Medicinal Products for Human Use has granted a positive opinion to tucatinib in combination with trastuzumab and capecitabine for use in adult patients with HER2-positive, locally advanced or metastatic breast cancer who had received at least 2 previous anti-HER2 therapies.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has granted a positive opinion to tucatinib (Tukysa) in combination with trastuzumab (Herceptin) and capecitabine for use in adult patients with HER2-positive, locally advanced or metastatic breast cancer who had received at least 2 previous ant-HER2 therapies.1
The recommendation is based on data from the pivotal phase 2 HER2CLIMB trial (NCT02614794), which demonstrated that the addition of tucatinib to trastuzumab/capecitabine reduced the risk of death by 34% vs trastuzumab/capecitabine alone in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive disease.2
The median overall survival (OS) was 21.9 months (95% CI, 18.3-31.0) with the triplet vs 17.4 months (95% CI, 13.6-19.9) with the doublet (HR, 0.66; 95% CI, 0.50-0.88; P = .0048). The OS rates at 1 year were 76% vs 45%, respectively; these rates at 2 years were 62% vs 27%, respectively. The survival benefit observed was found to be upheld across all prespecified subsets evaluated in the trial.
The small molecule TKI also reduced the risk of disease progression or death by 46% vs trastuzumab/capecitabine alone, with a median progression-free survival (PFS) of 7.8 months vs 5.6 months, respectively (HR, 0.54; 95% CI, 0.42-0.71; P <.00001). At 6 months, the PFS rate with the triplet was 63% vs 33% with the doublet; the 1-year PFS rates were 46% vs 12%, respectively. Again, the benefit was upheld across all prespecified subsets.
“We are pleased the CHMP has recognized [tucatinib] as a meaningful clinical advance for people with advanced HER2-positive metastatic breast cancer, including those with cancer that has spread to the brain, Roger Dansey, MD, chief medical officer at Seagen, stated in a press release. “This opinion brings us one step closer to making [tucatinib] available to patients in the EU and aligns with our commitment to bring innovative therapies to patients around the world.”
In the randomized, double-blind, phase 2 trial, investigators examined the safety and efficacy of the small molecule oral TKI in combination with trastuzumab/capecitabine in patients with HER2-positive metastatic breast cancer who had prior treatment with trastuzumab, pertuzumab (Perjeta), and trastuzumab emtansine (T-DM1; Kadcyla). To be eligible for enrollment, patients had to have an ECOG performance status of 0-1 and they needed to have a brain MRI completed at baseline. Patients were stratified based on presence of brain metastases, performance status, and geographic region.
Participants were randomized 2:1 to receive tucatinib at a twice-daily dose of 300 mg (n = 410) or matching placebo (n = 202) in combination with trastuzumab at a dose of 6 mg/kg every 3 weeks and a loading dose of C1D1 at 8 mg/kg and twice-daily capecitabine at a dose of 100 mg/m2 for days 1-14 of each 21-day treatment cycle.
Updated data presented during the 2020 ASCO Virtual Scientific Program focused on this subset of patients with brain metastases who received treatment with the tucatinib triplet.3 Of these patients, 66 had untreated, active metastases, while 117 had treated brain metastases that proved to be stable and showed no signs of disease progression. Of these 291 patients, 198 received the tucatinib triplet and 93 received the doublet.
At 1 year, the rate of central nervous system (CNS)–PFS, which was the time from randomization to disease progression in the brain or death, was 40.2% with tucatinib vs 0% with placebo; 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 median CNS-PFS in the triplet and doublet cohorts was 9.9 months and 4.2 months, respectively.
Additionally, the triplet led to a 1-year OS rate of 70.1% vs 46.7% with the doublet, leading to a 42% reduction in the risk of death in this population (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months with the tucatinib regimen versus 12.0 months with trastuzumab/capecitabine.
Most recently, at the 2020 ESMO Virtual Congress, updated data continued to show statistically significant improvements in PFS and OS with tucatinib in patients with HER2-positive breast cancer, irrespective of the presence of brain metastases.4
Two-year OS rates in the triplet and doublet arms were 45% vs 27%, respectively. The median OS with tucatinib was 21.9 months vs 17.4 months with placebo. In the cohort of 612 patients the tucatinib combination reduced the risk of death by 34% (95% CI, 0.50-0.88; P =.005). Moreover, the risk of progression or death with the tucatinib triplet was reduced by 46% (95% CI, 0.42-0.71; P <.001); this rate was 52% in those with brain metastases (95% CI, 0.34-0.69; P <.001).
Health-related quality-of-life (HRQoL) data were also shared at the meeting and showed that across all EQ-5D-5L domains analyzed—which included health dimensions like mobility, self-care, usual activities, pain/discomfort, and anxiety/depression—most patients reported only slight or no problems across the treatment arms.
The CHMP opinion is now being reviewed by the European Commission.
In April 2020, the FDA approved tucatinib for use in combination with trastuzumab/capecitabine for the treatment of patients with unresectable, locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, following at least 1 previous anti-HER2–based regimen in the metastatic setting based on data from HER2CLIMB.