Regulatory Decision Summary for Tukysa

Between 15% and 30% of breast cancers overexpress the HER2 receptor and are classified as HER2+ breast cancer. Tumours that overexpress HER2 are more aggressive and HER2+ breast cancer also disproportionately affects younger patients, where the proportion of HER2 positivity is higher compared to older patients.

The clinical trial data supporting the effectiveness of Tukysa in combination with trastuzumab and capecitabine is limited to patients who had received at least one prior HER2-directed therapy in the metastatic setting. The primary source of safety and efficacy support for the proposed indication is a randomized Phase 2 study in combination with capecitabine and trastuzumab in the target patient population.

The primary efficacy and safety data for the proposed indication for Tukysa was provided by the pivotal HER2CLIMB study. This was a randomized, double-blind, placebo-controlled trial performed in the target patient population. Enrolled patients had locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, with or without brain metastases, and had prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1) separately or in combination. Patients with brain metastases were eligible to enroll provided they were neurologically stable and did not require immediate radiation or surgery, and the study included patients with untreated brain metastases as well as patients with treated brain metastases that were either stable or progressive since the last treatment.

A total of 612 patients were randomized 2:1 to receive Tukysa in combination with trastuzumab and capecitabine (N = 410) or placebo in combination with trastuzumab and capecitabine (N = 202). All patients received prior trastuzumab and T-DM1, and all but two patients had prior pertuzumab. Patients had received at least 1 prior line of systemic therapy in the metastatic setting (median: 3 lines; range: 1 to 14). Men were eligible, and 5 men enrolled into HER2CLIMB.

The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in the first 480 randomized patients. The median duration of exposure to Tukysa was 7.3 months (range: <0.1, 35.1) for patients on the Tukysa + trastuzumab and capecitabine arm compared to 4.4 months (range <0.1, 24.0) to placebo for patients on the placebo + trastuzumab and capecitabine arm. Secondary efficacy endpoints were evaluated in all randomized patients (N = 612) and included overall survival (OS), PFS among patients with a history or presence of brain metastases (PFSBrainMets), and confirmed objective response rate (ORR).

After a median duration of follow-up of 10.4 months, there was a statistically and clinically significant reduction of 46% in the risk of disease progression or death in patients treated with tucatinib compared to the control arm, as assessed by the blinded independent review committee (hazard ratio [HR] = 0.54 [95% confidence interval [CI]: 0.42, 0.71]; P <0.00001).

Almost all patients enrolled in HER2CLIMB experienced a treatment-emergent adverse event (TEAE), and the overall incidence of TEAEs was similar between the tucatinib and the control arms.

The safety profile of tucatinib is considered acceptable, in the context of this severe, life-threatening disease, with adverse events typically manageable through the use of tucatinib dose reduction, temporary treatment discontinuation, and/or standard medical care. Appropriate labelling in the final Tukysa Product Monograph, including recommendations regarding adverse event monitoring and dose modifications, supports management of the risks associated with Tukysa therapy.

Overall, the benefit-risk profile of tucatinib based on the results of HER2CLIMB is favourable, and Tukysa represents a new treatment option for patients with advanced unresectable or metastatic HER2+ breast cancer, including those with brain metastases.