Seagen UK Ltd. today announced that the UK Medicines and Healthcare products Regulatory Agency (MHRA) has granted marketing authorisation in Great Britain for TUKYSA (tucatinib) in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least two prior anti-HER2 treatment regimens.

Tukysa is used with two other medicines, capecitabine and trastuzumab, and is used after at least 2 other treatments for HER2-positive cancer have already been tried.

AUSTRALIAN PRODUCT INFORMATION: TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Seattle Genetics, Inc. (Nasdaq:SGEN) today announced that Australian regulatory authorities have approved TUKYSA® (tucatinib) in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Seattle Genetics, Inc. (Nasdaq:SGEN) today announced that the Swiss Agency for Therapeutic Products (Swissmedic) has granted approval for TUKYSA™ (tucatinib) tablets in combination with trastuzumab and capecitabine, for the treatment of patients with metastatic HER2-positive breast cancer, who have previously received two or more anti-HER2 regimens in any setting, including trastuzumab, pertuzumab and trastuzumab-emtansine (T–DM1).

TUKYSA is a kinase inhibitor indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer.

Recommendation...The combination of tucatinib, and capecitabine and trastuzumab may be offered to patients with HER2-positive metastatic breast cancer who have brain metastases without symptomatic mass effect and whose disease has progressed on at least one previous HER2-directed therapy for metastatic disease.

The UK's National Institute for Health and Care Excellence on Friday recommended the National Health Service make Seagen's Tukysa (tucatinib) in combination with Genentech's Herceptin (trastuzumab) and capecitabine available for advanced, previously treated, HER2-positive breast cancer patients.

NON-SUPPORTIVE EVIDENCE: The UK's National Institute for Health and Care Excellence on Tuesday proposed that the National Health Service not provide tucatinib (Seagen's Tukysa) in combination with trastuzumab (Genentech's Herceptin) and capecitabine for previously treated, HER2-positive advanced breast cancer patients in England.

Invasive Breast Cancer: HER2-Positive Regimens...Tucatinib + trastuzumab + capecitabine

HER2-positive breast cancer...Recommendations...Second-line treatment...Tucatinib/capecitabine/trastuzumab or trastuzumab deruxtecan may be used in the second-line setting in selected patients with BMs

...Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology...

Median survival was 21.2 months, with 12- and 24-month OS rates of 84% and 50%, respectively. Median CNS-PFS was 11.3 months, with 12- and 24-month CNS-PFS rates of 44.9% at both time points….SRS in combination with tucatinib, capecitabine, and trastuzumab appears to be a safe and feasible treatment for HER2 + brain metastases.

Best response to TTC, evaluated by investigators in the 87/101 RECIST evaluable patients, was progressive disease, stable disease, partial response and complete response in 34%, 34%, 30% and 2% of patients respectively....In this large retrospective cohort, TTC shows significant efficacy for patients with HER2+ MBC previously exposed to T-DXd.

This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs.

At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively....With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer…Patients were randomized 2:1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine...the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

At a median follow-up of 29.6 months, median OS was 21.6 months vs 12.5 months in all patients with brain metastases (HR: 0.60; 95% CI: 0.44, 0.81), 21.4 months vs 11.8 months in patients with untreated/treated progressing brain metastases (HR: 0.52; 95% CI: 0.36, 0.77), and 21.6 months vs 16.4 months in patients with treated stable brain metastases (HR: 0.70; 95% CI: 0.42, 1.16). With 15.6 months of additional follow-up, the tucatinib-trastuzumab-capecitabine regimen resulted in a robust and durable prolongation of OS for all patients with HER2+ metastatic breast cancer and brain metastases. Additionally, this benefit was maintained in patients with untreated/treated progressing and treated stable brain metastases. Treatment with tucatinib continued to show clinically meaningful benefit in CNS-PFS consistent with the primary analysis.

With 15.6 months of additional follow-up, the tucatinib-trastuzumab-capecitabine regimen resulted in a robust and durable prolongation of OS for all patients with HER2+ metastatic breast cancer and brain metastases.

Eligible pts were adults with HER2+ metastatic breast cancer…In pts with LMD from HER2+ metastatic breast cancer who were treated with tucatinib, trastuzumab, and capecitabine, the median OS time was nearly 1 year. This is the first prospective evidence of clinical benefit with a systemic regimen for HER2+ LM.

...HER2CLIMB trial evaluating the addition of TUKYSA® (tucatinib) to trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer (MBC) with and without brain metastases....Median OS in the TUKYSA arm was 24.7 months (95% CI: 21.6, 28.9) compared to median OS of 19.2 months (95% CI: 16.4, 21.4) in the control arm (HR=0.73 [95% CI: 0.59-0.90]; p=0.004).

...Seagen Inc. (Nasdaq:SGEN) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion recommending the approval of TUKYSA® (tucatinib) in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least 2 prior anti-HER2 treatment regimens....The positive CHMP opinion is based on results of the pivotal trial HER2CLIMB...

All HER2+ MBC pts enrolled had a baseline brain MRI. Pts with BM were eligible and randomized 2:1 to receive tucatinib (TUC) or placebo, in combination with trastuzumab and capecitabine.291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm vs the control arm (HR: 0.32; P< 0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of overall death was reduced by 42% in the TUC arm (OS HR: 0.58; P=0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%) vs the control arm (20.0%). Median DOR-IC was 6.8 mo in the tucatinib arm vs 3.0 mo in the control arm. In pts with isolated brain progression who continued study therapy after local treatment (n=30), risk of second progression or death was reduced by 71% (HR: 0.29), and median time from randomization to second progression or death was 15.9 mo vs 9.7 mo, favoring the TUC arm.

Addition of TUC to T and C significantly improved PFS regardless of BM type, indicating delay of progression not only in the body but also in the brain.

Adding TUC to T and C significantly prolonged PFS and OS in heavily pretreated pts with HER2+ MBC, including pts with BM. If approved, tucatinib in combination with trastuzumab and capecitabine has the potential to become a new standard of care in pts who previously received 3 HER2-targeted agents.

All pts with HER2+ metastatic breast cancer (MBC) enrolled in HER2CLIMB...There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; 95% CI: 0.22, 0.48; P < 0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of death overall was reduced by 42% in the TUC arm (OS HR: 0.58; 95% CI: 0.40, 0.85; P = 0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%; 95% CI: 33.7, 61.2) vs the control arm (20.0%; 95% CI: 5.7, 43.7). Median DOR-IC was 6.8 mo (95% CI: 5.5, 16.4) vs 3.0 mo (95% CI: 3.0, 10.3).

In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo...

...HER2CLIMB trial, specifically focusing their investigation on the utility of the small-molecule oral tyrosine kinase inhibitor tucatinib in patients with brain-metastatic HER2-positive breast cancer. With regard to overall survival (OS), the results in the tucatinib arm (tucatinib plus the HER2 antibody trastuzumab and the cytotoxic chemotherapy drug capecitabine) were superior to those in the control arm (placebo plus trastuzumab and capecitabine), with median OS values of 18.1 months in the tucatinib group and 12.0 months in the control group. Importantly, the survival benefit of tucatinib was mostly seen in the 174 patients with active brain metastases, in whom the median OS was 20.7 months with tucatinib versus 11.6 months with placebo; in the 117 patients with stable brain metastases, the median OS was 15.7 months with tucatinib versus 13.6 months with placebo. However, tucatinib showed signs of central nervous system (CNS) activity in both groups, with CNS progression-free survival being 9.9 months with tucatinib versus 4.2 months with placebo among all patients, 9.5 months versus 4.1 months among patients with active brain metastases, and 13.9 months versus 5.6 months in patients with stable brain metastases.

Single-agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard-of-care trastuzumab/pertuzumab/docetaxel combination...

Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single-agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab...In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER; HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer.