Continued overall survival (OS) benefit and tolerability of tucatinib in combination with trastuzumab and capecitabine, demonstrated in a final analysis of the HER2CLIMB study, augments data from the primary analysis and further supports the use of this combination in patients with previously treated HER2-positive metastatic breast cancer after progression on two HER2-targeted therapies. The benefit in OS was consistent across all prespecified subgroups, including patients with brain metastases. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. The final OS analysis data is published by Prof. Giuseppe Curigliano of the Division of Early Drug Development, Istituto Europeo di Oncologia, Milan, IRCCS, Division of Medical Oncology, University of Milano in Italy and colleagues on 22 December 2021 in the Annals of Oncology.
The pivotal HER2CLIMB study evaluated tucatinib compared with placebo, each in combination with trastuzumab and capecitabine, for HER2-positive metastatic breast cancer after progression on trastuzumab, pertuzumab, and T-DM1 in any setting. Patients with and without brain metastases were enrolled, including those with active (progressive and/or untreated) brain metastases.
In the primary analysis with median 14.0 months of follow-up in the total study population, HER2CLIMB met all primary and alpha-controlled secondary endpoints, including a 46% reduction in the risk of progression or death in the first 480 patients, 34% reduction in risk of death in the total study population, and 52% reduction in the risk of progression or death in patients with brain metastases. The benefit of tucatinib was observed across all prespecified subgroups. The addition of tucatinib to trastuzumab and capecitabine was well tolerated.
In the latest article published in the Annals of Oncology, HER2CLIMB investigators report final efficacy and safety outcomes after an additional 15.6 months of OS follow-up. HER2CLIMB is a randomised, double-blind, placebo-controlled study in patients with locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases. Patients were randomised 2:1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine.
After the primary analysis, the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, progression-free survival (PFS) by investigator assessment, and safety were carried out at approximately 2 years from the last patient randomised.
In total, 612 patients were enrolled in the study. 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. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population.
Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death 0.57, 95% CI 0.47-0.70; p < 0.00001) and PFS at 1 year was 29% and 14%, respectively.
The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events.
The authors commented that with an additional 15.6 months of follow-up, tucatinib, added to trastuzumab and capecitabine, continued to demonstrate a significant improvement in OS, with a median survival benefit of 5.5 months. The median OS in patients treated with tucatinib combination was 24.7 months compared with 19.2 months for those treated in the placebo combination group.
This final analysis showed that treatment with tucatinib combination continued to provide a robust survival benefit in a HER2-positive metastatic breast cancer population that included patients with and without brain metastases whose disease had been previously treated with trastuzumab, pertuzumab, and T-DM1 in any treatment setting. This is the first treatment combination to show a clinically meaningful OS benefit for patients in this disease setting. In addition, the benefit across all prespecified subgroups was consistent with the primary analysis and was maintained with additional follow-up.
Tucatinib is approved in combination with trastuzumab and capecitabine in multiple regions of the world for patients with HER2-positive metastatic breast cancer, including those with brain metastases, whose cancers have progressed on at least one prior HER2-directed treatment in the metastatic setting in the United States of America (USA) or two prior HER2-directed treatment regimens in any setting in the European Union.
This work was supported by Seagen Inc. (Bothell, WA, USA), the manufacturer of tucatinib and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Annals of Oncology; Published online 22 December 2021. DOI: https://doi.org/10.1016/j.annonc.2021.12.005