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Outcomes of Tucatinib Combination Treatment After Trastuzumab Deruxtecan Therapy in Patients With ERBB2-Positive Metastatic Breast Cancer
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC).
OBJECTIVE
To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022.
EXPOSURE
Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose.
MAIN OUTCOMES AND MEASURES
Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR).
RESULTS
A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months.
CONCLUSIONS AND RELEVANCE
In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.
Additional Info
Disclosure statements are available on the authors' profiles:
Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer
JAMA Netw Open 2024 Apr 01;7(4)e244435, JS Frenel, J Zeghondy, C Guérin-Charbonnel, A Mailliez, E Volant, F Poumeaud, A Patsouris, M Arnedos, C Bailleux, J Cabal, L Galland, A de Nonneville, S Guiu, F Dalenc, B Pistilli, T Bachelot, JY Pierga, F Le Du, F Bocquet, L Larrouquere, D LoiratFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2+), conferring a particularly aggressive subtype of the disease with an increased patient risk of developing systemic and brain metastases. The advent of trastuzumab and, more recently, several other HER2-targeting novel therapies has resulted in significant improvements in disease prognosis, making the diagnosis a double-edged sword.
The current standard first-line therapy for patients with HER2+ metastatic breast cancer involves a taxane in combination with trastuzumab and pertuzumab. Based on the documented overall survival benefit and unprecedented median progression-free survival duration of 28 months demonstrated in the DESTINY-Breast03 trial, trastuzumab deruxtecan (T-DXd) should be used preferentially in the second-line setting. The only caveat is for patients who have a significant central nervous system burden, in which case the tucatinib, trastuzumab, and capecitabine regimen (HER2CLIMB) could be considered. If the previously referenced HER2CLIMB regimen was not utilized in the second-line setting, given its documented overall survival benefit, it would most commonly be used in the third-line setting post T-DXd therapy. Although patients in the HER2CLIMB trial were previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, they had not received T-DXd. This creates a data void, given the current treatment algorithm detailed above.
Therefore, the current cohort study of 101 patients with HER2+ metastatic breast cancer treated in 12 cancer centers in France provides results on the evaluation of the efficacy of the HER2CLIMB regimen post T-DXd therapy using the largest dataset to date. Reassuringly, the triple-drug regimen was shown to provide a clinically significant tumor response and progression-free survival after prior exposure to T-DXd. The treatment landscape for the disease is quickly evolving as new agents and treatment combinations are under development. Prospective studies that will clarify the optimal sequencing of therapies will be important going forward.