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. 2024 Apr 1;7(4):e244435.
doi: 10.1001/jamanetworkopen.2024.4435.

Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer

Jean-Sebastien Frenel  1 , Jean Zeghondy  2 , Catherine Guérin-Charbonnel  3 , Audrey Mailliez  4 , Elsa Volant  1 , François Poumeaud  5 , Anne Patsouris  6 , Monica Arnedos  7 , Caroline Bailleux  8 , Julie Cabal  9 , Loick Galland  10 , Alexandre de Nonneville  11 , Séverine Guiu  12 , Florence Dalenc  5 , Barbara Pistilli  2 , Thomas Bachelot  13 , Jean-Yves Pierga  14 , Fanny Le Du  9 , François Bocquet  15 , Louis Larrouquere  13 , Delphine Loirat  14
Affiliations

Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer

Jean-Sebastien Frenel et al. JAMA Netw Open. .

Abstract

Importance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Professor Frenel reported receiving grant funding from Seagen Inc during the conduct of the study; personal fees from Roche Genentech; and personal fees and nonfinancial support from Seagen Inc, Novartis AG, Pfizer Inc, Eli Lilly and Company, GSK, Clovis Oncology, AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, MSD, Pierre Fabre, and Amgen Inc outside the submitted work. Dr Mailliez reported receiving consulting or advisory fees from Daichii Sankyo, Pfizer Inc, and Seagen Inc and receiving funding for travel, accommodations, and expenses from AstraZeneca, Eli Lilly and Company, and Pierre Fabre. Dr Patsouris reported receiving funding for travel, accommodations, and expenses from AstraZeneca, Eisai, Novartis AG, Pfizer Inc, and Roche. Dr Arnedos reported receiving funding from Daiichi Sankyo and Pfizer Inc; consulting or advisory fees from Daiichi Sankyo, AstraZeneca, Gilead Sciences Inc, Menarini Group, Pfizer Inc, and Eli Lilly and Company; and funding for travel, accommodations, and expenses from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Novartis AG, and Pfizer Inc outside the submitted work. Dr Bailleux reported receiving consulting or advisory fees from Seagen Inc and AstraZeneca and nonfinancial support from AstraZeneca outside the submitted work. Dr de Nonneville reported receiving consulting or advisory fees from Daiichi Sankyo, Gilead Sciences Inc, Eli Lilly and Company, MSD, Novartis AG, Pfizer Inc, and Seagen Inc; receiving research funding to institution from Eli Lilly and Company and Pfizer Inc; and receiving funding for travel, accommodations, and expenses from AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, MSD, Novartis AG, and Pfizer Inc. Dr Guiu reported receiving consulting or advisory fees from AstraZeneca and funding for travel, accommodations, and expenses from Novartis AG. Dr Dalenc reported receiving consulting or advisory fees from AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, Novartis AG, Pfizer Inc, and Seagen Inc and funding for travel, accommodations, and expenses from Gilead Sciences and Pfizer Inc. Dr Pistilli reported receiving consulting or advisory fees from AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics Inc, Novartis AG, Pierre Fabre, and Puma Biotechnology; receiving research funding to institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, Merus NV, MSD, Pfizer Inc, and Puma Biotechnology; and receiving funding for travel, accommodations, and expenses from AstraZeneca, Daiichi Sankyo, MSD Oncology, Novartis AG, Pfizer Inc, and Pierre Fabre outside the submitted work. Dr Bachelot reported receiving consulting or advisory fees from Daiichi Sankyo/AstraZeneca, Eli Lilly and Company, Novartis AG, Pfizer Inc, Roche, and Seagen Inc; receiving research funding to institution from AstraZeneca, Daiichi Sankyo/AstraZeneca, Novartis AG, Pfizer Inc, Roche, and Seagen Inc; and funding for travel, accommodations, and expenses from AstraZeneca, Pfizer Inc, and Roche outside the submitted work. Professor Pierga reported receiving consulting or advisory fees from AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, Menarini Group, Novartis AG, Pfizer Inc, Menarini Stemline, Roche, Exact Sciences Corp, Eli Lilly and Company, MSD, and Eisai and funding for travel, accommodations, and expenses from AstraZeneca, Novartis AG, Pfizer Inc, and Gilead Sciences Inc outside the submitted work. Dr Le Du reported receiving consulting or advisory fees from Daiichi Sanyko/AstraZeneca, Eli Lilly and Company, Seagen Inc, Novartis AG, Pfizer Inc, Roche, Gilead Sciences Inc, Sandoz Group AG, and Myriad Genetics Inc, and travel expenses from Daiichi Sanyko/AstraZeneca, Eli Lilly and Company, Seagen Inc, Novartis AG, Pfizer Inc, and Gilead Sciences Inc during the conduct of the study. Dr Loirat reported receiving honoraria from AstraZeneca, Gilead Sciences Inc, Eli Lilly and Company, and MSD; receiving consulting or advisory fees from 4D Pharma, AstraZeneca, Gilead Sciences Inc, Immunomedics, Eli Lilly and Company, MSD Oncology, Novartis AG, Pfizer Inc, and Roche; and funding for travel, accommodations, and expenses from AstraZeneca, Gilead Sciences Inc, MSD, Pfizer Inc, and Roche. No other disclosures were reported.

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