Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer
Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A Hurvitz, Javier Cortes, Caleb Lee, Shuquan Chen, Lin Zhang, Javad Shahidi, Antoine Yver, Ian Krop, DESTINY-Breast01 Investigators, Hans Wildiers, Jean-Luc Canon, Guy Jerusalem, Wim W Wynendaele, Jill Wagemans, Luis Teixeira, William Jacot, Marjorie Baciuchka-Palmaro, You Benoit, Fabrice Andre, Christophe Perrin, Claire Jamet, Elsa Curtit, Julien Grenier, Marina Cazzaniga, Luca Gianni, Giuseppe Curigliano, Giulia Bianchi, Toru Mukohara, Kenji Tamura, Yoshinori Ito, Hiroji Iwata, Tsutomu Iwasa, Yasuaki Sagara, Toshimi Takano, Toshinari Yamashita, Kenjiro Aogi, Eriko Tokunaga, Naoki Hayashi, Seock-Ah Im, Yeon Hee Park, Jee Hyun Kim, Sung-Bae Kim, Joo Hyuk Sohn, Keun Seok Lee, Kyong Hwa Park, Yee Soo Chae, Manuel Ruiz-Borrego, Xavier Gonzalez Farre, Ignacio Delgado Mingorance, Jose Manuel Perez Garcia, Cristina Saura, Maria Fernandez Abad, Silvia Vazquez, Joaquin Gavila Gregori, Srinivisan Madhusudan, Timothy Crook, Peter Schmid, Peter Hall, Rebecca Roylance, Grace Wang, Ian Krop, Reshma Mahtani, Shanu Modi, Haeseong Park, Jane Raymond, Charles Redfern, Rashmi Murthy, Omkar Marathe, Musaberk Goksel, Amir Abdul Rasheed, Haythem Yousif Ali, David Chu, Jami Fukui, Adam Brufsky, Mahmoud Charif, Julie Taguchi, Donald Richards, Rachel Swart, Cynthia Osborne, Stephen Dyar, Sara Hurvitz, Vasileios Assikis, Hope Rugo, Neelima Denduluri, Marc Matrana, Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A Hurvitz, Javier Cortes, Caleb Lee, Shuquan Chen, Lin Zhang, Javad Shahidi, Antoine Yver, Ian Krop, DESTINY-Breast01 Investigators, Hans Wildiers, Jean-Luc Canon, Guy Jerusalem, Wim W Wynendaele, Jill Wagemans, Luis Teixeira, William Jacot, Marjorie Baciuchka-Palmaro, You Benoit, Fabrice Andre, Christophe Perrin, Claire Jamet, Elsa Curtit, Julien Grenier, Marina Cazzaniga, Luca Gianni, Giuseppe Curigliano, Giulia Bianchi, Toru Mukohara, Kenji Tamura, Yoshinori Ito, Hiroji Iwata, Tsutomu Iwasa, Yasuaki Sagara, Toshimi Takano, Toshinari Yamashita, Kenjiro Aogi, Eriko Tokunaga, Naoki Hayashi, Seock-Ah Im, Yeon Hee Park, Jee Hyun Kim, Sung-Bae Kim, Joo Hyuk Sohn, Keun Seok Lee, Kyong Hwa Park, Yee Soo Chae, Manuel Ruiz-Borrego, Xavier Gonzalez Farre, Ignacio Delgado Mingorance, Jose Manuel Perez Garcia, Cristina Saura, Maria Fernandez Abad, Silvia Vazquez, Joaquin Gavila Gregori, Srinivisan Madhusudan, Timothy Crook, Peter Schmid, Peter Hall, Rebecca Roylance, Grace Wang, Ian Krop, Reshma Mahtani, Shanu Modi, Haeseong Park, Jane Raymond, Charles Redfern, Rashmi Murthy, Omkar Marathe, Musaberk Goksel, Amir Abdul Rasheed, Haythem Yousif Ali, David Chu, Jami Fukui, Adam Brufsky, Mahmoud Charif, Julie Taguchi, Donald Richards, Rachel Swart, Cynthia Osborne, Stephen Dyar, Sara Hurvitz, Vasileios Assikis, Hope Rugo, Neelima Denduluri, Marc Matrana
Abstract
Background: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
Methods: In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.
Results: Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).
Conclusions: Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).
Copyright © 2019 Massachusetts Medical Society.
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Source: PubMed