Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

Modi, Shanu; Saura, Cristina; Yamashita, Toshinari; Park, Yeon Hee; Kim, Sung‐Bae; Tamura, Kenji; Varga, Andrea; Iwata, Hiroji; Ito, Yoshiaki; Tsurutani, Junji; Sohn, Joohyuk; Denduluri, Neelima; Perrin, Christophe; Aogi, Kenjiro; Tokunaga, Eriko; Im, Seock‐Ah; Lee, Keun Seok; Hurvitz, Sara A.; Cortés, Javier; Lee, Caleb; Chen, Shuquan; Zhang, Lin; Shahidi, Javad; Yver, Antoine; Krop, Ian E.

doi:10.1056/nejmoa1914510

Cited by 1,418 publications

(1,475 citation statements)

References 26 publications

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“…97 A phase II single-arm study evaluated fam-trastuzumab deruxtecan-nxki, a HER2 antibody conjugated with a topoisomerase I inhibitor, in adults (n5184) with pathologically documented HER2-positive metastatic breast cancer who had received multiple previous treatments including treatment with T-DM1. 98 After a median duration of follow-up of 11.1 months (range 0.7-19.9), the median response duration with fam-trastuzumab deruxtecan-nxki was 14.8 months (95% CI, 13.8-16.9), and the median PFS was 16.4 months (95% CI, 12.7-not reached). 98 Most commonly reported adverse events (grade 3 or higher) were a decreased neutrophil count (20.7%), anemia (in 8.7%), nausea (in 7.6%), and fatigue (6%).…”

Section: Other Regimens For Stage Iv/recurrent Her2-positive Breast Cmentioning

confidence: 96%

“…98 After a median duration of follow-up of 11.1 months (range 0.7-19.9), the median response duration with fam-trastuzumab deruxtecan-nxki was 14.8 months (95% CI, 13.8-16.9), and the median PFS was 16.4 months (95% CI, 12.7-not reached). 98 Most commonly reported adverse events (grade 3 or higher) were a decreased neutrophil count (20.7%), anemia (in 8.7%), nausea (in 7.6%), and fatigue (6%). 98 Interstitial lung disease was reported in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).…”

Section: Other Regimens For Stage Iv/recurrent Her2-positive Breast Cmentioning

confidence: 96%

“…98 Most commonly reported adverse events (grade 3 or higher) were a decreased neutrophil count (20.7%), anemia (in 8.7%), nausea (in 7.6%), and fatigue (6%). 98 Interstitial lung disease was reported in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). Based on this study and the approval from the US FDA, the NCCN panel has included this as an option for HER-2 positive metastatic disease noting that it is indicated in patients after 2 or more lines of prior HER2-targeted therapy regimens in the metastatic setting and contraindicated for those with a history of or active interstitial lung disease.…”

Section: Other Regimens For Stage Iv/recurrent Her2-positive Breast Cmentioning

confidence: 97%

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Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology

Gradishar

Anderson

Abraham

et al. 2020

Journal of the National Comprehensive Cancer Network

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Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

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Section: Other Regimens For Stage Iv/recurrent Her2-positive Breast Cmentioning

confidence: 96%

Section: Other Regimens For Stage Iv/recurrent Her2-positive Breast Cmentioning

confidence: 96%

Section: Other Regimens For Stage Iv/recurrent Her2-positive Breast Cmentioning

confidence: 97%

See 1 more Smart Citation

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology

Gradishar

Anderson

Abraham

et al. 2020

Journal of the National Comprehensive Cancer Network

1,036

602

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“…The ORR and DCR were 43% and 91%, respectively, for patients, who underwent multiple lines of standard therapy. A phase II study for heavily pretreated patients with HER2-positive breast cancer revealed promising efficacy for trastuzumab deruxtecan at a dose of 5.4 mg/kg, with an ORR and a DCR of 60.9% and 97.3%, respectively [60]. The high antitumor efficacy was further translated into prolongation of survival, with a median PFS of 16.4 months (95% CI of 12.7 months-not reached).…”

Section: Trastuzumab Deruxtecan (Ds-8201a)mentioning

confidence: 99%

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Mitani

Kawakami

2020

Cancers

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Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies. basis of these results, trastuzumab was approved for AGC with a high HER2 expression level, and trastuzumab-containing regimens are now a standard option for the first-line treatment of such patients, who accounted for 7% to 17% of all individuals with gastric cancer [3-5]. Derivatives of the ToGA Regimen in the First-Line SettingThe ToGA trial adopted a regimen of cisplatin combined with either 5-fluorouracil (5-FU) or capecitabine, whereas subsequent prospective studies found similar treatment outcomes with regimens containing oxaliplatin or tegafur-gimeracil-oteracil (S-1). In a single-arm, nonrandomized phase II trial (HER2-based strategy in stomach cancer (HERBIS)-1) performed in Japan [6], trastuzumab in combination with S-1 plus cisplatin yielded a confirmed ORR of 68%, with a median OS and a median PFS of 16.0 and 7.8 months, respectively, in HER2-positive AGC patients with measurable lesions, with these results being similar to those of the ToGA trial [2]. Similar efficacy was also apparent in AGC patients without measurable lesions (HERBIS-1B study) [7]. Three phase II studies that assessed the combination of trastuzumab with capecitabine plus oxaliplatin reported a median OS, a median PFS, and an ORR of 13.8 to 21.0 months, 7.1 to 9.8 months, and 46.7% to 67.3%, respectively [8][9][10]. Trastuzumab in combination with S-1 plus oxaliplatin was also shown to provide a similar treatment outcome in a phase II study, with a median OS, a median PFS, and an ORR of 18.1 months, 8.8 months, and 70.7%, respectively [11]. A meta-analysis of data from these trials revealed that S-1 or oxaliplatin can substitute effectively for capecitabine or 5-FU or for cisplatin, respectively [12].Immune checkpoint inhibitors such as antibodies to programmed cell death-1 (PD-1) have recently revolutionized treatment strategies for advanced cancer. Given that trastuzumab was found to stimulate T cell responses [13], the combination of trastuzumab-containing regimens with antibodies to PD-1 is receiving attention. A phase II study including 37 patients with HER2-positive AGC treated in the first-line setting with capecitabine, oxaliplatin, and trastuzumab in combination with the anti-PD-1 antibody pembrolizumab reported an ORR of 83%, with a median PFS of 11.4 months and a median ...

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“…Due to its membrane permeable nature, duocarmycin also reaches neighboring cells, a process known as bystander killing effect [19]. SYD985, and other second generation ADCs targeting HER2, are being tested in the clinic with promising results [20,21].…”

Section: Introductionmentioning

confidence: 99%

The Second Generation Antibody-Drug Conjugate SYD985 Overcomes Resistances to T-DM1

Nadal-Serrano

Morancho

Escrivá-de-Romaní

et al. 2020

Cancers

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Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer. T-DM1 consists of trastuzumab covalently linked to the cytotoxic maytansinoid DM1 via a non-cleavable linker. Despite its efficacy, primary or acquired resistance frequently develops, particularly in advanced stages of the disease. Second generation ADCs targeting HER2 are meant to supersede T-DM1 by using a cleavable linker and a more potent payload with a different mechanism of action. To determine the effect of one of these novel ADCs, SYD985, on tumors resistant to T-DM1, we developed several patient-derived models of resistance to T-DM1. Characterization of these models showed that previously described mechanisms-HER2 downmodulation, impairment of lysosomal function and upregulation of drug efflux pumps-account for the resistances observed, arguing that mechanisms of resistance to T-DM1 are limited, and most of them have already been described. Importantly, SYD985 was effective in these models, showing that the resistance to first generation ADCs can be overcome with an improved design.

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Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

Cited by 1,418 publications

References 26 publications

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

The Second Generation Antibody-Drug Conjugate SYD985 Overcomes Resistances to T-DM1

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