OA04.05 Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Interim Results of DESTINY-Lung01

Nakagawa, Kazuhiko; Nagasaka, Misako; Felip, Enriqueta; Pacheco, Jose M.; Baik, Christina S.; Goto, Yasushi; Saltos, Andreas; Li, B.; Udagawa, Hibiki; Gadgeel, S.; Murakami, Haruyasu; Planchard, David; Bazhenova, Lyudmila; Paz‐Ares, Luis; Pérol, Maurice; Mazières, Julien; Barlési, Fabrice; Saxena, Kapil; Shiga, Ryota; Acharyya, Suddhasatta; Cheng, Yun; Shahidi, Javad; Jänne, Pasi A.; Smit, Egbert F.

doi:10.1016/j.jtho.2021.01.285

Cited by 57 publications

(37 citation statements)

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“…Already FDA approved for breast cancer, trastuzumab deruxtecan appears the most promising, with data from the HER2 mutated cohort showing a RR of 61.9% and a median PFS of 14 months with the median OS not reached (27). Preliminary results of the HER2 amplified cohort reported a modest RR of 24.5%, a median PFS of 5.4 months and a median OS of 11.3 months although it must be noted that the patients in this cohort were heavily pretreated with a median number of 3 prior lines of therapy (28). In the RAIN-701 study, tarloxotinib showed an ORR of 22% in NSCLC with a HER2 activating mutation (29).…”

Section: Discussionmentioning

confidence: 77%

The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer

Nagasaka

Singh

Baca

et al. 2022

Clinical Lung Cancer

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Discussionmentioning

confidence: 77%

The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer

Nagasaka

Singh

Baca

et al. 2022

Clinical Lung Cancer

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“…OS data were still immature (95% CI, 11.8 months-NR). 88,89 The DESTINY-Lung01 trial also included 49 patients with HER2-overexpressing NSCLC (cohort 1). Results were promising albeit less spectacular in comparison with cohort 2, with an ORR of 24.5% (95% CI, 13.3%-38.9%), a median DoR of 6 months (95% CI, 3.2 months-NR) and a median PFS of 5.4 months (95% CI, 2.8-7 months).…”

Section: Antibodyedrug Conjugates Against Her2mentioning

confidence: 99%

“…Responses did not differ according to HER2 IHC expression levels (ORR 20.0% versus 25.6% in IHC3þ and IHC2þ patients, respectively). 89 Regarding T-Dxd toxicity, gastrointestinal and haematological events were the most common AEs of any grade, with neutropenia being the most common grade !3 AE. In the phase II study, up to 52%-55% of AEs were of grade 3 or higher and 22%-24% led to treatment discontinuation.…”

Section: Antibodyedrug Conjugates Against Her2mentioning

confidence: 99%

“…In the phase II study, up to 52%-55% of AEs were of grade 3 or higher and 22%-24% led to treatment discontinuation. 88,89 Importantly, five cases of T-Dxd-related interstitial lung disease (ILD) were reported in the phase I basket trial. Three of these patients required hospitalization and one died of respiratory failure; of note, the latter patient had a history of ongoing dyspnoea and had initially undergone pneumonectomy.…”

Section: Antibodyedrug Conjugates Against Her2mentioning

confidence: 99%

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Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations

et al. 2021

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Non-small-cell lung cancer (NSCLC) harbouring HER2 alterations is now considered a distinct molecular subtype. The activation of HER2 in NSCLC occurs via three mechanisms, i.e. gene mutation (1%-4% of cases), gene amplification (2%-5%) and protein overexpression (2%-30%), with different prognostic and predictive outcomes. So far, non-selective tyrosine kinase inhibitors (TKIs) have shown a minor benefit in H ER 2 -mutant NSCLC patients with objective response rates (ORRs) ranging from 0% to 19%. Trastuzumab-based chemotherapy was not found to be superior to chemotherapy alone [median progression-free survival (PFS) 6.1 versus 7 months, respectively] and dual HER2 antibody blockade with trastuzumab and pertuzumab had limited efficacy (ORR 13%-21%). In contrast, novel more selective HER2 TKIs such as poziotinib and pyrotinib have shown a promising activity in H ER 2 -mutant pre-treated NSCLC patients, with response rates up to 38% and 44%, respectively. The most encouraging data come from phase II studies that evaluated the antibody–drug conjugates (ADCs) ado-trastuzumab–emtansine and trastuzumab–deruxtecan in patients with H ER 2 -mutant NSCLC, with response rates of 50% and 62%, respectively. These agents are bringing hope to the management of HER2-altered NSCLC. Moreover, a paradigm shift from monotherapies towards combinations of agents with distinct mechanisms of action, such as ADCs with irreversible TKIs or immune checkpoint inhibitors, is already taking place and will change the therapeutic landscape of HER2-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with HER2 molecular alterations.

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“…Despite the demonstrated tolerability, ILD remains a concerning and serious adverse event. 58 In a phase I dose-escalation study, 24 patients with breast, gastric, and gastroesophageal cancers were treated with different doses of T-DXd. Gastrointestinal and hematological events were reported.…”

Section: Phase I/ii Trialsmentioning

confidence: 99%

Spotlight on Trastuzumab Deruxtecan (DS-8201,T-DXd) for HER2 Mutation Positive Non-Small Cell Lung Cancer

Azar¹,

Alkassis²,

Fukui³

et al. 2021

LCTT

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Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene that, when mutated or overexpressed, plays an important role in oncogenesis. The landscape of HER2-positive breast cancer has changed dramatically over the past 2 decades with the FDA approval of a growing number of agents (antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates) targeting the HER2 receptor. HER2 inhibition has also been approved for HER2-positive gastric cancer. HER2 is amplified in 9% and mutated in 3% of lung cancer. Historically, HER2-targeted therapy for lung cancer with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate a survival benefit. Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate with a tetrapeptide linker, which delivers a topoisomerase I inhibitor with a drug-to-antibody ratio of 7~8. The potency of the active payload, as well as its significant bystander effect, resulted in significant anti-tumor activity. The DESTINY-Lung01 trial evaluated T-DXd in HER2-positive non-squamous non-small cell lung cancer (NSCLC) and reported a progression-free survival of 14 months in HER2-mutated NSCLC, earning its breakthrough designation by the FDA. In this review, we will discuss the structural characteristics, pharmacodynamics, and pharmacokinetics of T-DXd. We will also shed light on the preclinical and ongoing clinical trials of T-DXd along with future directions in the management of HER2 positive lung cancer.

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OA04.05 Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Interim Results of DESTINY-Lung01

Cited by 57 publications

References 0 publications

The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer

The Effects of HER2 Alterations in EGFR Mutant Non-small Cell Lung Cancer

Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations

Spotlight on Trastuzumab Deruxtecan (DS-8201,T-DXd) for HER2 Mutation Positive Non-Small Cell Lung Cancer

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