A phase II study of trastuzumab monotherapy in pretreated patients with non-small cell lung cancers (NSCLCs) harboring HER2 alterations: HOT1303-B trial

Kinoshita, Ichiro; Goda, Tomohiro; Watanabe, Kana; Maemondo, Makoto; Oizumi, Satoshi; Amano, Toraji; Hatanaka, Yutaka; Matsuno, Yoshihiro; Nishihara, Hiroshi; Asahina, Hajime; Harada, Toshiyuki; Goto, Keiko; Isobe, Hiroshi; Nishimura, Masaharu; Dosaka‐Akita, Hirotoshi

doi:10.1093/annonc/mdy292.112

Cited by 21 publications

(17 citation statements)

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“… 41 In contrast, the only available phase II trial of trastuzumab monotherapy in H ER 2 -mutant refractory NSCLC included seven patients and failed to achieve objective responses although DCR and median PFS time were 70% and 5.2 months (95% CI, 1.4-6.3 months), respectively. 66 The previous results remain questionable in the absence of larger prospective randomized studies.…”

Section: Targeting Her2 In Lung Cancermentioning

confidence: 97%

“… 41 Ann Oncol , 2016 Ph II Single arm HOT1303-B trial 10 Median number of prior lines 3 (2-6) H ER 2 mutation ( n = 7) (4 A755_G776insYVMA, 1 G776>VC, 2 S310F) H ER 2 amplification/overexpression ( n = 3) (IHC3+ or IHC2+/DISH+) 0/15 (0) 11/15 (70) 5.2 (1.4-6.3) — — — — Kinoshita et al . 66 ESMO 2018 Trastuzumab–pertuzumab PhII Basket trial MyPathway ( NCT02091141 ) 14/30 Median number of prior lines 2.5 (0-9) H ER 2 mutation (exon 20 insertions, deletions in amino acids 755-759, and nonsynonymous amino acid substitutions) 3/14 (21) 6/13 (43) — — — — — Hainsworth et al . 70 JCO , 2018 16/30 H ER 2 amplification/overexpression (IHC3+, H ER 2/ CEP17 >2 by FISH, copy number >6/increased by NGS) 2/16 (13) 4/16 (25) — — AEs, adverse events; CBDCA, carboplatin; CDDP, cisplatin; CEP17, centromeric probe for chromosome 17; ChT, chemotherapy; CI, confidence interval; DISH, dual colour in situ hybridization; DCR, disease control rate; ECD, extracellular domain; FISH, fluorescence in situ hybridization; IHC, immunochemistry; LVEF, left ventricular ejection fraction; NR, not reached; ORR, objective response rate; OS, overall survival; Ph, phase; PFS, progression-free survival; TTF, time-to-treatment failure.…”

Section: Targeting Her2 In Lung Cancermentioning

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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Section: Targeting Her2 In Lung Cancermentioning

confidence: 97%

Section: Targeting Her2 In Lung Cancermentioning

confidence: 99%

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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“…Therefore, the definition of "HER2+ NSCLC" is insufficient, as it does not exhaustively distinguish the complexity of this gene alterations. Indeed, the failure of many clinical trials aimed at targeting HER2 may have been derived from considering these alterations as a single entity [127][128][129]. Conversely, the DESTINY-Lung01 trial, which distinguished between HER2 overexpression and HER2 mutation in the two different cohorts, is a good example of a successful trial.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

Rebuzzi

Zullo

Rossi

et al. 2021

IJMS

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In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal–epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.

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“…In contrast, trastuzumab showed no response in a phase II study of pre-treated NSCLC patients with HER2 alterations. 64 Ado-trastuzumab emtansine, also known as T-DM1, is a HER2-targeted antibody-toxin conjugate that is made up of trastuzumab and the potent cytotoxic agent DM1. 65 T-DM1 has a 3:4 chemotherapy drug-to-antibody ratio.…”

Section: Quality Assessment and Heterogeneitymentioning

confidence: 99%

Efficacy of targeted therapy in patients with HER2‐positive non‐small cell lung cancer: A systematic review and meta‐analysis

Zhuo²,

Wang

2021

Brit J Clinical Pharma

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Anti‐human epidermal growth factor receptor 2 (HER2) therapy is an effective treatment for HER2‐positive gastric and breast malignancies. However, the efficacy of HER2‐targeted therapy in non‐small cell lung cancer (NSCLC) patients with HER2 alterations remains controversial. We searched studies on HER2‐targeted therapy in NSCLC patients that reported objective response rate (ORR), disease control rate (DCR) and progressionfree survival (PFS) published from database inception to 30 May 2021. A total of 32 trials involving 958 patients were included. The ORRs of HER2‐TKIs targeted therapy, humanised monoclonal antibody, trastuzumab‐based treatment and antibody‐drug conjugate (ADC) (T‐DM1) were 22% (95% CI 11–31), 23% (95% CI 20–65), 26% (95% CI 14–39) and 16% (95% CI _6–37), while that of ADC (DS‐8201) was 60% (95% CI 35–85). The DCRs of these groups were 59% (95% CI 49–69), 39% (95% CI _9–88), 63% (95% CI 37–89), 31% (95% CI 4–58) and 87% (95% CI 62–112), respectively. In the subgroup analysis, numerically higher ORRs and DCRs were observed in the poziotinib (38%; 75%) and pyrotinib (35%; 83%) groups. The median PFSs of these groups were 5.51 months, 3.09 months, 4.61 months, 2.65 months and 12.04 months, respectively. HER2‐targeted therapy can be considered an acceptable treatment strategy for NSCLC patients with HER2 alterations. In particular, ADC (DS‐8201), pyrotinib and poziotinib demonstrated promising anti‐tumour activity in HER2‐positive NSCLC.

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A phase II study of trastuzumab monotherapy in pretreated patients with non-small cell lung cancers (NSCLCs) harboring HER2 alterations: HOT1303-B trial

Cited by 21 publications

References 0 publications

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

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

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

Efficacy of targeted therapy in patients with HER2‐positive non‐small cell lung cancer: A systematic review and meta‐analysis

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