Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head &amp; Neck 1): an open-label, randomised phase 3 trial

Machiels, Jean Pascal; Haddad, Robert I.; Fayette, Jérôme; Licitra, Lisa; Tahara, Makoto; Vermorken, Jan B.; Clément, Paul M.; Gauler, Thomas; Cupissol, Didier; Grau, Juan J.; Guigay, J.; Caponigro, Francesco; Castro, Gilberto de; Viana, Luciano de Souza; Keilholz, Ulrich; Campo, J.M. del; Cong, Xiuyu Julie; Ehrnrooth, Eva; Cohen, Ezra E.W.

doi:10.1016/s1470-2045(15)70124-5

Cited by 358 publications

(285 citation statements)

References 30 publications

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“…Afatinib activity has been seen in cetuximab refractory patients in clinical trials, suggesting a lack of cross-resistance in some instances (21,41). Similarly, our present study has shown that afatinib is effective for cetuximabresistant cell lines.…”

Section: Discussionsupporting

confidence: 82%

“…19,20). In addition, a recent phase III study showed the efficacy of afatinib in patients with recurrent or metastatic HNSCC after the failure of platinum-based therapy (21), and in a phase I study, one of 7 patients with esophageal cancer achieved a partial response with afatinib (22). In the present study, we tested the effects of HER inhibitors, including afatinib, in several ESCC and HNSCC cell lines in vitro and found two cell lines that were hypersensitive; one of these cell lines had an HER4 mutation with an unknown function.…”

Section: Introductionmentioning

confidence: 99%

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Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Nakamura

Togashi

Nakahara

et al. 2016

Molecular Cancer Therapeutics

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The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Nakamura

Togashi

Nakahara

et al. 2016

Molecular Cancer Therapeutics

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“…Actually just the addition of cetuximab to the combination of platinum and 5-Fluorouracil has improved OS and changed clinical practice in recent times. 84 And new treatments are currently on study (Table 2), some of them with promising results as afatinib 100 or cabacitaxel. 102 Although the cornerstone for laryngeal cancer eradication is to implement smoking cessation programs, survival progresses will be hopefully be seen in the future.…”

Section: Discussionmentioning

confidence: 99%

A genetic view of laryngeal cancer heterogeneity

2016

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During the recent decades significant improvements in the understanding of laryngeal molecular biology allowed a better characterization of the tumor. However, despite increased molecular knowledge and clinical efforts, survival of patients with laryngeal cancer remains the same as 30 years ago. Although this result may not make major conclusions as preservation approaches were not broadly used until the time of database collection, it seems to be clear that there is still window for improvement.

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“…Монотерапия новым инбигитором PD-1 рецепторов пембролизумабом дает выраженную противоопухолевую активность, которая превосходит по своей эффективности противоопухолевые препара-ты предыдущего поколения даже в группе предвари- [17]) N = 171 Table 3. Characteristics of patients included in the KEYNOTE-055 study (adapted from [17] тельно пролеченных пациентов с рефрактерными к стандартной химиотерапии рецидивными и метаста-тическими опухолевыми процессами [18,19]. Следует отметить, что существенных различий в группах боль-ных ВПЧ-положительным и ВПЧ-отрицательным ра-ком не выявлено, несмотря на большую частоту лим-фоидной инфильтрации опухоли и экспрессию PD-L1 ВПЧ-ассоциированного ПКР ОГШ в обоих исследо-ваниях (KEYNOTE 012 и KEYNOTE-055).…”

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New Opportunities for Immune Therapy in Patients With Disseminated Recurrent Squamous Cell Carcinoma of the Head and Neck

Мудунов¹,

Нариманов²,

Сафаров³

2017

Opuholi golovy šei

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Key words: head and neck tumors, squamous cell carcinoma, PD-1, immune therapy, nivolumab, pembrolizumabПлоскоклеточный рак (ПКР) органов головы и шеи (ОГШ) занимает 7-е место в структуре общей заболе-ваемости злокачественными опухолями в мире [1]. Пациенты, у которых диагностированы рецидивные опухоли или отдаленные метастазы, имеют наихудший прогноз при данном заболевании, что обусловлено ограниченными возможностями лечебного воздейст-вия [2, 3]. Основными препаратами, выступающими в качестве 1-й линии терапии, у таких пациентов, как правило, являются цетуксимаб, платиносодержащие производные и фторурацил, в то время как 2-я линия включает чаще всего таксаны и метотрексат [3]. Эф-фективность такого лечения остается ограниченной и позволяет добиться выраженного клинического эф-фекта (в виде полной или частичной регрессии опухоли) не чаще чем в 15 % случаев, при этом применяющиеся в настоящее время противоопухолевые препараты об-ладают достаточно серьезным профилем токсичности [3]. В связи с этим продолжается поиск более эффек-тивных и менее токсичных препаратов.Плоскоклеточный рак, не ассоциированный с ви-русом папилломы человека (ВПЧ), обладает высокой мутационной нагрузкой, чаще всего связанной с куре-нием табака, и крайне плохим прогнозом в отличие от ВПЧ-ассоциированного рака, у которого прогноз значительно лучше [4,5].У пациентов с плоскоклеточным раком ОГШ ча-сто наблюдаются мутации в генах, регулирующих иммунитет и воспалительную реакцию, в таких как HLA-A и -B, а также в nuclear factor-κB pathway (ядер-ный фактор транскрипции nf-κB) [4,6]. Нарушение регуляции этих генов связывают с увеличением лим-фоидной инфильтрации опухоли при плоскоклеточ-ном раке ОГШ почти в 40 % случаев, что в свою очередь открывает возможности для проведения им-мунотерапии [5].

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Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial

Cited by 358 publications

References 30 publications

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

A genetic view of laryngeal cancer heterogeneity

New Opportunities for Immune Therapy in Patients With Disseminated Recurrent Squamous Cell Carcinoma of the Head and Neck

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