Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors

Yap, Timothy A.; Vidal, Laura; Adam, Jan; Stephens, Peter; Spicer, James; Shaw, Heather; J, Ang; Temple, Graham; Bell, Sarah Beth; Shahidi, Mehdi; Uttenreuther-Fischer, Martina; Stopfer, Peter; Futreal, Andrew; Calvert, Hilary; Bono, Johann S. de; Plummer, Ruth

doi:10.1200/jco.2009.26.7278

Cited by 321 publications

(228 citation statements)

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“…However, these drugs are not active against the gatekeeper T315I mutation within ABL (31). Similarly in EGFRmutant lung cancer, second-generation, irreversible EGFR inhibitors are being explored to treat cancers that develop resistance via the gatekeeper T790M mutation (22,32). EML4-ALK-positive NSCLC represents another tyrosine kinasedriven cancer that is highly responsive to TKI therapy.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK

Katayama

Khan

Benes

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

486

420

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The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK–positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μM) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVP-TAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations.

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Section: Discussionmentioning

confidence: 99%

Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK

Katayama

Khan

Benes

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

486

420

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“…Дерматологические НЯ, такие как папуло-пустулезная (угревая) сыпь, зуд, сухость/трещины кожи, алопеция, гипертрихоз и паронихия, описывались у онкологических больных, получавших ИТК-EGFR [29]. В клинических иссле-дованиях ИТК-EGFR III фазы у 54-89% пациентов наблю-дались кожные НЯ любой степени и 0-16,2% -НЯ ≥ 3 степени [29][30][31][32][33][34][35][36][37][38][39][40][41]. Критерии NCI-CTCAE являются стандар-том классификации и методом оценки степени тяжести, широко используемым всем онкологическим сообществом при описании НЯ в клинических исследованиях терапии рака.…”

Section: дерматологические нежелательные явленияunclassified

Algorithms for Management of Patients With Adverse Events on Therapy With Tyrosine Kinase Inhibitors Egfr

Сакаева¹

2017

Med. sov.

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С емейство рецепторов ErbB является одной из наиболее широко изученных систем передачи сигналов [1]. Семейство ErbB включает четыре мембранно-связанных структурно родственных рецепто-ра тирозинкиназы: рецептор EGF (EGFR; также известен как ErbB1), HER2 (ErbB2), ErbB3 и ErbB4 [2]. Путь ErbB является одной из наиболее широко изученных систем передачи сигналов, вовлеченных в функционирование нормальных клеток, и при некоторых типах рака [1]. Нарушение регуляции активности рецепторов семейства ErbB и нисходящих сигнальных путей связано с развити-ем некоторых опухолей у человека.Механизм активации передачи сигналов ErbB зависит от лиганд-индуцированной стабильности гомо-или гете-родимеров, образованных различными тирозинкиназами рецепторов семейства ErbB [3]. Рецепторы семейства ErbB являются клинически доказанными мишенями для новых противоопухолевых препаратов [4][5][6][7].Ингибиторы EGFR показаны для лечения колорек-тального рака (панитумумаб, цетуксимаб), немелкокле-точного рака легкого (гефитиниб, эрлотиниб, афатиниб), плоскоклеточного рака головы и шеи (цетуксимаб), рака поджелудочной железы (эрлотиниб).В отличие от цитотоксической химиотерапии, лечение ингибиторами EGFR сопровождается минимальными неспеци фическими и гематологическими побочными эффектами.Активирующие мутации гена рецептора EGFR явля-ются наиболее значимыми предикторами ответа на ингибиторы тирозинкиназы EGFR (ИТК-EGFR) гефити- Ключевые слова: местнораспространенный и метастатический немелкоклеточный рак легкого, ингибиторы тирозин-киназы EGFR, терапия, нежелательные явления. D.D. SAKAEVA, MD, Prof., Republican Oncologic Dispensary of the Ministry of Health of the Republic of Bashkortostan, Ufa ALGORITHMS FOR MANAGEMENT OF PATIENTS WITH ADVERSE EVENTS ON THERAPY WITH TYROSINE KINASE INHIBITORS EGFRThe tyrosine kinase inhibitors (TKIs) of the epidermal receptor growth factor (EGFR) such as gefitinib, erlotinib and afatinib, are the standard first-line therapy in locally advanced and metastatic non-small cell lung cancer (NSCLC) with frequent mutations of the EGFR gene. These drugs are more effective from the point of view of frequency response (FR) and survival without progression (SWP), less toxic and better tolerated than the standard two-component chemotherapy based on platinum drugs. The most frequent adverse events (AE) are gastrointestinal (GI) (diarrhea and stomatitis/mucositis) and dermatological (rash, dry skin and paronychia). They are usually mild, but in some cases symptoms can be moderate and more severity and have a negative impact on quality of life (QOL) of the patient and can require dose adjustment or discontinuation of treatment. Management of AEs, including preventive measures, supportive therapy, temporary cancellation and a reduction in the dose of the drug is important. Recommendations for the prevention and treatment of dermatological toxicity (rash, dry skin and paronychia) and toxicity for the gastrointestinal tract (diarrhoea, stomatitis and mucositis) related to therapy TKI-EGFR are developed. These guidelines descri...

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“…Currently being developed are second-generation irreversible EGFR inhibitors, which inhibit EGFR kinase activity even when the T790M mutation is present. Neratinib (HKI-272) (Li, Shimamura et al 2007;Wong, Fracasso et al 2009;Sequist, Besse et al 2010) and afatinib (BIBW 2992) (Eskens, Mom et al 2008;Li, Ambrogio et al 2008;Yap, Vidal et al 2010) are dual inhibitors against EGFR and HER2, and PF-00299804 is a multi-inhibitor against EGFR, ERBB2, and ERBB4 ). For MET gene amplification, the MET inhibitor PHA-665752 has been developed .…”

Section: Activating Mutations At Egfrmentioning

confidence: 99%

Activating Mutations and Targeted Therapy in Cancer

Tuna¹,

Amos²

2012

Mutations in Human Genetic Disease

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Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors

Abstract: Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.

Cited by 321 publications

References 31 publications

Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK

Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK

Algorithms for Management of Patients With Adverse Events on Therapy With Tyrosine Kinase Inhibitors Egfr

Activating Mutations and Targeted Therapy in Cancer

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