Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer

Romanidou, Ourania; Landi, Lorenza; Cappuzzo, Federico; Califano, Raffaele

doi:10.1177/1758834016631531

Cited by 28 publications

(31 citation statements)

References 82 publications

(186 reference statements)

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“…It has been reported to occur mainly via two methods. The first includes secondary mutations of the driver oncogene, and the second is identified as the activation of bypass signal pathways other than the EGFR pathway [5,7,8]. The T790M gatekeeper point mutation at exon 20 is reported to be the most frequently observed (accounting for approximately 50%-60% of all causes) secondary mutation of the driver oncogene [8,9].…”

Section: Egfr-tki Resistance and Approaches To Over-coming The Resistmentioning

confidence: 99%

“…While deciding on treatment options for a patient progressed during EGFR-TKI treatment, we need to identify the type of progression [5,7]. In this manner, two types of progression have been described: oligoprogression and systemic progression.…”

Section: Approaches To Overcoming Egfr-tki Resistancementioning

confidence: 99%

“…Acquired resistance refers to disease progression after response to EGFR-TKI treatment [5,6]. It has been reported to occur mainly via two methods.…”

Section: Egfr-tki Resistance and Approaches To Over-coming The Resistmentioning

confidence: 99%

“…The T790M gatekeeper point mutation at exon 20 is reported to be the most frequently observed (accounting for approximately 50%-60% of all causes) secondary mutation of the driver oncogene [8,9]. As for the activation of other signaling pathways that continue the carcinogenesis process by bypassing the EGFR pathway, identified primary resistance mechanisms include the activation of downstream signaling pathways such as BRAF (1%) or PIK3CA (2%) [10]; activation of parallel signaling pathways such as c-MET (5%), HER-2 (8%-13%), and FGFR [11,12]; epithelial-mesenchymal transition (6%) or histological transformation manifesting as a recourse to the small-cell type [13]; and clonal heterogeneity [5,7,14,15]. Since acquired resistance mechanisms present such a broad range, a re-biopsy during the progression stage is of key importance to reveal resistance mechanisms (Table 2) [5,16].…”

Section: Egfr-tki Resistance and Approaches To Over-coming The Resistmentioning

confidence: 99%

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Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non- Small-Cell Lung Cancer

Kazaz

Öztop

2017

Turk Thorac J

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Systemic treatment is the basic treatment approach to advanced-stage non-small-cell lung cancer (NSCLC), and chemotherapy and targeted treatments are commonly employed in these patients. Recently, positive results achieved with immunotherapy have led to a growing number of treatment options and prolonged survival time. Today, specific tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and the TKI crizotinib, which targets anaplastic lymphoma kinase gene rearrangement, have become the standard treatment among targeted therapies for patients with sensitive molecular anomalies. However, resistance develops against all these agents after a while. Numerous genetic mutations, T790M+ in particular, have been identified as resistance mechanisms against EGFR-TKIs, and researchers are developing specific inhibitors against them. Among those inhibitors, third-generation EGFR-TKIs such as osimertinib and rociletinib have gained prominence due to their high level of effectiveness and low toxicity profile. Besides, systemic chemotherapy and immunotherapy are proper alternatives. A second biopsy during the progression stage and better clarification of the mechanisms causing secondary resistance will enable more successful treatments in the future. KEYWORDS:Epidermal growth factor receptor, tyrosine kinase inhibitors, resistance, non-small-cell lung cancer INTRODUCTIONLung cancer is still the primary cause of cancer-related death for both sexes worldwide, causing approximately 1.4 million deaths every year [1]. Non-small-cell lung cancer (NSCLC) cases comprise approximately 80%-85% of all lung cancers. More than half of the NSCLC cases are advanced-stage at the time of diagnosis, and those patients are characterized by poor prognosis. Systemic chemotherapy has long been employed as the primary treatment approach for advanced-stage NSCLC. Despite a series of advances in chemotherapy and the application of histology-based approaches in the course of time, median survival time does not exceed 1 year [2]. On the other hand, recent discoveries of somatic mutations in NSCLC and the employment of specific inhibitors against them have led to significant changes in the treatment of advanced-stage NSCLC. Currently, there are two key oncogenic molecular anomalies reflected in routine practice: epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase gene rearrangement.Epidermal growth factor receptor mutations are observed in approximately 10% of the whole patient group, whereas this rate may go up to 40% among Asians, non-smokers, and in patients who have adenocarcinoma histology. Deletion at exon 19 and point mutation at exon 21 (L858R) are the most common EGFR mutations [3]. The presence of these mutations indicates sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of erlotinib and gefitinib (first-generation TKIs) and afatinib (second-generation TKIs) in first-, second-, a...

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Section: Egfr-tki Resistance and Approaches To Over-coming The Resistmentioning

confidence: 99%

Section: Approaches To Overcoming Egfr-tki Resistancementioning

confidence: 99%

“…Acquired resistance refers to disease progression after response to EGFR-TKI treatment [5,6]. It has been reported to occur mainly via two methods.…”

Section: Egfr-tki Resistance and Approaches To Over-coming The Resistmentioning

confidence: 99%

Section: Egfr-tki Resistance and Approaches To Over-coming The Resistmentioning

confidence: 99%

See 2 more Smart Citations

Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non- Small-Cell Lung Cancer

Kazaz

Öztop

2017

Turk Thorac J

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“…3,24 In this sense, two types of progression have been described: oligoprogression and systemic progression. In oligoprogression, the primary tumor is under control, the disease progresses slowly and includes a limited number of intracranial or extracranial asymptomatic metastases.…”

Section: Influence Of the Progression Type On The Clinical Decisionmentioning

confidence: 99%

Treatment After Crizotinib Resistance in ALK+ Non-Small-Cell Lung Cancer

Kazaz¹

2017

UHOD

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Systemic chemotherapy, genotype-based targeted therapies and immunotherapy are widely used in the treatment of advanced nonsmall-cell lung cancer (NSCLC). Among the targeted therapies, the agents targeting the epidermal growth factor receptor (EGFR), the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement and C-ros oncogene 1 (ROS-1) have currently become standard treatment for cases presenting such molecular anomalies. Of them, cases with ALKrearrangement displayed dramatic results with a first generation ALK-inhibitor crizotinib; however, most of the patients develop a resistance in a few years. Especially the central nervous system relapses pose the most common clinical problem. Next generation ALK-inhibitors are promising with a high level of effectiveness in this resistance, in which various molecular mechanisms take part. Also, it gains increasing importance to re-perform a biopsy in the progression stage and reveal the mechanisms causing the secondary resistance in those patients. Keywords:Non-small-cell lung cancer, ALK, Crizotinib, Resistance ÖZET ALK-Pozitif Küçük Hücreli Dışı Akciğer Kanserinde Crizotinib Direnci Sonrası Tedaviİleri evre küçük hücreli dışı akciğer kanseri (KHDAK)'nin tedavisinde sistemik kemoterapi, genotipe dayalı hedef tedaviler ve immunoterapi yaygın olarak kullanılmaktadır. Hedef tedaviler arasında epidermal growth factor receptor (EGFR), the echinoderm microtubule-associated protein-like 4 anaplastic lypmhoma kinase (EML4-ALK) rearrangement ve C-ros oncogene 1 (ROS-1)'i hedefleyen ajanlar, bugün için bu moleküler anormalliklere sahip hastalarda standard tedavi haline gelmiştir. Bunlardan ALK-rearrangement'i olan hastalarda birinci jenerasyon ALK-inhibitörü crizotinib ile dramatik sonuçlar elde edilmiş olmakla birlikte hastaların çoğunda birkaç yıl içinde direnç gelişmektedir. Özellikle santral sinir sistemi relapsları en sık karşılaşılan klinik sorun olarak karşımıza çıkmaktadır. Çeşitli moleküler mekanizmaların rol oynadığı bu direnç durumunda yeni jenerasyon ALK-inhibitörleri yüksek etkinlikleri ile ümit vadetmektedir.Ayrıca bu hastalarda progresyon aşamasında tekrar biyopsi yapılması ve sekonder dirence neden olan mekanizmaların ortaya konması giderek önem kazanmaktadır.Anahtar Kelimeler: Küçük hücreli dışı akciğer kanseri, ALK, Crizotinib, Direnç

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The Effect of a High‐Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

Tugnait

Gupta

Hanley

et al. 2018

Clinical Pharm in Drug Dev

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Brigatinib, a next‐generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non–small‐cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90‐mg tablets) after a 10‐hour fast or after a high‐fat meal in a 2‐period, 2‐sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty‐four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK‐evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high‐fat meal) versus fasted conditions, with no effect on area under the concentration‐time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted conditions (2 hours). Treatment‐emergent adverse events were similar under fasted (48%) and fed (46%) conditions and were of mild intensity. Consumption of a high‐fat meal decreased the rate of brigatinib oral absorption but had no impact on the extent of absorption, thereby supporting brigatinib administration without regard to meals. These recommendations are reflected in the US prescribing information for brigatinib.

show abstract

Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer

Cited by 28 publications

References 82 publications

Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non- Small-Cell Lung Cancer

Treatment After First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non- Small-Cell Lung Cancer

Treatment After Crizotinib Resistance in ALK+ Non-Small-Cell Lung Cancer

The Effect of a High‐Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

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