Tyrosine kinase inhibitors for non-small-cell lung cancer: finding patients who will be responsive

Santarpía, Mariacarmela; Altavilla, Giuseppe; Salazar, María Fernanda; Magrí, Ignacio; Pettineo, Giuseppe; Benecchi, Sara; Rosell, Rafael

doi:10.1586/ers.11.27

Cited by 22 publications

(14 citation statements)

References 92 publications

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“…Inframe deletions around the LREA motif of exon and point mutation in exon 21 (L858R) account for about 45% and 40% of EGFR mutations in non-small cell lung cancer (NSCLC), respectively. These mutations are reportedly the strongest predictive markers for a response to EGFR-TKIs, independent of other clinical and molecular features [8,9]. Recently, in advanced inoperable NSCLC, EGFR Del- 19 and L858R have been suggested to have different sensitivities to afatinib, a second-generation EGFR-TKI, and to cytotoxic agents [10].…”

Section: Introductionmentioning

confidence: 99%

Clinical and pathological characteristics of EGFR mutation in operable early-stage lung adenocarcinoma

et al. 2017

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Section: Introductionmentioning

confidence: 99%

Clinical and pathological characteristics of EGFR mutation in operable early-stage lung adenocarcinoma

et al. 2017

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“…Based on recent developments, NSCLC is not anymore considered a single entity, but a heterogeneous disease including morphologically and molecularly distinct subsets of tumors characterized by different therapeutic vulnerabilities 5. The tyrosine kinase inhibitors (TKIs) targeting EGFR and ALK have consistently demonstrated superior efficacy compared to chemotherapy, and they currently represent the standard of care of these molecularly defined subgroups of NSCLC patients 6–8. Therefore, besides histopathologic assessments, molecular profiling of lung cancer has been rapidly incorporated into the diagnostic process to guide treatment decisions 9…”

Section: Introductionmentioning

confidence: 99%

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

Santarpía¹,

Daffinà²,

D’Aveni³

et al. 2017

DDDT

Self Cite

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The identification of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer (NSCLC) has radically changed the treatment of a subset of patients harboring this oncogenic driver. Crizotinib was the first ALK tyrosine kinase inhibitor to receive fast approval and is currently indicated as the first-line therapy for advanced, ALK-positive NSCLC patients. However, despite crizotinib’s efficacy, patients almost invariably progress, with the central nervous system being one of the most common sites of relapse. Different mechanisms of acquired resistance have been identified, including secondary ALK mutations, ALK copy number alterations and activation of bypass tracks. Different highly potent and brain-penetrant next-generation ALK inhibitors have been developed and tested in NSCLC patients with ALK rearrangements. Ceritinib, a structurally distinct and selective ALK inhibitor, showed 20 times higher potency than crizotinib in inhibiting ALK and had activity against the most common crizotinib-resistant mutations, including L1196M and G1269A, in preclinical models. In Phase I and II studies, ceritinib demonstrated pronounced activity in both crizotinib-naïve and crizotinib-refractory patients, with responses observed regardless of the presence of ALK resistance mutations. Ceritinib was the first ALK inhibitor to be approved for the treatment of crizotinib-refractory, ALK-rearranged NSCLC, and recent results from a Phase III study have demonstrated superior efficacy compared to standard chemotherapy in the first- and second-line setting. We provide an extensive overview of ceritinib from the design of the compound through preclinical data until efficacy and toxicity results from Phase I–III clinical studies. We review the molecular alterations associated with resistance to ceritinib and highlight the importance of obtaining tumor biopsy at progression to tailor therapy based upon the underlying resistance mechanism. We finally provide an outlook on novel rational therapeutic combinations.

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“…EGFR mutations have been demonstrated to be the strongest predictive biomarkers for the efficacy of EGFR-TKIs [4], [5], [6], [7], [8]. Patients with EGFR activating mutations, mainly in-frame deletions in exon 19 (19Del) and L858R substitutions in exon 21, have dramatic tumor responses and favorable survival benefit from EGFR-TKIs [9], [10]. However, most responsive patients would eventually experience progressive disease (PD).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Blood for Epidermal Growth Factor Receptor Mutation Detection in Non-Small Cell Lung Cancer Patients

Ren

et al. 2014

Translational Oncology

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OBJECTIVE: It is important to analyze and track Epidermal Growth Factor Receptor (EGFR) mutation status for predicting efficacy and monitoring resistance throughout EGFR-tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC) patients. The objective of this study was to determine the feasibility and predictive utility of EGFR mutation detection in peripheral blood. METHODS: Plasma, serum and tumor tissue samples from 164 NSCLC patients were assessed for EGFR mutations using Amplification Refractory Mutation System (ARMS). RESULTS: Compared with matched tumor tissue, the concordance rate of EGFR mutation status in plasma and serum was 73.6% and 66.3%, respectively. ARMS for EGFR mutation detection in blood showed low sensitivity (plasma, 48.2%; serum, 39.6%) but high specificity (plasma, 95.4%; serum, 95.5%). Treated with EGFR-TKIs, patients with EGFR mutations in blood had significantly higher objective response rate (ORR) and insignificantly longer progression-free survival (PFS) than those without mutations (ORR: plasma, 68.4% versus 38.9%, P = 0.037; serum, 75.0% versus 39.5%, P = 0.017; PFS: plasma, 7.9 months versus 6.1 months, P = 0.953; serum, 7.9 months versus 5.7 months, P = 0.889). In patients with mutant tumors, those without EGFR mutations in blood tended to have prolonged PFS than patients with mutations (19.7 months versus 11.0 months, P = 0.102). CONCLUSIONS: EGFR mutations detected in blood may be highly predictive of identical mutations in corresponding tumor, as well as showing correlations with tumor response and survival benefit from EGFR-TKIs. Therefore, blood for EGFR mutation detection may allow NSCLC patients with unavailable or insufficient tumor tissue the opportunity to benefit from personalized treatment. However, due to the high false negative rate in blood samples, analysis for EGFR mutations in tumor tissue remains the gold standard.

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Tyrosine kinase inhibitors for non-small-cell lung cancer: finding patients who will be responsive

Cited by 22 publications

References 92 publications

Clinical and pathological characteristics of EGFR mutation in operable early-stage lung adenocarcinoma

Clinical and pathological characteristics of EGFR mutation in operable early-stage lung adenocarcinoma

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy

Peripheral Blood for Epidermal Growth Factor Receptor Mutation Detection in Non-Small Cell Lung Cancer Patients

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