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Beyond EGFR and ALK: targeting rare mutations in advanced non-small cell lung cancer.

ABSTRACT: Lung cancer remains the leading cause of cancer-related death in men and women, despite its constantly declining rates in incidence and mortality in the developed world. The past decade has witnessed an unprecedented rise in the development of molecular targeted therapies in various types of tumors. In non-small cell lung cancer (NSCLC), the greatest paradigm shift is the implementation of EGFR and ALK tyrosine kinase inhibitors in the first line and subsequent lines of therapy, with impressive results. Though less frequent than the molecular alterations in the aforementioned genes, a number of aberrations in potential oncogenic drivers has been discovered, namely mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. A great number of clinical trials are currently underway, evaluating agents specifically designed to target these alterations, with mixed results so far. The greatest cumulative benefit offered by these trials is that, despite their success or failure in their objective goals, they have provided us with a better understanding of the complexity of the molecular intracellular processes, necessitating thus the accurate interpretation of the preclinical data in order to appropriately select the patients that may derive benefit from targeted treatment strategies.

SUBMITTER: Gkolfinopoulos S

PROVIDER: S-EPMC5952024 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Beyond EGFR and ALK: targeting rare mutations in advanced non-small cell lung cancer.

Gkolfinopoulos Stavros S Mountzios Giannis G

Annals of translational medicine 20180401 8

Lung cancer remains the leading cause of cancer-related death in men and women, despite its constantly declining rates in incidence and mortality in the developed world. The past decade has witnessed an unprecedented rise in the development of molecular targeted therapies in various types of tumors. In non-small cell lung cancer (NSCLC), the greatest paradigm shift is the implementation of EGFR and ALK tyrosine kinase inhibitors in the first line and subsequent lines of therapy, wi ...[more]

PMID: 29862231

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Project description:BackgroundEpidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatments for advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Osimertinib is an effective therapy for NSCLC patients with acquired resistance due to T790M mutation after first- and second-generation EGFR-TKI treatment. This study aimed to analyze the clinical outcomes of sequential therapy following first-line EGFR-TKIs and the predictive factors of an acquired T790M mutation.MethodsBetween January 2014 and December 2018, data from 2190 advanced NSCLC patients with common EGFR mutations (exon 19 deletion and L858R) receiving first- and second-generation EGFR-TKIs in Linkou, Kaohsiung, Chiayi and Keelung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed.ResultsUntil August 2021, among 1943 patients who experienced progressive disease, 526 underwent T790M mutation tests, and their T790M-positive rate was 53.6%. Exon 19 deletion mutation and progression-free survival (PFS) of >12 months were positively associated with secondary T790M mutation. Different first-line first- and second-generation EGFR-TKI therapies did not affect the appearance of acquired T790M mutations. The median overall survival (OS) was 58.3 [95% confidence interval (CI): 49.0-67.5] months among the patients with T790M mutation who received second-line osimertinib therapy compared with 31.0 (95% CI: 27.5-34.5) months among the patients without T790M mutation who received chemotherapy alone. The multivariate analysis showed that a poor performance status (score: >2), nonadenocarcinoma histology, stage IV cancer, liver metastasis, brain metastasis, PFS while on first-line EGFR-TKIs, and subsequent chemotherapy without third-generation EGFR-TKIs were significant independent unfavorable prognostic factors for OS.ConclusionThis study demonstrated the efficacy of first-line EGFR-TKIs and sequential osimertinib therapy. The results of our study suggest that T790M mutation tests are important for the use of subsequent osimertinib, which yielded favorable survival outcomes.

Project description:BackgroundThe prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non-small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments.MethodsEligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.ResultsIn total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR = 1.88, 95%CI: 1.59-2.23, p < 0.001, I2 = 0.0%, P = 0.792) and overall survival (OS) (HR = 1.92, 95%CI: 1.55-2.38, p < 0.001, I2 = 0.0%, P = 0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P < 0.001, I2 = 0.0%, P = 0.473; pooled HR for OS: 1.94, 95% CI 1.36-2.76, P < 0.001, I2 = 0.0%, P = 0.484). Begg's funnel plots and Egger's tests indicated no significant publication bias in this study.ConclusionsThis meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC.

Dataset Information

Beyond EGFR and ALK: targeting rare mutations in advanced non-small cell lung cancer.

Publications

Beyond <i>EGFR</i> and <i>ALK</i>: targeting rare mutations in advanced non-small cell lung cancer.

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