UNcommon EGFR Mutations: International Case Series on Efficacy of Osimertinib in Real-Life Practice in First-LiNe Setting (UNICORN)

Journal of Thoracic Oncology, Journal Year: 2022, Volume and Issue: 18(2), P. 169 - 180

Published: Oct. 25, 2022

IntroductionApproximately 10% of EGFR mutations (EGFRmuts) are uncommon (ucEGFRmuts). We aimed to collect real-world data about osimertinib for patients with ucEGFRmuts.MethodsThis is a multicenter, retrospective study ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC treated as first inhibitor. The Response Evaluation Criteria in Solid Tumors and response assessment neuro-oncology brain metastases objective rate (ORR) were evaluated by the investigators. Median progression-free survival (mPFS), median overall survival, duration (mDOR) calculated from initiation. Mutations found at resistance collected.ResultsA total 60 included (22 centers, nine countries), age 64 years, 75% females, 83% Caucasian. largest subgroups G719X (30%), L861Q (20%), de novo Thr790Met (T790M) (15%). ORR was 61%, mPFS 9.5 months, mDOR 17.4 24.5 months. Regarding no concurrent common or T790M (group A, n = 44), 60%, 8.6 11 For G719X, 47%, 8.8 9.1 L861Q, 80%, 16 T790M, 44%, 12.7 46.2 Compound EGFRmut including had better outcome compared only ucEGFRmut. 13 metastases–evaluable metastases, 46%. 14 patients, rebiopsy results analyzed: four additional mutation (C797S, D585Y, E709K), three new TP53 mutation, one c-Met amplification, PIK3CA neuroendocrine transformation.ConclusionsOsimertinib have an activity high disease control systemically intracranially. Several mechanisms identified. This report comprises, best our knowledge, set its kind.

Language: Английский

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Unveiling the Landscape of Uncommon EGFR Mutations in NSCLC-A Systematic Review

Journal of Thoracic Oncology, Journal Year: 2024, Volume and Issue: 19(7), P. 973 - 983

Published: March 16, 2024

Language: Английский

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Biomarker-Targeted Therapies in Non–Small Cell Lung Cancer: Current Status and Perspectives

Cells, Journal Year: 2022, Volume and Issue: 11(20), P. 3200 - 3200

Published: Oct. 12, 2022

Non-small-cell lung cancer (NSCLC) is one of the most common malignancies and leading causes cancer-related death worldwide. Despite many therapeutic advances in past decade, NSCLC remains an incurable disease for majority patients. Molecular targeted therapies immunotherapies have significantly improved prognosis NSCLC. However, vast advanced develop resistance to current eventually progress. In this review, we discuss potential NSCLC, focusing on immunotherapies. We highlight future role metabolic combination

Language: Английский

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Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study

JTO Clinical and Research Reports, Journal Year: 2023, Volume and Issue: 4(3), P. 100459 - 100459

Published: Jan. 10, 2023

EGFR mutations drive a subset of NSCLC. Patients harboring the common mutations, deletion exon 19 and L858R, respond well to osimertinib, third-generation tyrosine kinase inhibitor. Nevertheless, effect osimertinib on NSCLC with atypical is not described. This multicenter retrospective study evaluates efficacy among patients mutations.Patients metastatic treated at least one mutation, excluding concurrent 19, or T790M from six U.S. academic cancer centers were included. Baseline clinical characteristics collected. The primary end point was time treatment discontinuation (TTD) osimertinib. Objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 also assessed.A total 50 uncommon identified. most frequent L861Q (40%, n = 18), G719X (28%, 14), 20 insertion (14%, 7). median TTD 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall 10.7 CI: 3.2-18.1 first-line setting (n 20). objective 31.7% 18.1%-48.1%) 41.2% 18.4%-67.1%) setting. varied (17.2 mo), (7.8 (1.5 mutations.Osimertinib has activity mutations. Osimertinib differs type EGFR-activating mutation.

Language: Английский

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Targeting HER3 to overcome EGFR TKI resistance in NSCLC

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 4, 2024

Receptor tyrosine kinases (RTKs) play a crucial role in cellular signaling and oncogenic progression. Epidermal growth factor receptor kinase inhibitors (EGFR TKIs) have become the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations, but resistance frequently emerges between 10 to 14 months. A significant this is of human EGFR 3 (HER3), an family member. Despite its significance, effective targeting HER3 still developing. This review aims bridge gap by deeply examining HER3’s pivotal contribution TKI spotlighting emerging HER3-centered therapeutic avenues, including monoclonal antibodies (mAbs), TKIs, antibody-drug conjugates (ADCs). Preliminary results indicate combining HER3-specific treatments TKIs enhances antitumor effects, leading increased objective response rate (ORR) prolonged overall survival (OS) resistant cases. Embracing HER3-targeting therapies represents transformative approach against emphasizes importance further research optimize patient stratification understand mechanisms.

Language: Английский

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Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(11), P. 2123 - 2130

Published: March 13, 2023

Abstract Purpose: The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared with the common ex19del, E746_A750del in preclinical models. clinical efficacy of patients non–small cell lung cancer harboring L747_A750>P and other ex19dels is not known. Experimental Design: AACR GENIE database was interrogated characterize frequency individual relative variants, a multicenter retrospective cohort used compare outcomes for tumors E746_A750del, who received first line (1L) or second later lines therapy were T790M+ (≥2L). Results: comprised 45% mutations, 72 distinct variants ranging from 28.1% (E746_A750del) 0.03%, representing 1.8% mutant cohort. In our multi-institutional (N = 200), associated significantly prolonged progression-free survival (PFS) 1L versus [median 21.3 months (95% confidence interval, 17.0–31.7) vs. 11.7 (10.8–29.4); adjusted HR 0.52 (0.28–0.98); P 0.043]. Osimertinib varied on basis specific mutation present. Conclusions: ex19del inferior PFS treated osimertinib. Understanding differences among subtypes could alter management these future.

Language: Английский

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Overview on Therapeutic Options in Uncommon EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): New Lights for an Unmet Medical Need

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8878 - 8878

Published: May 17, 2023

The majority of epidermal growth factor receptor (EGFR) mutations (85-90%) are exon 19 deletions and L858R point 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon (10-15% EGFR mutations). predominant mutation types in this category include 18 mutations, 21 L861X, 20 insertions, S768I. This group shows a heterogeneous prevalence, partly due different testing methods the presence compound which some cases can lead shorter overall survival TKIs compared simple mutations. Additionally, EGFR-TKI may also vary depending on specific tertiary structure protein. best strategy remains uncertain, data EGFR-TKIs efficacy based few prospective retrospective series. Newer investigational agents still under study, there no other approved treatments targeting Defining treatment option for patient population an unmet medical need. objective review evaluate existing outcomes, epidemiology, clinical characteristics lung cancer patients with rare focus intracranial activity response immunotherapy.

Language: Английский

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Non-small cell lung cancer: an update on emerging EGFR-targeted therapies

Expert Opinion on Emerging Drugs, Journal Year: 2024, Volume and Issue: 29(2), P. 139 - 154

Published: April 2, 2024

Current research in EGFR-mutated NSCLC focuses on the management of drug resistance and uncommon mutations, as well opportunity to extend targeted therapies' field action earlier stages disease.

Language: Английский

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Meta-analysis of the prognostic impact of TP53 co-mutations in EGFR-mutant advanced non-small-cell lung cancer treated with tyrosine kinase inhibitors

Critical Reviews in Oncology/Hematology, Journal Year: 2023, Volume and Issue: 184, P. 103929 - 103929

Published: Feb. 10, 2023

To assess the prognostic impact of TP53 mutations in EGFR-mutant advanced NSCLC patients treated with TKIs. Studies exploring clinical outcomes EGFR mutant/TP53 wild-type versus EGFR/TP53 co-mutant TKIs were selected. Data cumulated by adopting a fixed and random-effect model. Overall, 29 trials eligible. The PFS analysis showed that group has shorter (HR = 1.67, 95% CI 1.51–1.83, heterogeneity I2 =20%, p 0.18). Patients affected have higher chance OS wild type (HR= 1.89, 1.67–2.14, 21%; 0.19). subgroup no significant difference between first-second third-generation both (p 0.31, 0.08). represent clinically relevant mechanism resistance to EGFR-TKIs, regardless their generation. A personalized therapeutical approach should be explored dedicated trials.

Language: Английский

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Co-occurring EGFR p.E709X Mutation Mediates Primary Resistance to the Third-Generation EGFR-TKIs in EGFR p.G719X-Mutant Patients with Advanced NSCLC

Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 30(12), P. 2636 - 2646

Published: April 5, 2024

Abstract Purpose: The current National Comprehensive Cancer Network (NCCN) guidelines recommend afatinib or osimertinib as the preferred first-line treatment strategy for patients with advanced NSCLC harboring EGFR p.G719X mutation. However, in absence of head-to-head trials comparing p.G719X-mutant patients, it is unclear which regimen option. Experimental Design: A large cohort 4,228 treatment-naïve lung cancer who underwent targeted next-generation sequencing (NGS) testing was screened multicenter involving 68 and NGS profiling retrospectively enrolled to evaluate clinical responses (n = 37) third-generation EGFR-TKIs 31). Ba/F3 cells stably expressing p.G719A mutation were created investigate response vitro. Results: Concurrent p.E709X mutations, being most frequent co-occurring (∼30%), exerted a detrimental effect on outcomes treated EGFR-TKI [G719X/E709X vs. G719X; objective rate (ORR): 0.00% 47.62%, P < 0.001; mPFS: 7.18 14.2 months, 0.04, respectively]. Conversely, no significant difference found efficacy between p.G719X/E709X (G719X/E709X ORR: 71.43% 56.67%, 0.99; 14.7 15.8 0.69, respectively). In vitro experiments elucidated resistant drug sensitivity poor inhibition phosphorylation p.G719A/E709K upon treatment. Conclusions: Co-occurring mediated primary resistance but remained sensitive afatinib. personalized should be undertaken based coexisting status.

Language: Английский

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