The Predictive Values of Advanced Non-Small Cell Lung Cancer Patients Harboring Uncommon EGFR Mutations—The Mutation Patterns, Use of Different Generations of EGFR-TKIs, and Concurrent Genetic Alterations

Tan, Jianxin; Deng, Pengbo; Wan, Rongjun; Li, Min; Yang, Huanming; Gu, Qing; An, Jian; Jiang, Juan

doi:10.3389/fonc.2021.646577

Cited by 14 publications

(17 citation statements)

References 39 publications

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“…Another retrospective study included 102 NSCLC patients with EGFR uncommon mutations and 99 with single EGFR mutations as control group, treated with first- or second-generation EGFR TKIs as first-line treatment [ 45 ]. Of note, among patients treated with first-line EGFR TKIs, RRs in combined common plus uncommon and combined uncommon EGFR mutations were lower compared to single common EGFR mutations (objective response rate, ORR 54.5% and 44.4% vs. 75%, respectively).…”

Section: Resultsmentioning

confidence: 99%

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Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence

et al. 2022

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Compound epidermal growth factor receptor (EGFR) mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations. We conducted a systematic review to investigate the available data on this patients’ subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4–26% of total EGFR mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding de novoEGFR exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40–80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20–70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound EGFR mutations, taking into account different sensitivity profile of accompanying EGFR mutations for selecting the most adequate EGFR TKI for individual patients.

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Section: Resultsmentioning

confidence: 99%

“…No differences were observed among compound subgroups treated with second-generation afatinib. Moreover, afatinib showed higher ORR and longer PFS compared to first-generation TKIs in combined common plus uncommon mutations (ORR 100% vs. 54.5%, p = 0.017; PFS NE vs. 13.6 months, p = 0.032, respectively) [ 45 ] ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence

et al. 2022

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“…Patients with compound uncommon mutations have better tumor response and prognosis than patients with single uncommon mutations ( Brindel et al, 2020 ; Yamada et al, 2020 ; Yang et al, 2020 ; Passaro et al, 2021 ; Tan et al, 2021 ). In the study by Yang et al, afatinib yielded better anti-tumor activity against compound uncommon mutations than against major uncommon mutations in both TKI-naïve patients and TKI-pretreated patients ( Yang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China

Gao

Cai³

et al. 2022

Front. Pharmacol.

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Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited.Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1–2 months. Adverse events were assessed by CTCAE 5.0.Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1–14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4–5 adverse events (AEs) occurred, but all patients had grade 1–2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs.Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.

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“…Different EGFR-targeted drugs have shown variable efficacy for uncommon mutations within EGFR exon 18-21 (27,28). Previous studies demonstrated that patients with uncommon EGFR mutations treated with afatinib might have a better prognosis than those treated with firstgeneration TKIs (4,7,29,30). Afatinib at 40 mg for LAD with major uncommon EGFR mutations (G719X, L861Q, and S768I) resulted in a varied PFS of 10.7-17.1 months and an ORR around 50-74% (6,31,32).…”

Section: Discussionmentioning

confidence: 99%

Afatinib 30 mg in the treatment of common and uncommon EGFR-mutated advanced lung adenocarcinomas: a retrospective, single-center, longitudinal study

Qian¹,

Ye²,

Huang³

et al. 2022

J Thorac Dis

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Background: Afatinib 30 mg has been proved to be with comparable efficacy but more tolerable than the dose of 40 mg for Asian patients with non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical outcomes of afatinib at 30 mg/d in the treatment of advanced lung adenocarcinomas (LAD) with common and uncommon epidermal growth factor receptor (EGFR) mutations.Methods: EGFR-mutated advanced LAD patients receiving afatinib (30 mg/d) from January 2017 to November 2021 were retrospectively included. EGFR status was classified into three subtypes, namely common mutations including exon 19 deletions (19del) and exon 21 L858R (21L858R), uncommon mutations including G719X, L861Q, S768I, and complex mutations, and separately exon 20 insertions (20ins).Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse events (AEs) were analyzed during regular follow-up. Results:The overall median PFS of totally 58 included patients was 9.83 [95% confidence index (CI): 5.76-13.91] months. The number of patients with common, uncommon, and 20ins mutations was 32 (55.2%), 19 (32.8%) and 7 (12.1%), respectively. Baseline characteristics did not differ significantly among the three subtypes. The corresponding median PFS was 13.97 (12.06-15.89), 8.48 (0.32-16.64), and 3.78 (1.93-5.64) months, respectively (P=0.002). In the first-line setting, patients with common and uncommon mutations had a significantly longer PFS compared to those with 20ins [14.53 (13.53-15.53) vs. 10.39 (4.87-15.91) vs. 2.37 (0.00-5.11) months, P<0.001]. The first-line ORR showed significant differences among the three subtypes (60% vs. 80% vs. 0.0%, P=0.023). All-grade AEs occurred in 22 patients (37.9%). AEs ≥ grade 3 mainly included diarrhea (8.6%), and none of the patients discontinued treatment due to severe AEs.Conclusions: Afatinib at 30 mg/d is associated with a favorable efficacy and tolerability in the treatment of advanced LAD with common and major uncommon EGFR mutations except 20ins. Further large-scale prospective studies are warranted to confirm our findings.

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The Predictive Values of Advanced Non-Small Cell Lung Cancer Patients Harboring Uncommon EGFR Mutations—The Mutation Patterns, Use of Different Generations of EGFR-TKIs, and Concurrent Genetic Alterations

Cited by 14 publications

References 39 publications

Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence

Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China

Afatinib 30 mg in the treatment of common and uncommon EGFR-mutated advanced lung adenocarcinomas: a retrospective, single-center, longitudinal study

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