Clinical Activity of Afatinib in Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Spanish Retrospective Multicenter Study

Morán, Teresa; Taus, Álvaro; Arriola, Edurne; Aguado, Carlos; Dómine, Manuel; Rueda, A. Gómez; Calles, Antonio; Cedrés, S.; Viñolas, Núria; Isla, Dolores; Palmero, Ramón; Sereno, María; Díaz, Víctor Jiménez; Juan, Óscar; Marsé, Raquel; Martorell, P; Torres, J.; Anguera, Geòrgia; Bosch, Joaquim; Cabezón, L.; Catot, Sílvia; Martinez, A.; Muñoz, Silvia; Ramos, Inmaculada

doi:10.1016/j.cllc.2020.04.011

Cited by 15 publications

(11 citation statements)

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“…Overall, available literature supports the use of EGFR TKIs as first-line treatment of advanced or metastatic NSCLC patients harboring EGFR compound mutations [ 30 ]. The median overall survival (OS) appears longer in NSCLC patients with compound mutations than in those with single uncommon EGFR mutations, consistently across different retrospective studies (~31–33 vs. 12–17 months) [ 31 , 32 , 33 , 34 , 35 ].…”

Section: Resultsmentioning

confidence: 77%

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: 77%

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

et al. 2022

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“…Another study reported a slightly higher efficacy of afatinib in patients with ex20ins, with an ORR of 23.4% and a median TTF of 4.2 months ( 17 ). A Spanish multicenter retrospective study also showed that the treatment efficacy of afatinib was significantly lower in patients carrying ex20ins than in patients with other types of mutations, with an ORR of 13.0% and a median OS of 10.7 month ( 34 ). Therefore, platinum-based combination chemotherapy, rather than afatinib, might be the preferred treatment option for patients with ex20ins.…”

Section: Discussionmentioning

confidence: 99%

Inconsistent clinical outcomes following afatinib treatment in NSCLC patients harboring uncommon epidermal growth factor receptor mutation

Dong

Wang

et al. 2022

Front. Oncol.

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BackgroundUncommon epidermal growth factor receptor (EGFR) mutations consist of a heterogeneous population of molecular alterations, and the available clinical data on the outcomes of patients with non-small-cell lung cancer (NSCLC) harboring uncommon EGFR mutations following afatinib treatment are limited. The purpose of this pooled analysis was to investigate the clinicopathological features of patients with uncommon EGFR mutations (um-EGFRms) along with their treatment response and survival outcomes following afatinib treatment.MethodsWe performed a literature search in the NCBI PubMed database to identify relevant articles and conducted this pooled analysis based on 70 studies. The relationships between patient clinical characteristics, EGFR mutation type and the response to afatinib treatment were analyzed using univariate chi-square analysis, and survival analysis was performed using the Kaplan–Meier method.ResultsData from a total of 99 patients were included in the pooled analysis. The objective response rate (ORR) to treatment with afatinib was53.5%, with a median progression-free survival (mPFS) of 9.0 months. For patients administered first-line afatinib treatment, the ORR and median PFS were 73.5% and 15.6 months, respectively, which were both superior to those of patients treated with second- or later-line treatments (ORR:37.0%, p < 0.001; mPFS: 6.0months, p = 0.001). Moreover, patients with a single um-EGFRm were more likely to have a favorable response and prognosis benefit after treatment with afatinib than patients with multiple one (ORR: 63.3% vs 38.5%, p=0.017; mPFS: 15.6 months vs 6.0 months,p=0.010). Moreover, single um-EGFRm were independent predictive factors for better treatment response and superior PFS. Subgroup analysis indicated that patients harboring major um-EGFRms (i.e., L861Q, G719X, and S768I) exhibited the best treatment responses and prognoses (ORR: 74.1%, mPFS: 15.6 months), by contrast, patients harboring multiple um-EGFRms comprising 19del/L858R had the worst treatment responses and prognoses (ORR: 23.5%, mPFS: 5.6months).ConclusionsPatients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following afatinib treatment, which closely related to the mutation pattern and cooccurring partner mutant genes. Administering afatinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances, but this recommendation requires further clinical studies for verification.

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“…In January 2018, this led to the approval of afatinib in advanced NSCLC harboring alterations in these less common subgroups (S768I, L861Q, and/or G719X). Further data supporting the activity of afatinib in these cohorts have Table 2, supplemental online Table 1) [40][41][42][43]. Daily dosing of afatinib at 40-50 mg in clinical trials has been associated with significant rates of treatment discontinuations and dose reductions because of treatment-related adverse events (TRAEs).…”

confidence: 99%

Section: Molecular Tumor Boardmentioning

confidence: 99%

Clinical Benefit of Tyrosine Kinase Inhibitors in Advanced Lung Cancer with EGFR-G719A and Other Uncommon EGFR Mutations

et al. 2020

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The optimal management of advanced non-small cell lung cancer (NSCLC) with noncanonical epidermal growth factor receptor (EGFR) mutations (i.e., exon 19 deletion and exon 21 L858R) is constrained by the heterogeneous behavior of individual uncommon mutations and limited prospective clinical data in this setting. Despite encouraging results with osimertinib from a recently published phase II trial from South Korea, afatinib remains the only currently approved drug for patients with tumors harboring uncommon EGFR mutations (i.e., S768I, L861Q, and/or G719X). When used at the standard dose of 40 mg daily, afatinib is associated with significant rates of treatment-related adverse events, leading to frequent dose reductions and treatment discontinuations. We report a case of a woman with advanced NSCLC harboring EGFR-G719A mutation treated with afatinib (at an off-label pulse dose strategy that merits further evaluation in prospective studies) with sustained partial response for 20 months with manageable expected toxicities. Subsequent disease progression was mediated by off-target pan-EGFR inhibitor (including osimertinib)-resistant KRAS mutation and not by acquisition of EGFR-T790M. We further present the current state of evidence in the literature behind use of first-, second-, and third-generation tyrosine kinase inhibitors and summarize the evolving spectrum of activity ascribed to osimertinib (and newer EGFR inhibitors with a more favorable therapeutic window and intracranial penetration) in this population of patients with advanced NSCLC and uncommon EGFR mutations. The Oncologist 2020;25:1-7 KEY POINTS • Uncommon EGFR mutations characterize a heterogeneous group of patients with advanced non-small cell lung cancer (NSCLC). • Afatinib is the only currently U.S. Food and Drug Administration-approved drug for management of advanced NSCLC with uncommon EGFR mutations (S768I, L861Q, and/or G719X). • Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. • Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.

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Clinical Activity of Afatinib in Patients With Non–Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Spanish Retrospective Multicenter Study

Cited by 15 publications

References 50 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

Inconsistent clinical outcomes following afatinib treatment in NSCLC patients harboring uncommon epidermal growth factor receptor mutation

Clinical Benefit of Tyrosine Kinase Inhibitors in Advanced Lung Cancer with EGFR-G719A and Other Uncommon EGFR Mutations

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