Computational Analysis of Epidermal Growth Factor Receptor Mutations Predicts Differential Drug Sensitivity Profiles toward Kinase Inhibitors

Akula, Sravani; Kamasani, Swapna; Sivan, Sree Kanth; Manga, Vijjulatha; Vudem, Dashavantha Reddy; Kancha, Rama Krishna

doi:10.1016/j.jtho.2018.01.003

Cited by 13 publications

(10 citation statements)

References 15 publications

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“…1 [6], major studies reviewed in Table 1 [7, 8] and Table 2 [7–10], and additional studies reviewed in supplemental online Table 1 [11–28]). Preclinical experiments and computational analysis by other groups have suggested augmented sensitivity of EGFR ‐G719A to afatinib compared with first‐ and third‐generation TKIs [29, 30]. Similar preclinical results were reported for EGFR ‐S768I and other exon 18 (E709K and exon 18 deletion) mutations, whereas L861Q mutations are sensitive to both afatinib and osimertinib [29, 31].…”

Section: Molecular Tumor Boardsupporting

confidence: 58%

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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Section: Molecular Tumor Boardsupporting

confidence: 58%

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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“…Preclinical and computational analysis of uncommon mutations has demonstrated a high degree of heterogeneity in terms of sensitivity to different EGFR TKIs. 22,23,26 The variable sensitivity of different uncommon mutations to different EGFR TKIs indicates that a personalized treatment strategy should be undertaken in patients depending on the underlying uncommon EGFR mutation. However, effective treatment decisions are compromised by the paucity of prospective clinical data.…”

Section: Introductionmentioning

confidence: 99%

Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases

Yang

Schüler

Popat

et al. 2020

Journal of Thoracic Oncology

201

198

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Introduction: Limited clinical data are available regarding the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) in patients with NSCLC harboring uncommon EGFR mutations. This pooled analysis assessed the activity of afatinib in 693 patients with tumors harboring uncommon EGFR mutations treated in randomized clinical trials, compassionate-use and expanded-access programs, phase IIIb trials, noninterventional trials, and case series or studies. Methods: Patients had uncommon EGFR mutations, which were categorized as follows: (1) T790M; (2) exon 20 insertions; (3) "major" uncommon mutations (G719X, L861Q, and S768I, with or without any other mutation except T790M or an exon 20 insertion); (4) compound mutations; and (5) other uncommon mutations. Key end points were overall response rate (ORR), duration of response, and time to treatment failure (TTF). Results: In EGFR TKI-naive patients (n ¼ 315), afatinib demonstrated activity against major uncommon mutations (median TTF ¼ 10.8 mo; 95% confidence interval [CI]: 8.1-16.6; ORR ¼ 60.0%), compound mutations (median TTF ¼ 14.7 mo; 95% CI: 6.8-18.5; ORR ¼ 77.1%), other uncommon mutations (median TTF ¼ 4.5 mo; 95% CI: 2.9-*Corresponding author.

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“…Tumor EGFR mutations are the strongest predictor for response to EGFR TKI therapy [4,11,13,28]. In our study, all patients with EGFR mutations (both common and uncommon) showed radiological tumor regression on afatinib therapy, while patients with a wild type EGFR showed tumor progression.…”

Section: Correlation Between Tumor Tracer Uptake and Responsementioning

confidence: 48%

Identifying advanced stage NSCLC patients who benefit from afatinib therapy using 18F-afatinib PET/CT imaging

et al. 2021

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Non-small cell lung cancer (NSCLC) tumors harboring common (exon19del, L858R) and uncommon (e.g. G719X, L861Q) activating epidermal growth factor receptor (EGFR) mutations are best treated with EGFR tyrosine kinase inhibitors (TKI) such as the first-generation EGFR TKI erlotinib, second-generation afatinib or third-generation osimertinib. However, identifying these patients through biopsy is not always possible. Therefore, our aim was to evaluate whether 18 F-afatinib PET/CT could identify patients with common and uncommon EGFR mutations. Furthermore, we evaluated the relation between tumor 18 F-afatinib uptake and response to afatinib therapy. Materials and methods: 18 F-afatinib PET/CT was performed in 12 patients: 6 EGFR wild type (WT), 3 EGFR common and 3 EGFR uncommon mutations. Tumor uptake of 18 F-afatinib was quantified using TBR_WB 60− 90 (tumor-to-whole blood activity ratio 60− 90 min post-injection) for each tumor. Response was quantified per lesion using percentage of change (PC): [(response measurement (RM)-baseline measurement (BM))/BM]×100. Statistical analyses were performed using t-tests, correlation plots and sensitivity/specificity analysis.Results: Twenty-one tumors were identified. Injected dose was 348 ± 31 MBq. Group differences were significant between WT versus EGFR (common and uncommon) activating mutations (p = 0.03). There was no significant difference between EGFR common versus uncommon mutations (p = 0.94). A TBR_WB 60− 90 cut-off value of 6 showed the best relationship with response with a sensitivity of 70 %, a specificity of 100 % and a positive predictive value of 100 %. Conclusion: 18 F-afatinib uptake was higher in tumors with EGFR mutations (common and uncommon) compared to WT. Furthermore, a TBR_WB 60− 90 cut-off of 6 was found to best predict response to therapy. 18 F-afatinib PET/ CT could provide a means to identify EGFR mutation positive patients who benefit from afatinib therapy.

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Computational Analysis of Epidermal Growth Factor Receptor Mutations Predicts Differential Drug Sensitivity Profiles toward Kinase Inhibitors

Abstract: The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations toward multiple inhibitors, which may help clinicians in deciding mutant-specific treatment strategies.

Cited by 13 publications

References 15 publications

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

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

Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases

Identifying advanced stage NSCLC patients who benefit from afatinib therapy using 18F-afatinib PET/CT imaging

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