Sequential Afatinib and Osimertinib in Patients with
            <i>EGFR</i>
            Mutation-Positive Non-Small-Cell Lung Cancer: Updated Analysis of the Observational Giotag Study

Hochmair, Maximilian; Morabito, Alessandro; Hao, Desirée; Yang, Cheng‐Ta; Soo, Ross A.; Yang, James Chih Hsin; Gucalp, Rasim; Halmos, Balázs; Wang, Lara; Märten, Angela; Čufer, Tanja

doi:10.2217/fon-2019-0346

Cited by 73 publications

(81 citation statements)

References 27 publications

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“…However, this result should be interpreted with caution since the number of patients in this group was small [27]. Another retrospective study on the efficacy of second-line osimertinib is the GioTag study [55], a global observational study, assessing as first end-point the time on treatment. They observed that subsequent use of afatinib and osimertinib, in patients who had developed T790 M mutation, led to a median overall survival of 41.3 months (90% CI: 36.8-46.3) overall and 45.7 months (90% CI: 45.3-51.5) in patients with Del19-positive tumors (n = 149).…”

Section: Expert Opinionmentioning

confidence: 94%

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

Bergonzini

Leonetti

Tiseo

et al. 2020

Expert Opinion on Pharmacotherapy

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2020): Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?, Expert Opinion on Pharmacotherapy, ABSTRACT Introduction: Non-small cell lung cancer (NSCLC) is a highly lethal disease. During the past 20 years, the epidermal growth factor receptor (EGFR) has been a relevant target for anticancer drug-design, and a large family of EGFR tyrosine kinase inhibitors (TKI) were designed, which improved therapeutic outcomes compared to conventional chemotherapy in NSCLC patients with specific EGFR mutations. However, resistance to these inhibitors occurs; therefore, the debate on which inhibitor should be used first is still open. Dacomitinib was approved in 2018 for the first-line treatment of NSCLC with EGFR activating mutations. Areas covered: This manuscript reviews the properties of dacomitinib, including the current information from clinical trials and its potential application as stand-alone therapy, or in combination. Expert opinion: Dacomitinib is a second-generation EGFR-TKI that has demonstrated significant improvement in overall survival in a phase III randomized study compared with gefitinib, a first-generation TKI. However, the rapid development and approval of a new generation of TKIs (osimertinib), with better clinical profiles, raises the question of which role can dacomitinib play in NSCLC. Further studies are required to evaluate the efficacy of this drug on brain metastases, as a second-line treatment after third-generation TKIs, or in combination with other types of treatments. ARTICLE HISTORY

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Section: Expert Opinionmentioning

confidence: 94%

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

Bergonzini

Leonetti

Tiseo

et al. 2020

Expert Opinion on Pharmacotherapy

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“…92 An interim analysis has demonstrated a median OS of 41.3 months (90% CI: 36.8-46.3) overall and 45.7 months (90% CI: 45.3-51.5) in patients with Del19-positive tumors (n=149). 93 The 2-year survival was 80% and 82%, respectively, for patients overall and those with Del19 tumors. 93 A key challenge of the second line use of osimertinib is to ensure that all patients who develop T790M-driven resistance are identified; this requires re-biopsy, and the widespread availability of sensitive T790M detection assays.…”

Section: Second-line Treatment Options For Nsclc Patients and The Neementioning

confidence: 96%

“…93 The 2-year survival was 80% and 82%, respectively, for patients overall and those with Del19 tumors. 93 A key challenge of the second line use of osimertinib is to ensure that all patients who develop T790M-driven resistance are identified; this requires re-biopsy, and the widespread availability of sensitive T790M detection assays. EGFR mutations can be analyzed in tumor biopsies and in cellfree plasma DNA from blood samples (liquid biopsy).…”

Section: Second-line Treatment Options For Nsclc Patients and The Neementioning

confidence: 96%

“…49 Hence, there is no established targeted treatment following the failure of osimertinib, so it is widely debated whether osimertinib should be reserved for second-line use following progression with a secondgeneration EGFR-TKI. 90 In the confirmatory phase III AURA 3 trial, osimertinib was superior to platinum-pemetrexed in patients with T790Mpositive advanced NSCLC, who had disease progression after first-or second-generation EGFR-TKI therapy. 15 12; p = 0.277); the survival rate at 24 months was 55% versus 43% and at 36 months was 37% versus 30%, respectively.…”

Section: Second-line Treatment Options For Nsclc Patients and The Neementioning

confidence: 99%

“…91 In a real-world clinical practice setting, EGFR-TKI-naive patients who received first-line afatinib and went on to develop T790M-positive acquired resistance subsequently received second-line osimertinib. 90 At the initial database lock the median time to treatment failure (TTF), the primary outcome, was 27.6 months (90% CI: 25.9-31.3 months). 92 Results were also promising in patients with an EGFR Del19 activating mutation (30.3 months) and Asian patients (46.7 months).…”

Section: Second-line Treatment Options For Nsclc Patients and The Neementioning

confidence: 99%

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Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Meisel

Prof

2020

healthbook TIMES Onco Hema

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Over the past decade numerous large-scale sequencing approaches have identified increasingly more oncogenic driver mutations in non-small cell lung cancer (NSCLC) (Figure 1A) 1 , which have facilitated the rational development of targeted therapies and led to marked survival benefits compared to classical treatment approaches with chemotherapy (Figure 1B). 2 Mutations in the epidermal growth factor receptor (EGFR) gene are amongst the most frequently observed 1,3,4 , but significant differences in mutation frequency exist depending on histology, gender, smoking status and ancestry. The highest rate of EGFR mutations (≥50%) has been found in Asian female non-smokers with adenocarcinoma histology and a bronchioalveolar subtype. 5-7 The EGFR family, also referred to as HER or ErbB receptors, comprises four receptor tyrosine kinases: EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). 5 Ligand binding to the extracellular region of EGFR leads to autophosphorylation, activation and EGFR dimerization, which in turn initiates intracellular signalling cascades. 5 Signal transduction subsequently leads to cell proliferation and survival via activation of RAS/ RAF/MEK and PI3K/AKT pathways, among others. 5 EGFR became a prime therapeutic target in NSCLC in 2004, following the discovery that somatic mutations in the EGFR gene enhance tyrosine kinase activity in lung cancer patients. 5 These somatic EGFR mutations activate the kinase receptor in the absence of ligand binding, and can trigger oncogenesis by inducing a constitutively active state that leads to sustained downstream signalling. 8 Subsequently, targeted therapy with tyrosine kinase inhibitors (TKIs) has emerged as the mainstay treatment for advanced NSCLC patients with activating mutations (Figure 1C). 9 Three generations of EGFR-TKIs are currently approved but they are not all equal in terms of EGFR binding, metabolism, anti-tumor activity (Table 1A) and safety. 10 First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) reversibly bind to EGFR and inhibit the binding of adenosine triphosphate (ATP) to the tyrosine kinase domain (Figure 2A-B). Although gefitinib and erlotinib have shown efficacy in first-, second-, and third-line treatment of NSCLC, the benefit seen is usually transient because NSCLC with EGFR-activating mutations treated with first-generation EGFR-TKIs inevitably develop resistance. 11 Up to half of patients treated with first-generation EGFR-TKIs develop acquired resistance through a T790M EGFR substitution mutation. 12 Second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) form irreversible, covalent attachments to the EGFR kinase domain and have demonstrated improvements in progressionfree survival (PFS) relative to those treated with first-generation EGFR-TKIs. 13, 14 Moreover, the third-generation EGFR-TKI, osimertinib, is highly active in NSCLC patients with the EGFR T790M mutation who had disease progression with first-and second-generation EGFR-TKIs. 15 Although the treatment landscape of advanced NSCLC has dramatically ch...

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Sequential treatment of afatinib and osimertinib or other regimens in patients with advanced non‐small‐cell lung cancer harboring EGFR mutations: Results from a real‐world study in South Korea

et al. 2021

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Sequential Afatinib and Osimertinib in Patients with EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Updated Analysis of the Observational Giotag Study

Cited by 73 publications

References 27 publications

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Sequential treatment of afatinib and osimertinib or other regimens in patients with advanced non‐small‐cell lung cancer harboring EGFR mutations: Results from a real‐world study in South Korea

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