A phase II study of low starting dose of afatinib as first-line treatment in patients with EGFR mutation-positive non-small-cell lung cancer (KTORG1402)

Yokoyama, Toshihide; Yoshioka, Hiroshige; Fujimoto, Daichi; Demura, Yoshiki; Hirano, Katsuya; Kawai, Takahiro; Kagami, Ryogo; Washio, Yasuyoshi; Ishida, Tadashi; Kogo, Mariko; Tomii, Keisuke; Okuno, Takehiro; Akai, Masaya; Hirabayashi, Masataka; Nishimura, Takashi; Nakahara, Yasuharu; Kim, Young Hak; Miyakoshi, Chisato; Yoshimura, Kenichi; Hirai, Toyohiro

doi:10.1016/j.lungcan.2019.03.030

Cited by 25 publications

(28 citation statements)

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“…41 A more recent study by Yokoyama et al shows that a low starting dose of afatinib therapy (20 mg daily) with dose modification according to severity of adverse events is a better strategy in treatment-naïve patients who have NSCLC associated with common activating EGFR mutations, both in terms of effectiveness and tolerability, than starting with a standard afatinib dose (40 mg daily). 42 In this phase II trial, the PFS was 15.2 months, which was similar to previous reports with the standard 40 mg dose of afatinib, and toxicities were generally mild. Importantly, the low starting dose of afatinib was also effective in high-risk patients with common EGFR M+ NSCLC who had asymptomatic brain metastasis.…”

Section: Co-mutations and Outcomes With Egfr-tkissupporting

confidence: 88%

“…Importantly, the low starting dose of afatinib was also effective in high-risk patients with common EGFR M+ NSCLC who had asymptomatic brain metastasis. 42 The ARCHER 1050 trial is the first randomized, phase III study that directly compared a second-gen vs. a first-generation EGFR-TKI to demonstrate an OS benefit. 43 Although, in contrast to the LUX-Lung 3, 22…”

Section: Co-mutations and Outcomes With Egfr-tkismentioning

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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Section: Co-mutations and Outcomes With Egfr-tkissupporting

confidence: 88%

Section: Co-mutations and Outcomes With Egfr-tkismentioning

confidence: 99%

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

Meisel

Prof

2020

healthbook TIMES Onco Hema

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“…A real word practice study in Japan that enrolled 128 patients reported a median PFS of 17.8 months [20], while a phase 2 study which used a lower starting dose of 20 mg afatinib that increased in 10-mg increments up to 50 mg/day, reported a PFS of 15.2 months [19]. Another phase 2 study that enrolled 40 elderly patients had a shorter PFS of 12.9 months [22]. The current study revealed that the median PFS of patients who harbored exon 19 and exon 21 mutations and took afatinib 30 or 40 mg afatinib as their starting dose was 14.5 and 14.8 months, respectively; no signi cant difference in PFS was observed between the two groups, the result is similar to our previous small-scaled study [23].…”

Section: Discussionmentioning

confidence: 99%

“…There is an urgent need to nd a reliable strategy for reducing ADRs associated with afatinib, whilst maintaining its clinical e cacy for the management of lung cancer. Therefore, in clinical practice many clinicians prescribe a lower starting dose of afatinib [22,23] or perform dose modi cation [19,21] to try and improve patient outcomes and adherence. In a non-interventional, observational study [21] of patients who started on 40 mg afatinib daily, 67.1% underwent dose reduction, 86.5% of which occurred in the rst 6 months.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, methods for ameliorating ADRs whilst maintaining clinical e cacy are urgently needed for lung cancer patients receiving afatinib as their rst line therapy. A lower starting dose of afatinib was tested by clinicians in clinical practice and several trials [22]. In May 2014, the Taiwan Nation Health Insurance Bureau permitted both 30 mg and 40 mg afatinib daily as a rst line therapy for advanced lung adenocarcinoma with activating EGFR mutations.…”

Section: Introductionmentioning

confidence: 99%

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Lower Starting Dose of Afatinib for the Treatment of Metastatic Lung Adenocarcinoma Harboring Exon 21 and Exon 19 Mutations

Chen

Tsai

Lee

et al. 2020

Preprint

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BackgroundAfatinib has shown favorable response rates (RRs) and longer progression free survival (PFS) in lung cancer patients harboring EGFR mutations compared with standard platinum-based chemotherapy. However, serious adverse drug reactions (ADRs) limit the clinical application of afatinib. MethodsWe designed a retrospective study, enrolled all patients with metastatic lung adenocarcinoma who were diagnosed and treated with 30 or 40 mg afatinib as their starting dose in three Kaohsiung Medical University-affiliated hospitals in TaiwanResultsA total of 179 patients were enrolled in the study, of which 102 (57%) and 77 (43%) received 30 mg and 40 mg afatinib daily as their initial treatment, respectively. The patients initially using 30 mg afatinib daily had a similar RR (74% vs. 82%, p = 0.1661), median PFS (14.5 months vs. 14.80 months, log-rank p = 0.465) and median OS (34 months vs 25.2 months, log-rank p = 0.5982) compared with those initially using 40 mg afatinib daily. Patients with the lower starting dose had fewer ADRs compared with patients receiving 40 mg as their starting dose. The overall incidence of moderate (49% vs 77%, p=0.002) or severe (7% vs 24%, p<0.0001) ADRs was significantly lower in patients receiving 30 mg afatinib compared with those receiving 40 mg. ConclusionPatients receiving 30 mg afatinib as their starting dose had non-inferior RRs, PFS, OS and significantly fewer serious ADRs compared with those patients who received standard 40 mg afatinib as their starting dose.

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