First-line afatinib for advanced EGFRm+ NSCLC: Analysis of long-term responders in the LUX-Lung 3, 6, and 7 trials

Schüler, Martin; Paz‐Ares, Luis; Sequist, Lecia V.; Hirsh, Vera; Lee, Ki Hyeong; Wu, Yi‐Long; Lü, Shun; Zhou, Caicun; Feng, Jifeng; Ellis, Stuart H.; Samuelsen, Carl; Tang, Wenbo; Märten, Angela; Ehrnrooth, Eva; Park, Keunchil; Yang, James Chih‐Hsin

doi:10.1016/j.lungcan.2019.04.006

Cited by 27 publications

(21 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is slightly lower than observed in clinical trials (10%-12%). 64 Overall, these extensive and robust data support the use of afatinib as a firstline treatment option against major uncommon EGFR mutations.…”

Section: Discussionmentioning

confidence: 88%

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

Self Cite

211

198

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 88%

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

Self Cite

211

198

View full text Add to dashboard Cite

show abstract

“…13 The frequency of Del19 mutation-positive NSCLC was slightly higher among long-term responders in the LUX-Lung 3,6,7 analysis, which supports its known role as a biomarker for improved outcomes with EGFR-TKIs vs other mutation types. 13 These studies also demonstrate that afatinib can provide clinical benefit in advanced NSCLC patients with brain metastases or uncommon mutations. 17,22,23 Although the LUX-Lung 7 trial showed that afatinib compared to gefitinib significantly improves PFS and the time-to-treatment failure, more serious drug-related adverse events were reported in the afatinib group than in the gefitinib group.…”

Section: Co-mutations and Outcomes With Egfr-tkismentioning

confidence: 60%

“…17 Overall, analysis of the LUX-Lung 7 data together with the LUX-Lung 3 and LUX-Lung 6 data show that afatinib results in approximately 10% of patients achieving long-term clinical benefit (long term response ≥3 year PFS and OS), which is greater than that observed with first-generation EGFR-TKIs. 13 Stratification factors in these trials included: Del19 versus L858R EGFR and vs. other 'uncommon' mutations in LUX-Lung 3 and LUX-Lung 6; race (Asian versus non-Asian) in LUX-Lung 3 only, and brain metastases (presence versus absence) in LUX-Lung 7 only. 13 The frequency of Del19 mutation-positive NSCLC was slightly higher among long-term responders in the LUX-Lung 3,6,7 analysis, which supports its known role as a biomarker for improved outcomes with EGFR-TKIs vs other mutation types.…”

Section: Co-mutations and Outcomes With Egfr-tkismentioning

confidence: 99%

“…13 Stratification factors in these trials included: Del19 versus L858R EGFR and vs. other 'uncommon' mutations in LUX-Lung 3 and LUX-Lung 6; race (Asian versus non-Asian) in LUX-Lung 3 only, and brain metastases (presence versus absence) in LUX-Lung 7 only. 13 The frequency of Del19 mutation-positive NSCLC was slightly higher among long-term responders in the LUX-Lung 3,6,7 analysis, which supports its known role as a biomarker for improved outcomes with EGFR-TKIs vs other mutation types. 13 These studies also demonstrate that afatinib can provide clinical benefit in advanced NSCLC patients with brain metastases or uncommon mutations.…”

Section: Co-mutations and Outcomes With Egfr-tkismentioning

confidence: 99%

“…71 68 Seven (6.8%) EGFR-TKI naïve patients in the real-world dataset continued with afatinib treatment for more than three years; this is only marginally lower than reported in clinical trials (10-12%). 13 Furthermore, whilst exon 20 insertions are traditionally not considered responsive to EGFR-TKIs based on retrospective analyses 77,79,80 , analysis of the aforementioned real-world dataset demonstrated that some exon 20 insertions are clinically sensitive to afatinib; analysis of 70 NSCLC patients with exon 20 insertions treated with afatinib showed an ORR of 24.3% with a median duration of response (DoR) of 11.9 months. 71 In a preclinical study by Kohsaka et al (2019), it was shown that afatinib, possibly due to its alternative mechanism of action, reduced the viability of cells expressing numerous compound mutations, including those involving Del19, G719X and/or S768I mutations; only compound mutations involving T790M were considered to be resistant to afatinib.…”

Section: Strategies To Further Improve Survival Outcomes For Nsclc Pamentioning

confidence: 99%

See 2 more Smart Citations

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

Meisel

Prof

2020

healthbook TIMES Onco Hema

View full text Add to dashboard Cite

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...

show abstract