Afatinib treatment response in advanced lung adenocarcinomas harboring uncommon mutations

Abstract

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved the prognosis of mutant lung cancer; however, the clinical application value of TKIs for nonclassical EGFR mutation is unclear, especially for patients with rare uncommon mutations. Methods: A retrospective study based on electronic medical records was conducted to collect data on the effectiveness of afatinib in patients with stage IIIB/IV lung adenocarcinoma (LUAD) bearing uncommon mutations between January 2017 and January 2021. Results: Forty-two patients with uncommon mutations treated with afatinib were enrolled. The objective response rate (ORR) was 50.0% (10 of 20 patients). The median time to treatment failure (TTF) was 11.7 months (95% confidence interval = 8.5-18.3 months). Of the 42 patients, the median TTF was 15.0, 11.7, and 16.6 months in patients with Gly719Xaa (G719X), Ser768Ile (S768I), and Leu861Gln (L861Q) mutations, respectively. In patients with the rare uncommon mutation, the median TTF was 10.0 months, and the ORR was 50.0%. Afatinib demonstrated clinical activity across a set type of specific rare uncommon mutations, including EGFR L747P, A767_V769dup, and L833V/H835L, with a case having a TTF of more than 1 year. Molecular profiling reports of 16 afatinib-resistant biopsy samples were available, and the secondary T790M mutation was detected in one patient with L833V/ H835L mutation and one harboring S768I/L858R mutation. Conclusions: Our findings suggested that afatinib is effective in patients with uncommon mutations. Mechanisms of afatinib resistance vary and need further investigation.

Comparison of afatinib and erlotinib combined with bevacizumab in untreated stage IIIB/IV epidermal growth factor receptor-mutated lung adenocarcinoma patients: a multicenter clinical analysis study

“… 3 , 4 Other EGFR point mutations, including exon 18 Gly719Xaa (G719X), exon 20 Ser768Ile (S768I), and exon 21 Leu861Gln (L861Q), are uncommon (1−3% of EGFR mutations) but respond to EGFR-TKI therapy. 5 , 6 …”

“… 7 , 8 Afatinib is classified as a second-generation EGFR-TKI because of its characteristic of irreversible covalent binding to pan-ErbB receptors. 2 , 6 Previous prospective clinical studies (LUX-Lung 3, 6, and 7 trials) have shown that afatinib is promising for untreated advanced NSCLC with EGFR mutations (55–70% ORRs and 11 months of PFS). 9 , 10 Therefore, afatinib has been approved as a first-line therapy for patients with EGFR-mutated advanced NSCLC.…”

EGFR uncommon alterations in advanced non-small cell lung cancer and structural insights into sensitivity to diverse tyrosine kinase inhibitors

“…Similarly, the most comprehensive report to date also demonstrated that single and compound uncommon alterations both could benefit from afatinib (Yang et al,.2020). In addition, several realword studies have further verified the activity of afatinib against EGFR uncommon alterations (Li et al, 2021;Hang et al, 2022).…”

Afatinib 30 mg in the treatment of common and uncommon EGFR-mutated advanced lung adenocarcinomas: a retrospective, single-center, longitudinal study

“…Previous studies demonstrated that patients with uncommon EGFR mutations treated with afatinib might have a better prognosis than those treated with firstgeneration TKIs (4,7,29,30). Afatinib at 40 mg for LAD with major uncommon EGFR mutations (G719X, L861Q, and S768I) resulted in a varied PFS of 10.7-17.1 months and an ORR around 50-74% (6,31,32). However, little evidence has been released concerning the efficacy of afatinib at 30 mg in these patients.…”