Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon Mutations: Are They Different from Those with Common Mutations?

Approximately 10% of the epidermal growth factor receptor () mutations in non-small-cell lung cancer (NSCLC) are uncommon mutations. Although the efficacy of second (2G) or third generation (3G) tyrosine kinase inhibitors (EGFR-TKIs) in the patients with uncommon mutation has been proven, further studies are warranted to define the optimal treatment approach for uncommon mutation-positive NSCLC. This study retrospectively investigated the treatment patterns and outcomes of patients with uncommon mutation-positive NSCLC from January 2011 to December 2019 at the Samsung Medical Center, Seoul, Korea. During the study, 2121 patients with mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. Of this, 135 (6.4%) patients harbored uncommon mutations. Of 135, 54 (40%, 54/135) patients had overlapping mutations with major mutations. The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8-13.5), 11.7 months (95% CI: 6.6-16.7), 7.7 months (95% CI: 4.9-17.4), and 5.0 months (95% CI: 3.7-6.1) for major uncommon mutation (G719X, L861Q), compound mutation with major mutation (Del 19 or exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The median overall survivals (OSs) were 25.6 months (16.9-34.2), 28.8 (95% CI: 24.4-33.4), 13.5 months (95% CI: 7.4-27.8), and 9.4 months (95% CI: 3.4-10.5) for major uncommon mutation (G719X), compound mutation with major mutation (Del 19 or exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The response rate, median PFS, and OS were 63.3%, 16.3 months (95% CI: 15.6-16.9), and 37.5 months (95% CI: 35.4-39.6) for common mutation-positive NSCLC. After failing 1L -TKI, repeated tissue or liquid biopsy were carried out on 44.9% (35/78) of patients with T790M detected in 10/35 (28.6%) patients. With subsequent 3G -TKI after failing the first-line -TKI, the ORR and PFS for 3G -TKI were 80% and 8.9 months (95% CI: 8.0-9.8). These patients showed a median OS of 34.6 months (95% CI: 29.8-39.4). The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common mutations. T790M was detected in 28.6% of the uncommon mutation-positive patients for whom prior 1G/2G -TKIs failed and underwent repeat biopsy at the time of progression.