Research Summary
For patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), EGFR-tyrosine kinase inhibitors (TKIs) can be used as first-line treatment. However, treatment resistance often occurs with first- or second-generation EGFR-TKI treatment, with T790M mutation being the most common acquired resistance mechanism. EGFR amplification following EGFR-TKI therapy might also act as an acquired resistance mechanism. Treatment with third-generation EGFR-TKIs, such as osimertinib, can potentially improve outcomes following acquired T790M mutation, but the impact of acquired EGFR amplification on this treatment method is unclear. Zhang et al1 conducted a retrospective study to evaluate the potential effect of acquired EGFR amplification on second-line osimertinib treatment in patients with EGFR-mutated advanced NSCLC who acquired T790M mutation after first-generation EGFR-TKI treatment. Their findings are summarized below.
Eligible patients harbored exon 19 deletions (19del) or L858R point mutation in exon 21 (21L858R) before first-line EGFR-TKI treatment, had disease progression after treatment with first-generation EGFR-TKI, underwent rebiopsy and next-generation sequencing (NGS) following NSCLC progression, and acquired T790M mutation following first-generation EGFR-TKI treatment. Exclusion criteria included presence of EGFR amplification prior to first-generation EGFR-TKI initiation, absence of first-line treatment with first-generation EGFR-TKI, lack of rebiopsy following first-generation EGFR-TKI treatment resistance, no detectable T790M mutation upon rebiopsy, receipt of rebiopsy genetic testing other than NGS, and loss to follow-up during first-generation EGFR-TKI treatment or incomplete patient data.
A total of 275 patients with advanced NSCLC were included, 59 of whom (21.5%) had acquired EGFR amplification. All patients had histologically confirmed lung adenocarcinoma. Median age was 60 years, and most patients were female (59.6%) and had no smoking history (77.5%). The prevalence of EGFR 19del was 61.0 and 63.9 percent in the EGFR amplification and nonamplification groups, respectively. EGFR 21L858R mutation was detected in 39.0 and 36.1 percent of the EGFR amplification and nonamplification groups, respectively. In both groups, the most common sites of metastasis were bone and brain. Patients with EGFR amplification had significantly higher median age (66 years), compared to those without EGFR amplification (59 years).
Osimertinib efficacy was assessed at median follow-up of 33.34 months. In both the EGFR amplification and nonamplification groups, partial response (PR) was the most common response, observed in 34 and 104 patients, respectively. In the EGFR amplification group, 18 patients experienced stable disease (SD) and seven experienced progressive disease (PD). One patient in the nonamplification group achieved complete response (CR), 93 patients had SD, and 18 experienced PD. The objective response rate (ORR) was 57.6 percent in the EGFR amplification group and 48.6 percent in the nonamplification group; disease control rate (DCR) was 88.1 and 91.6 percent, respectively. There were no significant differences in ORR or DCR between groups.
Median progression-free survival (PFS) was significantly longer in the EGFR amplification group, compared to the nonamplification group (12.20 months vs. 12.03 months). Six- and 12-month PFS rates were 72.9 and 52.5 percent, respectively, in the EGFR amplification group. In the nonamplification group, six- and 12-month PFS rates were 78.2 and 50.9 percent, respectively.
Median overall survival (OS) was 33.90 months in EGFR amplification group and 23.30 months in the nonamplification group; this difference was not significant. In the EGFR amplification group, one- and two-year OS rates were 79.7 and 59.7 percent, respectively. The nonamplification group had a one-year OS rate of 77.8 percent and a two-year OS rate of 48.5 percent.
Acquired EGFR amplification and EGFR 19del mutation were identified as significant prognostic factors for PFS through multivariate analysis. Independent prognostic factors for OS included EGFR 19del mutation, no bone metastasis, and history of lung cancer surgery.
Among patients with acquired EGFR amplification, after osimertinib monotherapy, median PFS was significantly prolonged in patients with EGFR 19del mutation, at 17.73 months, compared to those with EGFR 21L858R mutation, at 9.17 months. Patients with EGFR 19del mutation also had numerically longer median OS (35.77 months vs. 28.73 months). Survival outcomes among patients with EGFR amplification were not significantly different when stratifying by presence of liver, brain, or bone metastasis. Due to imbalanced sample sizes, the impact of concurrent mutations on osimertinib efficacy in patients with acquired EGFR amplification could not be determined.
Limitations include the retrospective nature of the study, small sample size, the use of small-panel NGS, and the potential that de novo EGFR amplifications went undetected in the small number of patients who underwent genetic testing by amplification-refractory mutation system before first-line EGFR-TKI treatment.
These findings indicated that osimertinib treatment is effective in patients with acquired T790M mutation and EGFR amplification following first-generation EGFR-TKI resistance; those with EGFR 19del mutation might particularly benefit from this treatment.
Reference
Zhang Y, Xu Y, Xu J, et al. Osimertinib for EGFR-mutant NSCLC patients with acquired T790M and EGFR amplification after first-generation EGFR-TKI resistance. Cancer Sci. 2024. Epub ahead of print.