As a result of the unique heterogeneity of non–small-cell lung cancer (NSCLC), in terms of its histologic features, genomics, and molecular biology, developing novel treatment options has proved inherently challenging.
Several oncogenic drivers have been identified during the past decade and have been actively targeted in isolated studies consisting of a few patients. The mutated form of the epidermal growth factor receptor (EGFR) is the best characterized oncogenic driver in NSCLC to date.
However, for many oncologists, selection of treatment for EGFR mutation–positive NSCLC is unclear, when considering the varying pharmacologic characteristics and clinical profiles of the available 3 generations of EGFR-tyrosine kinase inhibitors (TKIs).
Second-generation (ie, afatinib, dacomitinib) and third-generation (ie, osimertinib) TKIs have demonstrated improved efficacy when compared with the first-generation TKIs (eg, erlotinib, gefitinib) in recent head-to-head clinical trials. However, regardless of which agent has been chosen as first-line therapy, acquired resistance has been inevitable. Therefore, a critical concern is the availability and efficacy of subsequent treatment options.
Recent studies have evaluated first-generation EGFR-TKIs and demonstrated that osimertinib bestows an overall survival benefit, and in an exploratory analysis dacomitinib has exhibited an overall survival benefit compared with gefitinib.
It has remained unclear whether there are relative benefits of different sequential EGFR-TKI regimens, especially those involving second- and third-generation agents, and therefore this requires prospective evaluation.
There is a need to better inform treatment choices; therefore, researchers presented a summary overview of current clinical data, carefully surveying the varying pharmacologic attributes of available treatment options. Groundbreaking head-to-head trials such as LUX-Lung 71 and FLAURA2 have demonstrated the benefits of second- and third-generation EGFR-TKIs as first-line treatment compared with first-generation EGFR-TKIs. In particular, the results of the FLAURA trial showed a progression-free survival and an overall survival benefit of osimertinib compared with gefitinib/erlotinib; it also highlighted the drug’s tolerability and central nervous system activity, positioning osimertinib as a potential first-line treatment. However, since there is a dearth of head-to-head trial data evaluating and comparing second- and third-generation EGFR-TKIs, more research may help clearly define the optimal sequence of TKIs.
For patients with uncommon EGFR-activating mutations, optimal therapy remains uncertain for patients harboring tumors.
The tolerability profile differs between second- and third-generation EGFR-TKIs; second-generation EGFR-TKIs are possibly linked with a greater incidence of adverse events than third-generation TKIs. For afatinib, dacomitinib, and osimertinib, there is a similar discontinuation rate due to adverse events in clinical trials. This suggests that each therapeutic option is similar, supporting treatment continuation as long as patients are deriving clinical benefit. To evaluate predefined sequential regimens or combination regimens, prospective trials are warranted; thus, patients may maximize overall survival as well as the interval of chemotherapy-free treatment, potentially improving quality of life and reducing the burden of symptoms on each patient.
Evolving data and knowledge on the molecular mechanisms of resistance across the span of EFGR-TKIs will help elucidate the optimal treatment choice and assist clinicians in determining treatment choices based on efficacy and safety, particularly for specific subgroups of patients.
Shah R, Lester JF. Tyrosine kinase inhibitors for the treatment of EGFR mutation–positive non-small-cell lung cancer: a clash of the generations. Clin Lung Cancer. 2020;21:e216-e228.
- Park K, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17:577-589.
- Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis. Ann Oncol. 2019;30:v851-934.