The EGFR tyrosine kinase inhibitor (TKI) dacomitinib showed superior overall survival (OS) vs gefitinib in patients with treatment-naïve EGFR-positive non-small-cell lung cancer (NSCLC) in the final analysis of the ARCHER 1050 study.

The results make dacomitinib the first EGFR TKI to show a significant OS benefit over another EGFR TKI in a randomized head-to-head comparison in this context. [Mok T, et al, ASCO 2018, abstract 9004; J Clin Oncol 2018, doi: 10.1200/JCO.2018.78.7994]

“In this phase III study, 452 patients with Eastern Cooperative Oncology Group performance status of 0 or 1 and newly diagnosed advanced NSCLC with activating EGFR mutations were randomized to receive the second-generation EGFR TKI dacomitinib 45 mg/day or the standard-of-care first-generation EGFR TKI gefitinib 250 mg/day,” said investigator Professor Tony Mok of the Chinese University of Hong Kong, Hong Kong.

The primary analysis, reported previously, showed a significant 41 percent PFS improvement with dacomitinib vs gefitinib (median PFS, 14.7 months vs 9.2 months; hazard ratio [HR], 0.59). [Lancet Oncol 2017;18:1454-1466]

The present final OS analysis showed a significant 24 percent OS improvement in patients receiving dacomitinib vs gefitinib (median OS, 34.1 months vs 26.8 months; HR, 0.76; p=0.0438). The 30-month OS rate was 56.2 percent in the dacomitinib arm vs 46.3 percent in the gefitinib arm.

One patient in the dacomitinib arm and 11 patients in the gefitinib arm developed brain metastases as the primary site of progression.

“Although the study was not powered to test interaction, preliminary subgroup OS analyses by baseline characteristics were generally consistent with the primary OS analysis,” noted Mok. “In the Asian subgroup, for example, the median OS was 34.2 months with dacomitinib vs 29.1 months with gefitinib [HR, 0.812; p=0.1879].”

Two other studies have compared second- or third-generation EGFR TKIs with first-generation EGFR TKIs. The LUX-Lung 7 study, which compared the second-generation EGFR TKI afatinib with gefitinib, showed significant improvement in PFS (HR, 0.73; p=0.017) but not OS (HR, 0.86; p=0.258). [Lancet Oncol 2016;17:577-589] The OS data of the FLAURA study, which compared the third-generation EGFR TKI osimertinib with gefitinib or erlotinib, were only at 25 percent maturity at the time of the interim analysis. [N Engl J Med 2018;378:113-125]

“In the ARCHER 1050 study, the previously reported significant PFS benefits with dacomitinib vs gefitinib successfully translated into significant OS benefits,” concluded Mok. “Dacomitinib is the first to show a significant OS improvement in a head-to-head comparison with another EGFR TKI in locally advanced or metastatic EGFR-positive NSCLC."

According to the investigators, dacomitinib should be considered one of the standard treatment options for this population. The optimal sequence of therapy, however, remains controversial. Patients with inadequate responses to second-generation EGFR TKIs have an approximately 50 percent chance of developing EGFR T790M mutation, and these patients are likely to benefit from osimertinib. In the present study, the median OS was 36.7 months in patients who received first-line dacomitinib followed by a third-generation EGFR TKI. Nevertheless, these results should be interpreted with caution because the sample size was small.