Dacomitinib is superior to gefitinib in delaying disease progression in newly-diagnosed, EGFR mutation positive non-small cell lung cancer
Results from a large phase III study comparing the second generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) dacomitinib to the first generation EGFR inhibitor gefitinib as first-line treatment for EGFR mutation positive, advanced non-small-cell lung cancer (NSCLC), showed that dacomitinib leads to a significant 5.5 month delay in the median time to progression. This trial, named ARCHER 1050, is the first phase III head-to-head comparison of two EGFR TKIs.
Approximately a decade ago, the introduction of EGFR TKIs changed the treatment paradigm for EGFR-positive lung cancer. Due to its chemical properties, dacomitinib blocks EGFR more effectively than first-generation inhibitors, such as gefinitib and erlotinib. As such, it should theoretically be more effective in keeping the tumor growth in control, leading to a longer progression-free survival. On the other hand, this higher potency also leads to stronger suppression of the normal EGFRs in healthy tissues, causing more side effects such as skin rash, acne, and diarrhoea. In a previously reported single arm phase II study, where dacomitinib was studied as first-line therapy in a subgroup of patients with EGFR-activating mutation, the drug yielded a response rate of 75.6% with a median progression-free survival (PFS) of 18.2 months.
In the presented phase III ARCHER 1050 trial, 452 patients with stage IIIB/IV/recurrent NSCLC harboring an EGFR-activating mutation were randomized (1:1) to dacomitinib (45 mg PO QD) or gefitinib (250 mg PO QD). Patients with metastases in the central nervous system were excluded from the study. The primary endpoint of the trial was PFS per blinded independent review (IRC), while secondary objectives included overall survival (OS), objective response rate (ORR), duration of response (DoR), PFS per Investigator (INV), time to treatment failure (TTF), restricted mean survival time (RMST) for PFS, safety and patient-reported outcomes (PROs).
Patients who received dacomitinib in the trial had a 41% lower chance of cancer progression or death than those who received gefitinib. The median PFS was 14.7 months with dacomitinib as compared to 9.2 months with gefitinib (HR[95%CI]: 0.59[0.47-0.74]; p< 0.0001). Similar findings were reported when investigators assessed the PFS: median PFS 16.6 months with dacomitinib versus 11.0 months with gefitinib (HR[95%CI]: 0.62[0.50-0.78]; p< 0.001). At 2 years, the PFS rate was more than three time as high with dacomitinib as compared to gefitinib at 30.6% and 9.6%, respectively.
The response rate with both EGFR TKIs was comparable at 74.9% with dacomitinib and 71.6% with gefitinib (p=0.3883). However, the median DoR with dacomitinib was significantly longer than with gefitinib at a median of 14.8 months versus 8.3 months, respectively (HR[95%CI]: 0.40[0.31-0.53]; p< 0.001). Longer follow up is needed to assess the median OS with both treatments.
The most common severe (grade 3) side effects observed with dacomitinib were acne (in 14% of patients), diarrhoea (in 8% of patients) and paronychia (7.5%). The dose of dacomitinib was lowered in 66.1% of patients due to side effects as compared to 8% with gefitinib. Liver enzyme abnormalities were the most common severe (grade 3) side effect with gefitinib (in 8.5% of patients).
In summary, ARCHER 1050 demonstrated statistically significant and clinically meaningful improvements in efficacy for dacomitinib over gefitinib in the first-line treatment of EGFR-mutation positive advanced NSCLC, with a manageable safety profile. As dacomitinib is a more potent, second-generation EGFR inhibitor, it shares the issue of increased side effects in the skin and gastrointestinal tract with afatinib. In spite of this, the activity seen in this study should allow for consideration of this therapy in this patient population.
Mok T, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): A randomized, open-label phase 3 trial. Presented at ASCO 2017;Abstract LBA9007.