Dacomitinib For Advanced EGFR-Mutated NSCLC

ARCHER Supports First-Line Dacomitinib For Advanced EGFR-Mutated NSCLC
Progression-free survival in patients with newly diagnosed advanced non-small-lung cancer with an epidermal growth factor receptor mutation is higher with dacomitinib than gefitinib

Date: 09 Jun 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Non-Small-Cell Lung Cancer, Metastatic

medwireNews: Results from the ARCHER 1050 trial of patients with newly diagnosed advanced EGFR-positive non-small-cell lung cancer (NSCLC) suggest that first-line dacomitinib is superior to gefitinib for both progression-free survival (PFS) and duration of response (DOR).

“Dacomitinib should be considered as one of the new treatments for first-line management of patients with the EGFR mutation and in addition to the three existing drugs, we now have a fourth one,” presenting author Tony Mok, from the Chinese University of Hong Kong, told delegates at the 2017 annual meeting of the American Society of Oncology, held in Chicago, Illinois, USA.

The phase III trial compared the second-generation irreversible EGFR Tyrosine kinase inhibitor (EGFR–TKI) with the first-generation EGFR–TKI gefitinib as a first-line treatment for patients with advanced NSCLC with an activating EGFR mutation but no central nervous system metastases or prior TKI therapy.

After a median of 22.1 months, the primary endpoint of PFS by blinded independent review was 14.7 months for the 227 patients randomly assigned to receive dacomitinib 45 mg/day versus 9.2 months for the 225 patients who received gefitinib 250 mg/day, giving a significant hazard ratio (HR) of 0.59 in favour of dacomitinib.

“The median PFS with dacomitinib of 14.7 months is actually among the highest in most of the randomised phase III study in the first-line setting”, Mok said.

He noted that the PFS curves began to separate at 5–6 months and this resulted in a 2-year PFS rate of 30.6% for dacomitinib-treated patients and 9.6% for their gefitinib-treated counterparts.

Subgroup analysis favoured dacomitinib with the exception of nonAsian patients, who had an insignificant HR for PFS of 0.89, whereas there was a significant HR of 0.51 for their Asian counterparts. However, exploratory analysis of the 72 nonAsian patients who responded to treatment failed to explain this difference.

An objective response was achieved by a comparable 74.9% of dacomitinib-treated patients versus 71.6% of gefitinib-treated patients, but the dacomitinib patients had a significantly longer duration of response, at a median 14.8 versus 8.3 months.

Analysis of the objective response rate by change in tumour size suggested that the improved duration of response may be explained by the greater change in tumour size experienced by patients given dacomitinib.

Overall survival data are yet to mature, Mok said, noting that just 36.9% of events had occurred at data cut off in July 2016.

Safety analysis revealed that patients given dacomitinib had higher rates of grade 3 diarrhoea (8.4 vs 0.9%), Paronychia (7.5 vs 1.3%), dermatitis acneform (13.7 vs 0%) and Stomatitis (3.5 vs 0.4%). One patient given dacomitinib had grade 5 diarrhoea.

However, patients given gefitinib had higher rates of grade 2 (10.7 vs 2.2%) and grade 3 (8.5 vs 0.9%) alanine aminotransferase elevation than dacomitinib-treated patients.

Serious adverse events (SAEs) occurred in a comparable 27.3% of the dacomitinib group versus 22.3% of the gefitinib-treated patients, but the rate of treatment-related SAEs were higher in the dacomitinib arm, reported in 9.3% and 4.5%, respectively. The corresponding rates of permanent discontinuation and treatment-related deaths were 9.7% versus 6.7% and 0.9% versus 0.4%.

Dose modification was required after a median of 2.8 months of dacomitinib and lasted 11.3 months, with reduction to a 30 mg/day dose required in 38.3% of patients and to 15 mg/day in 27.8%, affecting 66.1% of patients overall.

By contrast, 8.0% of patients given gefitinib required a dose reduction to 250 mg every 2 days after a median of 3.3 months and this lasted for 5.2 months.

However, Tony Mok emphasized that the high efficacy, good tumour response and efforts to manage toxicity resulted in improved patient quality of life (QoL) in both treatment groups with regard to management of tumour symptoms, such as cough, dyspnoea and pain, with a slight benefit for dacomitinib.

Dacomitinib was associated with poorer QoL with regard to treatment-related symptoms but both treatments were neutral with regard to the global QoL measure.

Reference

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 III trial. J Clin Oncol; 35: 2017 (suppl; abstr LBA9007).