The investigational second-generation tyrosine kinase inhibitor dacomitinib improved overall survival compared with gefitinib as first-line treatment in patients with advanced non-small cell lung cancer harboring activating EGFR mutations.
Tony Mok, MD, associate professor of oncology and urology at Johns Hopkins Medicine
Tony Mok, MD
The investigational second-generation tyrosine kinase inhibitor (TKI) dacomitinib improved overall survival (OS) compared with gefitinib as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. Median OS was 34.1 months in patients randomized to dacomitinib versus 26.8 months in those randomized to gefitinib (Iressa), according to the open-label, phase III ARCHER 1050 study presented at the 2018 ASCO Annual Meeting.1
With a median duration follow-up of 31.1 months, the data provide the first evidence of an OS advantage in a randomized direct comparison of 2 EGFR TKIs as first-line therapy for EGFR mutation-positive NSCLC.
Based on the finding, “dacomitinib should be considered as a new treatment option for first-line management of patients with EGFR mutation-positive advanced NSCLC,” said presenter Tony Mok, MD, professor and chair of the Department of Clinical Oncology, Chinese University of Hong Kong.
Previously reported findings from ARCHER 1050 showed a significant improvement in progression-free survival (PFS) with dacomitinib (HR, 0.59; P <.0001).2
Patients (n= 452) with newly diagnosed stage IIIb/IV or recurrent NSCLC harboring an EGFR mutation (exon 19 del or exon 21 L858R ± exon 20 T790M) and without central nervous system (CNS) metastasis were randomized 1:1 to 28-day cycles of oral dacomitinib (n= 227) at 45 mg/day or oral gefitinib (n= 225) at 250 mg/day. Patients were stratified by race and EGFR mutation type (exon 19 vs exon 21).
Baseline patient characteristics were balanced across the 2 arms. In the dacomitinib arm, 75% of patients were Asian and nearly 65% were never-smokers. In the gefitinib arm, 78% were Asian and 64% were never-smokers. The median age was 61 to 62 years for both arms.
Median PFS was 14.7 months in the dacomitinib arm compared with 9.2 months in the gefitinib arm.
The data cut-off for the OS analysis was February 17, 2017, with 220 (48.7%) deaths observed at that time. The hazard ratio for OS was 0.76 (P =.0438) in favor of dacomitinib. The OS probability at 30 months was 56.2% in the dacomitinib arm and 46.3% in the gefitinib arm. One patient randomized to dacomitinib and 11 randomized to gefitinib had CNS metastases at progression. However, not all patients had computed tomography scans at progression, said Mok. “So some of these patients will have asymptomatic CNS metastases.”
OS subgroup analyses were consistent with the primary OS analysis across most baseline characteristics. Patients with exon 19 deletion had a median OS of 34.1 months with dacomitinib versus not reached with gefitinib (HR, 0.880 favoring dacomitinib; 95% CI, 0.613-1.262, P =.486). Those with exon 21 L858R mutation had a median OS of 32.5 months in the dacomitinib arm compared with 23 months in the gefitinib (HR, 0.71; 95% CI, 0.478-1.045; P =.0805). The OS probability at 30 months in patients with exon 21 L858R mutation was 51.6% in the dacomitinib arm compared with 36.7% in the gefitinib arm.
In the Asian subgroup, median OS was 34.2 months and 29.1 months in the dacomitinib and gefitinib arms, respectively (HR, 0.812; 95% CI, 0.595-1.108; P= .1879).
In the dacomitinib arm, 27.8% of patients received subsequent chemotherapy versus 35.6% in the gefitinib arm. In this group, the median OS was 29.5 months versus 24.6 months, respectively.
Third-generation EGFR TKI exposure was 9.7% in the dacomitinib arm and 11.1% in the gefitinib arm. In this group, median OS was 36.7 months and not reached in either arms, respectively. Among the patients who received other EGFR TKIs at subsequent therapy (slightly more than 8% in either arm), median OS was 34.7 months in those assigned to dacomitinib and 32.1 months in those randomized to gefitinib.
With the more potent inhibition of tyrosine kinase, more adverse events (AEs) would be expected and this was borne out in the trial, noted Mok. Rates of grade ≥3 diarrhea (8.8% vs 0.0%), paronychia (7.5% vs 1.3%), dermatitis acneiform (13.7% vs 0%), and stomatitis (3.5% vs 0.4%) were higher in dacomitinib-treated patients. AEs induced by dacomitinib may be managed by dose reduction to 30 mg/day or 15 mg/day, he said. Some patients (38.8%) assigned to dacomitinib required dose reduction to 30 mg/day and others (27.8%) to 15 mg/day. The median time to dose reduction in this group was 2.8 months and the median duration of dose reduction was 11.3 months.
Whether sequencing a third-generation TKI after dacomitinib failure or using a third-generation TKI upfront is the preferred treatment strategy for NSCLC with activating EGFR mutations remains to be determined, said invited discussant Daniel S. Tan, BSc, MBBS, PhD, senior consultant, Division of Medical Oncology, National Cancer Center of Singapore. T790M mutations can emerge as a resistance mechanism to dacomitinib, he said, and the third-generation TKI osimertinib (Tagrisso) has T790M-specific activity.
Two thirds of dacomitinib-treated patients required dose reduction, necessitating that the optimal pharmacologically active dose needs to be defined, said Tan.