Regulatory Decision Summary for Vizimpro

Dacomitinib is an irreversible pan-human epidermal growth factor receptor (HER) (EGFR/HER1, HER2, and HER4) inhibitor, with clinical activity against mutated EGFR with deletions in exon 19 or the L858R substitution in exon 21. The evidence in support of the proposed indication stemmed mainly from the pivotal Study 1050 (ARCHER) that aimed at demonstrating the superiority of oral dacomitinib 45 mg QD (n = 227) over oral gefitinib 250 mg QD (n = 225) in prolonging progression-free survival (PFS) in EGFR-mutated NSCLC patients. Study 1050 was a randomized (1:1), open-label, active control Phase 3 trial where 452 patients were randomized to receive either study drug. The primary efficacy endpoint was progression-free survival (PFS) assessed by blinded independent review and the main secondary endpoints were objective response rate (ORR) and overall survival (OS).

Study 1050 met its primary objective in demonstrating the superiority of dacomitinib over gefitinib in prolonging PFS with median PFS times of 14.7 months and 9.5 months respectively (HR: 0.589; 95% CI: 0.469 - 0.739 with a p-value < 0.0001). With the exception of patients aged above 75 years, the subgroup analyses of the primary endpoint were consistent overall with the primary analysis. A cautionary statement was added to the Product Monograph stating that exploratory analyses did not show a benefit in efficacy endpoints for patients aged above 75 years.

Dacomitinib did not improve the ORR when compared to gefitinib (74.9% vs 71.6%). The median OS was 34.1 months (95% CI: 29.5 to 37.7 months) in dacomitinib-treated patients and 26.8 months (95% CI: 23.7 to 32.1 months) in gefitinib-treated patients. As the hierarchical statistical testing order was PFS, followed by ORR and then OS, the statistical testing procedures for OS were not carried out as ORR was not statistically significant. The median duration of response was longer for dacomitinib-treated patients (14.8 months; 95% CI: 12.0, 17.4) compared to gefitinib-treated patients (8.3 months; 95% CI: 7.4, 9.2).

The safety profile of dacomitinib was consistent with the known safety profile of other EGFR tyrosine kinase inhibitors (TKIs). Safety findings in the pivotal Study 1050 indicated that most subjects in both study arms experienced AEs (99.6% vs 98.2%). AEs observed in more than 20% of dacomitinib-treated patients were: diarrhea, paronychia, dermatitis acneiform, stomatitis, decreased appetite, dry skin, weight decreased, alopecia, and cough. Serious AEs (SAEs) were reported at a similar frequency between the two study arms (dacomitinib: 27.3% vs gefitinib: 22.3%). The most frequently reported SAEs in dacomitinib-treated patients included diarrhea, interstitial lung disease, rash, and decreased appetite. Grade 5 AEs occurred at a similar frequency between the dacomitinib arm and the gefitinib arm (9.7% vs 8.9%). Treatment-emergent adverse events (TEAEs) leading to death in more than 0.5% of patients in the dacomitinib arm were disease progression, pneumonia, and respiratory failure.

In conclusion, dacomitinib provided a clinically significant gain in PFS over gefitinib, a standard of care in the first-line setting for patients with unresectable locally advanced or metastatic EGFR-mutated NSCLC. The risks associated with the use of dacomitinib are not unexpected for an EGFR TKI and are adequately managed with dose reductions or dose interruptions. The overall benefit-harm-uncertainty profile of dacomitinib is considered favorable for the recommended indication.

For more information on Health Canadas decision, please view the Summary Basis of Decision.