Dacomitinib monotherapy approved as first-line treatment for metastatic NSCLC

The National Pharmaceutical Regulatory Agency (NPRA) has approved dacomitinib (VIZIMPRO®, Pfizer) as a monotherapy for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations.

The new molecule is an irreversible inhibitor of human EGFR tyrosine kinases, including HER1, HER2 and HER 4. The irreversible inhibition is achieved via covalent bonding of dacomitinib with the cysteine residues in the catalytic domains of HER receptors. [https://go.drugbank.com/drugs/DB11963]

Dacomitinib’s approval was powered by the ARCHER 1050* study. ARCHER 1050 was a randomized, multicentre, multinational, open-label Phase 3 study looking into the efficacy of dacomitinib in patients with locally advanced or metastatic NSCLC with EGFR-activating mutations. The dacomitinib arm reported a significantly higher progression-free survival (PFS)** compared with patients treated with gefitinib (HR, 0.59; 95% CI, 0.47–0.74; p<0.0001). Median PFS in the group was 14.7 months (95% CI, 11.1–16.6) compared with 9.2 months (95% CI, 9.1–11.0) in the gefitinib arm. [Lancet Oncol 2017;18(11):1454–1466]

Additionally, an updated overall survival (OS)** analysis from an extended follow-up of ARCHER 1050 revealed a clinically meaningful 8.6-month improvement in OS with first-line dacomitinib versus gefitinib in Asian patients with EGFR-positive advanced NSCLC. “This is the first time that EGFR TKI (tyrosine kinase inhibitors) has been shown to improve overall survival in Asian patients with advanced NSCLC who have EGFR positivity,” said Dr John Low Seng Hooi, consultant clinical oncologist. “These findings are noteworthy for patients in the region, as the investigation included 346 Asian patients from Mainland China, Hong Kong Special Administrative Region, Japan, and Korea. These patients made up roughly 77% of the ARCHER 1050 trial population.” [ARCHER 1050 ESMO-Asia Poster 2019]

The new molecule has also been shown to be effective in difficult-to-treat EGFR mutation subtypes—the exon 21 L858R mutation, which was seen in an extended follow-up of the overall patient population of the ARCHER 1050 study. In this extended follow-up, patients with the exon 21 L858R mutation demonstrated a median OS improvement of 9.3 months with dacomitinib   compared to gefitinib (median OS of 32.5 months for dacomitinib vs. 23.2 months for gefitinib; HR,0.665 via unstratified analysis; 95% CI, 0.470–0.941; 2-sided p=0.0203). [Presented at ESMO Asia 2019, Singapore, 22–24 November 2019]

Low noted the observed survival benefit in patients with the exon 21 L858R substitution mutation is important. In comparison to patients with other frequent EGFR mutations, patients with this specific mutation have a poorer prognosis when treated with currently available EGFR TKIs. He added: “The exon 21 L858R mutation is one of the most common EGFR mutations among Asian patients with EGFR-mutated NSCLC, accounting for up to 40 percent of overall activating mutations in EGFR-positive NSCLC patients in Asia.” [Arch Pathol Lab Med 2018;142:163–167]

The commonly reported adverse events were diarrhoea, paronychia, and dermatitis acneiform and could be easily managed either by dose reduction or symptom management.

*ARCHER 1050: Dacomitinib vs gefitinib for the first-line treatment for patients with EGFR-mutation-positive non-small cell lung cancer

** Progression-free survival (PFS) is the time from treatment initiation until disease progression or worsening, while overall survival (OS), the duration of patient survival from the time of treatment initiation.

Editor’s note: What ‘price’ is extra 9 months of life in advanced cancer care? – One website lists dacomitinib’s price ranging from around USD 100 to 500 per tablet, another quotes 3000 euro for a month’s supply. A difficult decision, indeed, especially for cash strapped family members…