Dacomitinib superior to gefitinib for EGFR-positive NSCLC

CHICAGO — Dacomitinib significantly prolonged PFS compared with gefitinib among patients with newly diagnosed, advanced EGFR–positive non–small cell lung cancer, according to randomized phase 3 study results presented at the ASCO Annual Meeting.

Perspective from John V. Heymach, MD, PhD

“In my personal opinion, dacomitinib should be considered as a new treatment for first-line treatment for patients with advanced EGFR-mutated NSCLC,” Tony Mok, MD, professor and chair of the department of clinical oncology at The Chinese University of Hong Kong, said during a press conference.

Gefitinib (Iressa, AstraZeneca) — an EGFR inhibitor — is approved for first-line treatment of patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 substitution mutations.

Dacomitinib (PF-00299804, Pfizer) is an investigational second-generation EGFR tyrosine kinase inhibitor that has demonstrated clinical activity in patients with advanced NSCLC.

The open-label ARCHER 1050 trial was the first phase 3 trial with head-to-head comparisons of two EGFR tyrosine kinase inhibitors.

Mok and colleagues randomly assigned 452 patients with newly diagnosed EGFR-positive NSCLC to 45 mg dacomitinib (n = 227) or 250 mg gefitinib (n = 225) once daily.

Researchers stratified patients by race and EGFR mutation subtype. Baseline characteristics appeared similar between groups. Patients with central nervous system metastases were excluded.

PFS according to independent review served as the primary endpoint. Secondary endpoints included OS, objective response rate, duration of response, investigator-assessed PFS, time to treatment failure, restricted mean survival time for PFS, safety and patient-reported outcomes.

Dacomitinib-treated patients achieved longer PFS as determined by independent review (14.7 months vs. 9.2 months; stratified HR = 0.59; 95% CI, 0.47-0.74) and investigator assessment (16.6 months vs. 11 months; stratified HR = 0.62; 95% CI, 0.5-0.68). Dacomitinib-treated patients also achieved longer median duration of response (14.8 months vs. 8.3 months; stratified HR = 0.4; 95% CI, 0.31-0.53).

Researchers reported similar ORRs in the dacomitinib and gefitinib groups (75% vs. 72%). OS data are not mature.

Common grade 3 adverse events in dacomitinib-treated patients included dermatitis acneiform (13.7%) and diarrhea (8.4%). Approximately 8.5% of gefitinib-treated patients experienced elevated alanine aminotransferase levels.

Higher potency led to higher inhibition, which leads to higher rates of grade 3 diarrhea, dermatitis and other effects. As a result, 8% of dacomitinib-treated patients required dose modifications, compared with 0.9% of gefitinib-treated patients.

Researchers used two dose-modification levels for patients assigned gefitinib (30 mg daily or 15 mg daily). Investigators used one dose-modification level for patients assigned dacomitinib (250 mg every 2 days).

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The time to dose reduction was comparable between treatment groups, but the duration of dose reduction was longer in the dacomitinib group (11.3 months vs. 5.2 months). – by Melinda Stevens

Reference:

Mok T, et al. Abstract LBA9007. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Disclosure: Mok reports employment with The Chinese University of Hong Kong. He reports a leadership role with and stock or other ownership interests in Sanomics Limited; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer and Roche/Genentech; consultant or advisory roles with ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Cirina, Clovis Oncology, Eli Lilly, geneDecode, Ignyta, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGeneX, Pfizer, Roche/Genentech, SFJ Pharmaceuticals Group and Vertex; and research funding to his institution from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eisai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals Group and Taiho Pharmaceutical. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

John V. Heymach, MD, PhD

In the United States, we have three drugs we commonly use for patients with EGFR mutations — gefitinib (Iressa, AstraZeneca), erlotinib (Tarceva; Genentech, Astellas) and afatinib (Gilotrif, Boehringer Ingelheim). There aren’t many studies that compare them head-to-head but [rates] are typically within 2 months of each other when we look at them from separate studies. In this study, we see more than a 5-month difference in PFS. From the perspective of doctors who treat lung cancer, this is a substantial advance. ... I think it really puts dacomitinib at the front of the pack in terms of efficacy.

This does come at the cost of some toxicity. About 10% of patients had grade 3 toxicity involving skin and diarrhea. A substantial number had dose reduction, but I’d like to emphasize that these aren’t life threatening toxicities. These are toxicities that doctors who treat this for a living become accustomed to managing. This drug clearly requires close monitoring and careful surveillance by experienced care providers to manage toxicities.

This provides a clear, potential option for patients. And as a physician, I think discussing the different options in the trade-off of toxicity versus efficacy would be entirely appropriate if the drug were approved in the United States. It’s not approved yet but I think the efficacy here is quite promising when compared head to head with the standard drug.

John V. Heymach, MD, PhD

The University of Texas MD Anderson Cancer Center

Disclosures: Heymach reports grant support from or advisory board roles with AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, Novartis and Synta.