Emerging Data Could Rearrange Frontline EGFR TKIs in NSCLC

Gina Columbus @ginacolumbusonc
Published: Saturday, Nov 12, 2016

Howard L. “Jack” West, MD

Howard L. “Jack” West, MD

Individualizing frontline therapy for patients with non–small cell lung cancer (NSCLC) based on preferences and clinical experience, as well as efficacy and safety data from pivotal trials, is an appropriate method for selecting EGFR-targeted agents, according to H. Jack West, MD, who lectured on choosing the best upfront treatment for patients with EGFR-mutant NSCLC during the 11th Annual New York Lung Cancer Symposium®.

With the current 3 EGFR tyrosine kinase inhibitors (TKIs) that are FDA approved—erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif)—West picked apart key clinical trial findings comparing the trio's efficacy to determine if one is superior to another. 

Afatinib was explored in the LUX-Lung 3 and LUX-Lung 6 studies.1 In both studies, afatinib was compared with chemotherapy in patients with NSCLC and was associated with a median overall survival (OS) of 27.3 months with afatinib versus 24.3 for chemotherapy-treated patients. Specifically in patients with exon 19 deletion, there was a more significant difference; the median OS was 31.7 months with afatinib versus 20.7 months with chemotherapy (HR, 0.59; CI 95%, 0.45-0.77; P = .0001).  

A head-to-head comparison of EGFR-targeted agents was observed in LUX-Lung 7 of daily gefitinib (n = 159) and afatinib (n = 160) in the first-line setting in patients with EGFR-positive disease who also harbored exon 19 or exon 21 deletions.2 Results showed that there was minimal difference in duration of response between patients with exon 19 deletions and L858R substitution. Patients treated with afatinib had an overall response rate (ORR) of 70% while afatinib’s was 50% (P = .0083). Duration of response was 10.1 and 8.4 months with afatinib and gefitinib, respectively.

In terms of safety, the most common grade 3/4 adverse events (AEs) with afatinib were diarrhea (11.9%) and rash/acne (9.4%). With gefitinib, alanine aminotransferase increase was the most common grade 3/4 AE (7.5%). Additionally, treatment-related interstitial lung disease occurred in 2.5% of patients treated with gefitinib versus 0% with afatinib.

The study also showed that serious treatment-related AEs were more frequent with afatinib (10.6%) versus gefitinib (4.4%). AEs that led to dose reductions occurred in 41.9% of patients treated with afatinib versus 1.9% with gefitinib; however, treatment discontinuation due to AEs was the same in each arm (6.3%).

Regarding adverse events, West stressed, this is an important part of distinguishing these targeted agents from one another.

“The overall summary is not that different in adverse events or discontinuation in the gefitinib and afatinib arms,” stated West, a thoracic oncologist of Swedish Cancer Institute at Swedish Medical Center. “Afatinib is a somewhat more challenging agent to deliver, but [...] when you look at the drug-related AEs, gefitinib was associated with a higher incidence of LFT abnormalities, including some grade 3 abnormalities.” 

Overall, West said that as physicians balance efficacy and side effects of these EGFR TKIs to guide treatment decision-making, it is imperative to individualize patients.

Additionally, they should recognize that “efficacy might be marginally greater with afatinib and it may be a good choice for a robust and motivated patient,” West concluded. “However, the tolerability issues would favor erlotinib over gefitinib intentionally. In the United States, we generally see that erlotinib is the most commonly prescribed [treatment], while afatinib also represents a significant fraction. Gefitinib is a very fine choice for patients who are concerned specifically about toxicity issues, or their ability to tolerate a treatment.” 

Promise With Combinations

An in-development 2-drug regimen including erlotinib plus bevacizumab (Avastin) is already garnering excitement in the field, and is an option West said he prefers in most cases.

While not yet available for use in the United States, the European Medicines Agency approved the combination as a frontline treatment for patients with unresectable advanced, metastatic, or recurrent EGFR-mutant NSCLC in June 2016.

The European approval was based on findings from the phase II JO25567 study, which demonstrated a 46% reduction in the risk of progression or death with erlotinib/bevacizumab versus single-agent erlotinib.3 The median PFS with bevacizumab added was 16 months compared with 9.7 months with erlotinib alone (HR, 0.54; 95% CI, 0.36-0.79; P = .0015). 

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Year in Review™: Reflecting on Recent Evidence With an Eye to the Future of Lung Cancer ManagementMar 30, 20191.5
Online Medical Crossfire®: 5th Annual Miami Lung Cancer ConferenceMay 30, 20196.5
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