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EGFR-Inhibitors and the JCO Study that Cleared the Way for FDA Approval

Aug 11, 2014

        Key Points
  • This 2013 study showed that, among patients with EGFR mutation-positive metastatic lung adenocarcinoma, the tyrosine-kinase inhibitor (TKI), afatinib, was superior to the chemotherapy combination of cisplatin plus pemetrexed in terms of progression-free survival (PFS) and patient-reported outcomes (PRO).
  • Patients who received afatinib had a PFS of 11.1 months, compared to a PFS of 6.9 months among patients who received chemotherapy. In patients with common EGFR mutations (del 19 and L858R), the PFS was 13.6 months for afatinib and 6.9 months for chemotherapy. 

By Shira Klapper, Senior Writer/Editor

A “From the Archives” Exclusive— “From the Archives” features articles from past issues of the Journal of Clinical Oncology (JCO), selected by the Editor-in-Chief based on their important contribution to oncology research.

The story of epidermal growth factor receptor (EGFR) inhibitors began in the early-2000s when two small molecules, gefitinib and erlotinib, showed exceedingly good activity in phase I and II clinical trials in a small percentage of lung cancer patients who had failed chemotherapy treatment. These two molecules were known to inhibit EGFR tyrosine kinase, thus earning the name, “tyrosine-kinase inhibitors” (TKIs).

Soon, researchers uncovered the reason this group of patients had responded to gefitinib and erlotinib: Most of these patients had tumors with specific mutations on the tyrosine kinase part of the EGFR gene. For the most part, patients who did not have EGFR mutations in their tumor did not respond to gefitinib or erlotinib.  Further studies demonstrated that the EGFR mutations make tumor-growth exceedingly dependent on signals coming from the EGFR activating gene pathways.  Studies showed that when TKIs were used as first-line treatment among patients with EGFR mutation-positive metastatic lung adenocarcinoma, the new drugs were superior to conventional chemotherapy in shrinking tumors and increasing progression free survival (PFS).

The introduction of afatinib

 James Chih-Hsin
Yang, MD, PhD 

In 2013, a new EGFR TKI, afatinib, came on the scene. Hailed as a “second-generation” TKI, afatinib was different from gefitinib and erlotinib in that it was shown to be irreversibly active not only on EGFR (HER1) mutations, but also on other HER family pathways such as HER2, HER3, and HER4 as well. In 2012, the Lancet Oncology published the first large phase II study showing that afatinib was highly effective in patients harboring EGFR mutations.

But it wasn’t until a 2013 Journal of Clinical Oncology (JCO) article that the FDA approved afatinib as the preferred first-line treatment for patients with metastatic lung adenocarcinoma. That study, “Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations,” published online, July 1, 2013, showed that afatinib led to greater PFS when compared to the standard chemotherapy, cisplatin and pemetrexed. Specifically, the study reported that in 90% of patients whose tumors contained common EGFR mutations (deletion in exon 19 or L858R), the PFS was 13.6 months for afatinib and 6.9 months for chemotherapy. In addition, the afatinib group reported higher response rates and better patient-reported outcomes (PRO) in terms of cough, dyspnea, and pain, compared to chemotherapy .

According to one of the study’s principle investigators, Professor James Chih-Hsin Yang, MD, PhD, the FDA was not the only regulatory body to approve the drug as a result of the study.

“After this study, afatinib was approved in the U.S., in Europe, and countries in Asia and the Americas,” said Dr. Yang. “At this point, more than 40 countries have approved the drug because of this study.”

According to Dr. Yang, the JCO study provided the definitive evidence in support of EGFR, likely making it the last study that will do so.

“I think this study along with a sister study, Lux-Lung-6, will remain the last ones because after eight studies, we have already established that in an EGFR-mutation population, EGFR is much better than chemotherapy,” said Dr. Yang.

A strong study design makes the difference for the FDA

The 2013 study of afatinib was designed with FDA and global approval in mind. First, the study included a large cohort of 345 patients randomly assigned to receive chemotherapy or afatinib. Second, the cohort was international in scope. Third, this is also the only study that compared afatinib to pemetrexed and cisplatin, the chemotherapy regimen that is regarded as one of the best in lung adenocarcinoma patients. Most importantly, the study endpoint of PFS was arrived at by both the investigators and independent reviewers.

“What is unique about our study is that it was the only global study that was performed comparing EGFR to chemotherapy,” said Dr. Yang. ”Previous studies were performed either in Asia or in countries in which the cohorts were mainly from a white population.”

In addition, other aspects of the study’s design met strict FDA criteria, for example, the requirement that laboratory companion diagnostic tests be consistent across research sites.

“The EGFR mutation test was performed uniformly in three central laboratories,” said Dr. Yang. “In addition to that, the testing was done through a standard operation procedure, as well as with a single companion diagnostic kit, which is a requirement of the FDA to approve a drug in a biomarker-selected population.”

New information on progression-free survival vs. overall survival

Importantly, the JCO study used PFS as the study’s “endpoint,” a term that refers to the outcome used to measure whether treatment is beneficial. According to ASCO’s patient-information website, Cancer.Net, PFS refers to the length of time in which “patients do not experience any new tumor growth or cancer spread during or after treatment.” OS refers to the length of time from diagnosis or start of treatment that the patient is still alive. The JCO study found that afatinib, compared to chemotherapy, led to greater PFS for patients with metastatic lung adenocarcinoma who were EGFR mutation-positive. When it came to OS, there was no difference between the groups at the time of the study’s publication. The distinction within the study is important since the relative merits of PFS compared to OS is a contested topic in the oncology community. (For the pro and con side, as played out in JCO in 2012, see this article and Letter to the Editor).

Which is why Dr. Yang was enthusiastic to mention that, one year later, at the 2014 Annual Meeting of the American Society of Clinical Oncology, the same research group reported encouraging news from the Lux-Lung-3 study. In the matured analysis of 345 patients in this study, afatinib was found to have a distinct advantage in OS of more than one year, compared to chemotherapy in patients who had a deletion in exon 19 (about 50% of all EGFR mutations). This OS advantage among patients who had del 19 EGFR mutation and received afatinib was also confirmed in a sister study, Lux-Lung-6. 

Which makes Dr. Yang confident that continuous effort to improve EGFR TKIs are the future of cancer care for patients with metastatic lung adenocarcinoma who are EGFR mutation-positive.

 “In future studies,” said Dr. Yang, “we will just be comparing one EGFR TKI to another or adding novel targeted therapy to EGFR TKIs for the first line treatment in EGFR mutation positive patients.”

James Chih-Hsin Yang, MD, PhD, is a Professor at the Graduate Institute of Oncology and the Director of the Cancer Research Center at the College of Medicine, National Taiwan University. He is also the Director of the Department of Medical Research and the Deputy Director of the Department of Oncology at the National Taiwan University Hospital. He currently serves on the Editorial Board of JCO.



Click here to read the abstract.


Click here to read the PDF.


Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. Published online 7.1.2013.

The Exclusive Coverage series on ASCO.org highlights selected research from JCO and JOP with additional perspective provided by the lead or corresponding author.


@ 2014 American Society of Clinical Oncology

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