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Pennell Provides Perspective on EGFR-Targeted Agents in NSCLC

Gina Columbus @ginacolumbusonc
Published: Thursday, Jul 21, 2016

Nathan Pennell, MD, PhD

Nathan Pennell, MD, PhD

As more patients with non–small cell lung cancer (NSCLC) are being tested for EGFR mutations and more therapies are being approved by the FDA, a new challenge is rising in the field, explains Nathan Pennell, MD, PhD.

“The question is, ‘What is the best one to use?’” says Pennell, who gave a lecture on EGFR-positive NSCLC during the 2016 OncLive State of the Science Summit on Metastatic Non–Small Cell Lung Cancer. “We actually have 3 approved first-line EGFR TKIs in the United States. We have erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif), which is a second-generation irreversible pan-HER inhibitor.”

Pennell cautions, however, that these agents should not be administered to patients unless they carry the EGFR mutation.

In an interview with OncLive during the meeting, Pennell, associate professor of Medicine at Cleveland Clinic, discussed these 3 available—and competing—agents in this space, as well as ongoing clinical trials at Cleveland Clinic exploring other regimens for the EGFR-mutant patient population.

OncLive: What is the latest news in the realm of EGFR-positive NSCLC?

Pennell: EGFR-mutant non–small cell lung cancer is the most common genetically driven type of lung cancer. It was first identified in 2004 from subgroups of the large unselected trials of the EGFR inhibitors erlotinib and gefitinib, when they discovered that about 10% of patients on those trials had these really dramatic responses. Interestingly, they happened to be women who had never smoked and had adenocarcinoma. Researchers took those tumors, sequenced their EGFR gene, and found that they had recurring mutations in the EGFR tyrosine kinase domain.

Since then, we know that these are present in 10% to 15% of everyone with adenocarcinoma. In people who have never smoked, it is actually probably closer to 40%. For a number of years now, it has been very standard for patients in the United States to have their EGFR gene mutation status tested at diagnosis if they have any nonsquamous tumor. The reason for that is we now have several very good randomized trials of EGFR inhibitors versus chemotherapy in the first-line setting.

The first one was called the Iressa Pan-Asia (IPASS) Trial, which was done in Asia. It compared gefitinib with carboplatin and paclitaxel and showed that people with an EGFR mutation had a much better progression-free survival (PFS), a much higher response rate, and less toxicity with gefitinib. Those who didn’t have an EGFR mutation—even if they were never-smokers with an adenocarcinoma—actually did much worse with the EGFR inhibitor.

That really was the first time we saw that. It’s the genotype that matters, and not the phenotype. That has been reproduced in western Caucasian populations and has been reproduced in half a dozen different trials. We now know that EGFR inhibitors are clearly superior to chemotherapy with a longer PFS, higher response rate, less toxicity, and longer duration of control, so that is standard everywhere.

Can you shed more light on afatinib?

There were a couple of phase III trials that led to the approval of afatinib. Afatinib versus chemotherapy in EGFR-mutant lung cancer had a very similar improvement in PFS and response rate compared with chemotherapy that we saw in the first-generation inhibitors.

What is a little unique about afatinib is that, in subgroup analyses of the exon 19 deletion, there was a very significant improvement in overall survival for afatinib compared with chemotherapy. That was not seen in the second most common group, which were the patients with an exon 21-point mutation. Those did not have a survival benefit, but still had the same PFS benefit. This suggests that perhaps afatinib is a better choice than the other EGFR inhibitors, specifically for the exon 19 deletion patients.


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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 18th Annual International Lung Cancer Congress®Oct 31, 20181.5
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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