Joshua Bauml, MD
Pivotal trials have laid the groundwork for available EGFR-targeted agents—afatinib (Gilotrif), erlotinib (Tarceva), and gefitinib (Iressa)—for patients with non–small cell lung cancer (NSCLC).
The EURTAC trial, for example, demonstrated the efficacy of erlotinib versus gemcitabine and docetaxel in 173 EGFR-mutant patients. Those who were treated with erlotinib had an overall response rate of 58% and median progression-free survival (PFS) of 9.7 months, compared with 15% and 5.2 months for gemcitabine and docetaxel. These findings led to the FDA approval of erlotinib in the first-line setting in 2013.
Today, ongoing studies are exploring how to target the most common resistance mutation that EGFR
-mutant patients develop: T790M
. Osimertinib (Tagrisso) was granted an accelerated approval by the FDA in November 2015 for patients with advanced EGFR
T790M–mutant NSCLC following progression on a prior EGFR tyrosine kinase inhibitor (TKI).
Osimertinib is also being explored in a phase III study for use following tumor resection, with or without adjuvant chemotherapy, in patients with EGFR-positive NSCLC (NCT02511106). A second ongoing phase III study is comparing frontline osimertinib with gefitinib and erlotinib for patients with EGFR
-mutant disease (NCT02296125).
Joshua Bauml, MD, shared the latest updates in EGFR-targeted therapy for NSCLC during the 2016 OncLive
State of the Science Summit on Advanced Non–Small Cell Lung Cancer, which took place on September 17 in Philadelphia.
“Really the goal—the ‘holy grail’ of targeted therapy, so to speak—is to actually look at this disease like a chronic disease where we can give [patients] a pill and identify what is leading to development of resistance,” said Bauml, an assistant professor of Medicine at the University of Pennsylvania. “How we can prolong the response to these therapies is going to be critical. Once we identify resistance, we need to give a targeted therapy to treat that.”
In an interview with OncLive
during the meeting, Bauml discussed the evolution of EGFR-targeted therapies, resistance mutations in patients with NSCLC, the evolution of next-generation sequencing (NGS), and ongoing trials that could have an impact in this space.
OncLive: What were the main takeaways from your lecture on EGFR-targeted therapies?
mutations are present in 10% to 15% of Caucasians. There’s a higher rate in East Asians, but this is the most common targetable mutation for NSCLC, and we have a lot of data at this point showing that these patients can respond very well to a targeted therapy. This is giving them a pill instead of giving them chemotherapy.
One of the studies I mentioned was the EURTAC study that compared erlotinib to platinum doublet chemotherapy in patients with EGFR-mutant adenocarcinoma. We found that there were markedly improved PFS and response rates. This is echoed in multiple trials that have compared TKIs to chemotherapy in EGFR-mutant lung cancers. You don’t necessarily see an overall survival advantage, but that’s probably due to the fact that the rate of crossover in these studies is approaching 100%.
The reason for that is quite simple. If you have a trial that you’re running, which is randomized between a pill that’s highly active in the cancer you’re treating and chemotherapy with its known side effects, how do you not put a single patient on that study? Unless any patient is randomized to chemotherapy, I know they will get the pill at crossover. That is, in fact, what we saw happen.
There are some questions regarding whether afatinib can prolong survival for exon 19 deletion patients. That analysis, which was done by Dr James Chih-Hsin Yang, et al in Lancet Oncology
, has significant limitations. At this point, erlotinib, gefitinib, or afatinib are reasonable approaches for the first-line treatment of EGFR
-mutant lung cancer.
What about developing resistance to these EGFR-targeted therapies?
This is where things get a little bit complicated. At the time of diagnosis for a patient with EGFR
-mutant lung cancer, their tumors are relatively homogonous. Any place you biopsy is going to have these same exon 19 or L858R
mutation. At the time of resistance, however, that develops in a heterogeneous fashion. One part might be growing and have the T790M
mutation—which is the most common resistance mutation to a first-generation TKI—but another area that’s stable may not have it or may have a different resistance mutation.