Christine M. Lovly, MD, PhD
The third-generation EGFR inhibitor osimertinib (Tagrisso) has already demonstrated game-changing efficacy for patients with EGFR T790M
-mutant non–small cell lung cancer (NSCLC). Now, ongoing clinical trials are looking to see how much more power the agent could have when used in combination with other therapies.
The TATTON trial, preliminary results of which were presented at the 2015 ASCO Annual Meeting, is a phase Ib multi-arm trial exploring osimertinib with 2 regimens: the MET inhibitor savolitinib or the MEK inhibitor selumetinib. Early findings showed that both regimens had good safety and were synergistic. Two partial responses (PRs) were reported with osimertinib/savolitinib and 2 PRs with osimertinib/selumetinib.
Secondly, an ongoing phase I study is looking at the safety and maximum-tolerated dose of the combination of osimertinib and necitumumab (Portrazza) in patients with stage IV or recurrent EGFR
-positive NSCLC that has progressed on a prior EGFR tyrosine kinase inhibitor (TKI; NCT02496663).
The addition of osimertinib, potentially even in the frontline setting, poses even more sequencing questions for physicians as they decipher which EGFR TKI to administer to their patients first.
Christine M. Lovly, MD, PhD, an assistant professor of medicine (hematology/oncology), assistant professor of cancer biology, medical oncologist, Vanderbilt-Ingram Cancer Center, discussed the changing treatment landscape for patients with EGFR
-mutant and ALK
-positive NSCLC during the 2017 OncLive®
State of the Science Summit on Advanced Non–Small Cell Lung Cancer.
OncLive: Please provide an overview of your talk on EGFR- and ALK-targeted therapies in NSCLC.
There are a lot of different targets in lung cancer right now. We focused on EGFR
because we know the most about them. We talked about identifying EGFR
and what to do when you find it. Now, more than 10 years after we found EGFR
, we have multiple different drugs to treat patients with EGFR
-positive lung cancer or with ALK-positive lung cancer. The question now is, “How do you sequence these drugs, and is there rationale for sequencing them?”
This is a wonderful problem to have, because we have lots of options for our patients but we need to think critically about how we deliver the drugs in a specific sequence to optimize the effects we get against the tumor.
What should physicians know about the available EGFR TKIs?
There are 3 different classes of EGFR TKIs that we use now. There are the first-generation inhibitors erlotinib (Tarceva) or gefitinib (Iressa); those are the ones that we have had around the most and we have the most experience with. They are both FDA approved as frontline therapy for patients with metastatic EGFR
There is also afatinib (Gilotrif), which is a second-generation EGFR TKI. It is a little bit different than erlotinib and gefitinib in that it’s an irreversible inhibitor. That is important to know because afatinib tends to have a little bit more toxicity—skin rash and diarrhea—than erlotinib or gefitinib.
However, all those drugs were designed against wild-type EGFR. That is important because the newest class of EGFR
inhibitors is the third-generation inhibitor osimertinib. This was designed against the EGFR
mutations, which we find in the lung cancer itself. That is important because those drugs tend to have better efficacy against the tumor with fewer side effects—less diarrhea and less rash than you see with the first- and second-generation inhibitors.
What are the next steps with these agents?
There are lots of exciting directions for these therapies. We identify these mutations, and patients can be treated for years with different specific targeted therapies and now, especially with the evolution of these mutant selective inhibitors like osimertinib, because they have less toxicity that also gives us potentially a greater therapeutic window to do combination therapies. One of the big things in the field right now is how to put drugs together with osimertinib in rational combinations to make the good results we see with this drug even better.