Jonathan Riess, MD, discusses the game-changing efficacy of osimertinib in NSCLC and its potential in combination, considering factors for choosing an EGFR TKI, and the burgeoning questions clinicians still have with the<em> EGFR</em>-mutant population.
Jonathan Riess, MD
Beyond the standard EGFR tyrosine kinase inhibitors gefitinib (Iressa), afatinib (Gilotrif), and erlotinib (Tarceva), osimertinib (Tagrisso) is also making its mark in the treatment of patients withEGFR-mutant nonsmall cell lung cancer (NSCLC).
The FDA granted osimertinib a full approval in March 2017 for the treatment of patients with metastaticEGFR T790Mmutationpositive NSCLC following prior treatment with an EGFR TKI based on its impressive progression-free survival (PFS) findings. Osimertinib is also being explored as a frontline agent in the phase III FLAURA trial compared with gefitinib or erlotinib in these patients.
Researchers are also studying osimertinib in combination regimens. For example, a phase I trial is exploring osimertinib in combination with the EGFR monoclonal antibody necitumumab (Portrazza) after progression on a previous EGFR TKI. Primary endpoints include incidence of toxicity and maximum-tolerated dose.
Jonathan Riess, MD, Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center, shared his insight on the game-changing efficacy of osimertinib in NSCLC and its potential in combination, considering factors for choosing an EGFR TKI, and the burgeoning questions clinicians still have with theEGFR-mutant population.
TARGETED ONCOLOGY:How has the EGFR-positive NSCLC field evolved?
EGFR-mutant NSCLC represents about 15% of all NSCLC. We have some special drugsEGFR TKIs—that are very effective against treating this type of lung cancer. However, invariably, people develop progressive disease within 2 years, so new treatments and combinations are desperately needed.
We have had some remarkable advances over the past several years, including a third-generation TKI, osimertinib, which is for patients who develop theT790Mmutation. I also talked about the sequencing of treatment; future directions, including potentially bringing up these third-generation drugs to frontline therapy and what that means; and how the resistance mechanisms may change and whether that would be a viable strategy in future research.
TARGETED ONCOLOGY:Osimertinib just received a full FDA approval. Can you discuss its impact?
It is very exciting that this now has full approval forT790MNSCLC, which is the most common resistance mechanism to earlier-generation TKIs, so that has been a tremendous advance. However, work is needed forEGFR-mutant lung cancer that doesn’t have resistance viaT790M. It has other resistance mechanisms, so we are looking at other combination therapies. Also, there are implications for if osimertinib does move up to the frontline setting with the pivotal ongoing FLAURA trial. What does that mean for the resistance mechanisms that may change; it may not beT790M, so how do we deal with that?
TARGETED ONCOLOGY:What combination studies are being conducted with osimertinib?
There is the TATTON trial that’s being led by Dr Geoff Oxnard at Dana-Farber Cancer Institute that’s looking at the various combinations including MET inhibitors, MEK inhibitors, and other drugs. We have a clinical trial at UC Davis through our UC consortium that is actually looking at osimertinib and the EGFR monoclonal antibody necitumumab in combination; that’s very exciting.
There are other ones with bevacizumab (Avastin), other VEGF targets, and other rational combinations to see if we can even do better inT790M-positive NSCLC and raise the bar forT790M-negative NSCLC, where single-agent osimertinib is not as effective as it is inT790M-positive disease.
TARGETED ONCOLOGY:What is osimertinib’s safety profile, and how should physicians manage its associated side effects?
That’s a great question. Overall, it’s generally pretty well tolerated. It’s moreEGFRwild-type sparing than erlotinib and afatinib, so rash and diarrhea seems to be a bit less, but it does happen still and needs to be managed.
There have been cases of pneumonitis, so that’s something to be aware of. It requires some monitoring of heart function according to the package insert. These are things that you need to look at. But, the major concern is risk of pneumonitis.
TARGETED ONCOLOGY:What other EGFR TKIs are in development?
In addition to the previous trials mentioned, there are some other EGFR TKIs that have been studied. There are some of the third-generation EGFR TKIs that are being looked at and, eventually, researchers are going to be screening drugs to overcome the newC797Smutation that can develop as a resistance mechanism to osimertinib, but that is in the early days right now.
TARGETED ONCOLOGY:What are the considering factors for which EGFR-targeted agent you give a patient?
I generally individualize patient treatment. For example, the ones approved now in the first-line setting are erlotinib, gefitinib, and afatinib. For patients who are older and more frail, I’ll use gefitinib because the side effect profile can be a little bit more favorable in terms of rash or diarrhea versus erlotinib or afatinib. The other option is to start at a lower dose of erlotinib. In patients who haveEGFR-mutant NSCLC with an exon 19 deletion, afatinib showed an overall survival benefit. That’s something that I talk about with patients.
At UC Davis Comprehensive Cancer Center, we have the S1403 trial of the combination of afatinib plus cetuximab (Erbitux) versus afatinib alone, so that’s also an option that we offer to our patients on a trial basis.
TARGETED ONCOLOGY:Some physicians administer the combination of erlotinib/bevacizumab to these patients. Why do this?
There was a randomized phase II study in Japan that showed a great progression-free survival benefit with bevacizumab/erlotinib, so the thought is that patients who are younger withEGFRmutations may do better with the addition of VEGF inhibition. It is definitely a consideration for patients who are bevacizumab eligible. Further trials will tell us how far it gets in terms of getting regulatory approval in the future, but bevacizumab is approved in combination with carboplatin/paclitaxel and platinum-based chemotherapy, so it’s something to think about in certain select patients, because there is activity there.
TARGETED ONCOLOGY:What questions do we still have withEGFR-mutant NSCLC?
The key is bringing rational combinations upfront to forestall resistance, and how best to do that is a large unanswered question. Targeting all of these resistance mechanisms to third-generation EGFR TKIs, such asC797S, is going to be major challenge. The prevalence ofC797Smutations in NSCLC is 20% to 25%.
TARGETED ONCOLOGY:What do community oncologists need to know about this field right now for their practice?
The major takeaway point is molecular testing to determine if patients haveEGFRmutations; then, there are great treatment options with EGFR TKIs. Upon resistance, they should be screened forT790Min either plasma, tissue, or both. If the plasma is negative, then find out if they do have aT790M