Osimertinib Shakes Up EGFR-Mutant NSCLC Landscape

Jonathan Riess, MD

Beyond the standard EGFR tyrosine kinase inhibitors gefitinib (Iressa), afatinib (Gilotrif), and erlotinib (Tarceva) for patients with EGFR-mutant non—small cell lung cancer (NSCLC), the osimertinib (Tagrisso) is also making its mark.

The FDA granted osimertinib a full approval in March 2017 for the treatment of patients with metastatic EGFR T790M mutation—positive 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.

OncLive: You spoke on EGFR-positive NSCLC. How has this field evolved?

Jonathan Riess, MD, Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center, spoke on these topics at the 2017 OncLive^® State of the Science Summit on Advanced Non—Small Cell Lung Cancer. In an interview at the meeting, he 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 the EGFR-mutant population.Riess: I had the privilege to speak on EGFR-mutant NSCLC, which represents about 15% of all NSCLC. We have some special drugs—EGFR 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.

Osimertinib just received a full FDA approval. Can you discuss its impact?

What combination studies are being conducted with osimertinib?

We have had some remarkable advances over the past several years, including a third-generation TKI, osimertinib, which is for patients who develop the T790M mutation. 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. It is very exciting that this now has full approval for T790M NSCLC, which is the most common resistance mechanism to earlier-generation TKIs, so that has been a tremendous advance. However, work is needed for EGFR-mutant lung cancer that doesn’t have resistance via T790M. 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 be T790M, so how do we deal with that? 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.

What is osimertinib’s safety profile, and how should physicians manage its associated side effects?

There are other ones with bevacizumab (Avastin), other VEGF targets, and other rational combinations to see if we can even do better in T790M-positive NSCLC and raise the bar for T790M-negative NSCLC, where single-agent osimertinib is not as effective as it is in T790M-positive disease. That’s a great question. Overall, it’s generally pretty well tolerated. It’s more EGFR wild-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.

What other EGFR TKIs are in development?

What are the considering factors for which EGFR-targeted agent you give a patient?

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. 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 new C797S mutation that can develop as a resistance mechanism to osimertinib, but that is in the early days right now.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 have EGFR-mutant NSCLC with an exon 19 deletion, afatinib showed an overall survival benefit. That’s something that I talk about with patients.

Some physicians administer the combination of erlotinib/bevacizumab to these patients. Why do this?

What questions do we still have with EGFR-mutant NSCLC?

What do community oncologists need to know about this field right now for their practice?

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.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 with EGFR mutations 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. 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 as C797S, is going to be major challenge. The prevalence of C797S mutations in NSCLC is 20% to 25%.The major takeaway point is molecular testing to determine if patients have EGFR mutations; then, there are great treatment options with EGFR TKIs. Upon resistance, they should be screened for T790M in either plasma, tissue, or both. If the plasma is negative, then find out if they do have a T790M mutation because then they would be a candidate for osimertinib, which has a high response rate and PFS in these patients.