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Osimertinib Shakes Up EGFR-Mutant NSCLC Landscape

Gina Columbus @ginacolumbusonc
Published: Tuesday, May 02, 2017

Jonathan Riess, MD

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.

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.

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

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.

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. 

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

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? 

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 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. 

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 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.

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