Goldberg Gives Expert Insight on EGFR-TKI Resistant NSCLC

Angelica Welch
Published: Wednesday, Mar 07, 2018

Sarah B. Goldberg, MD
Sarah B. Goldberg, MD
In September 2017, the NCCN updated its clinical practice guidelines to include frontline osimertinib (Tagrisso) for the treatment of patients with locally-advanced or metastatic EGFR-positive non–small cell lung cancer (NSCLC).

Although osimertinib is still only approved by the FDA in the second-line (the frontline decision date is pending), physicians are already excited about using the treatment in the frontline setting, according to Sarah B. Goldberg, MD. She adds that upfront use of osimertinib is prompting questions related to testing, sequencing, and resistance.

“This is still something that is constantly evolving, and we are still learning about the best ways to understand resistance and manage patients,” Goldberg explains.

In an interview with OncLive ahead of the 5th Annual Miami Lung Cancer Conference, Goldberg, an assistant professor of medicine at the Yale School of Medicine and Yale Cancer Center, discussed the key points of her lecture on testing for and treating resistance to EGFR TKI therapy in NSCLC.

OncLive: You are giving a presentation on resistance to EGFR TKI therapy. How has this topic evolved in just over the last year?

Goldberg: There have been a lot of changes in testing for and treating EGFR TKI resistance in the last year. Many of these changes are because we are now starting to treat with osimertinib in the first-line setting, both on trial and off trial. As we start to do that, we see different mechanisms of resistance come up after first-line osimertinib, and that leads to different ways of thinking on how to overcome resistance. Also, as we are sequencing the EGFR inhibitors using first- or second-generation inhibitors first and then using osimertinib; we are learning more about mechanisms of resistance after second-line osimertinib. We are also trying to better understand how to overcome resistance there. What we are starting to understand is that resistance after osimertinib may be different after first- and second-line treatment. That has become such an important area of research.

In terms of how to test for it, this is something that started several years ago. Whether to get a liquid biopsy or a tissue biopsy is still an evolving question. Many of us are doing both, and while a liquid biopsy is much easier for patients, it can sometimes limit the information that you get.

The lung cancer community is anticipating the FDA’s decision to approve osimertinib in the frontline setting. What are your thoughts on how this potential approval could impact the landscape?

We saw that the FLAURA trial, which compared first-line osimertinib versus either erlotinib (Tarceva) or gefitinib (Iressa), demonstrated a significant benefit in terms of response rate and progression-free survival (PFS) for osimertinib. Based on those results, there has been a lot of enthusiasm to use osimertinib in the first-line setting. It has become a part of the NCCN guidelines, which a lot of people look to for guiding treatment. Technically it is not yet an approved therapy in the first-line setting. An FDA approval gives oncologists a stronger backing to use a drug, and it becomes easier for patients to get through insurance. It will lead to more people using it as a first-line treatment. 

It will also be useful to see more data from FLAURA, specifically the overall survival (OS) data. We had some of that information in the initial presentation and paper from the FLAURA trial, but the data for OS were still immature. Over the next few months, that data will be more important. The FDA approval is important, but so are the trial data. 

If osimertinib is approved in the first-line setting, will we face sequencing challenges? If we treat with osimertinib upfront, what could you give as a second-line treatment?

We learned from the FLAURA trial that using frontline osimertinib does improve PFS compared with using a first-generation EGFR TKI. If you use the first-generation EGFR TKI first, you can use osimertinib second in about half of the patients who will develop T790M. You can use osimertinib in the first-line setting, but what do you do in the second-line setting? That is the potential sequencing challenge. 

Currently, we do not have an option that has been proven to be effective as a second-line targeted therapy after osimertinib. There have been some emerging data that show, depending on the mechanism of resistance, that there may be options in the targeted therapy realm after osimertinib.

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