Optimal Sequencing Still a Question in EGFR-Mutant NSCLC

Ramaswamy Govindan, MD

Ramaswamy Govindan, MD

Results from the ongoing BEVERLY trial —if positive— would add another wrinkle to the debate on optimal sequencing in EGFR-positive non-small cell lung cancer (NSCLC).

The randomized phase III BEVERLY study is exploring the combination of bevacizumab (Avastin) and erlotinib (Tarceva) to see if it can prolong progression free survival (PFS) versus erlotinib alone as a first-line treatment in patients with EGFR-positive NSCLC (NCT02633189). In an interview withTargeted Oncology, Ramaswamy Govindan, MD, professor, Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in St. Louis, spoke to the rapid therapeutic changes and sequencing questions physicians are currently asking.

TARGETED ONCOLOGY:Can you provide an overview on your talk on EGFR-positive NSCLC?

Govindan:

EGFR mutations is in 10% to 15% of lung adenocarcinoma tumor samples, and are more common of course in never smokers.EGFR-mutant lung cancers have a distinct clinical course and these tumors respond well to EGFR tyrosine kinase inhibitors. Fifteen years ago, we had nothing for this subgroup of patients, we didn’t even know that it existed and we had no knowledge ofEGFRmutations. But today, we have several options. I am glad to report that in today's discussion, we covered a number of new drugs and strategies, both in the frontline and second-line setting.

TARGETED ONCOLOGY:What are some of these newer strategies?

Govindan:

The first thing is in the frontline setting. At the moment, the issue is, what can we do? Should we really look at theEGFRgenotype and select patients for specific agents? For example, afatinib has been around for a couple of years based on 2 studies; the LUX Lung 3 and LUX Lung 6 trials both randomized patients to afatinib versus chemotherapy. Both studies independently showed, in a subset analysis of the exon 19 patients, a better OS with afatinib than chemotherapy—that was not seen in the L858R group. The most important thing to appreciate is both the studies met the primary endpoint of improving PFS with afatinib; both subsets had that benefit and this is approved for both subsets.

The other issue is adding bevacizumab to EGFR TKIs. A Japanese study showed an increased improvement in PFS when you combine erlotinib and bevacizumab together compared with erlotinib alone, but that’s based on a small randomized phase II 150-patient study. There is a US study that has now completed accrual and we are all awaiting the results of it. It is certainly something we could consider using as well in the frontline setting.

TARGETED ONCOLOGY:What sequencing challenges could occur if osimertinib ends up getting approved in the frontline setting, based on the FLAURA trial findings?

Govindan:

That is an interesting question. If osimertinib is shown to be superior to a first-generation EGFR TKI, we will be faced with the question: are we better off giving the first-generation TKI for 9 to 12 months and then, in selected patients, giving osimertinib, or just better off starting with osimertinib? The answer to that question will come from the results of the study.

It is impossible to look at every different sequence; that is just not going to happen. In some ways, we are dealing with this question every few months when results of a new study come out—especially with the ALK inhibitors. When these things come up, we need to address that. The answer is we don’t know whether A plus B will be better than A followed by B, or it may be better with B followed by A. It is hard to know.

However, there are 2 schools of thoughts here. Some physicians believe that we should go with the best drug first. Others believe, and that includes me, that we need to maximize every single thing. Sometimes, you can go to the third drug first, but then what happens to the disease evolution of a cancer? Would the drugs that work on the mutations be the more important drugs, which would give you a little longer PFS, or are you going to be better doing it the old-fashioned way? That is a very tough question. We are trying to answer that with the ALK Master Protocol trial forALK-positive NSCLC, but it is not going to happen withEGFR-mutant NSCLC at the moment.

TARGETED ONCOLOGY:Are there any other novel agents in development right now?

Govindan:

The issue is that this is a field that is rapidly evolving. A lot of interest is coming up with a new class of inhibitors that would overcome the emerging resistance in EGFR TKIs to make drugs better than osimertinib. I am sure that will continue and we will have better drugs in that area.

The other issue is to fully understand what is driving these tumors to begin with. What is the other cooperating influence that these tumors get beyondEGFR, other mutations, amplification, and other oncogenes? Can we come up with ways to target them, as well, along with targetingEGFR? Also, can we combine that with immunotherapy at some point, for it to be a more personalized therapy?

TARGETED ONCOLOGY:What does the future landscape ofEGFR-mutant NSCLC look like?

Govindan:

Very soon, we already changing our practice; we are biopsying our patients at the time of disease progression and are getting cell-free DNA analyses. We are deciding a second-line therapy based on the gene alterations; this is not just based on what we tested to begin with, but what is happening at the moment. That is a big change; we never did that before.

Secondly, we do have a good strategy for at least half of the patients who progress beyond the first-generation inhibitor. In the coming years, we will find a way to combine various agents and, hopefully, we will come up with novel agents that move downstream to work alongside EGFR inhibitors, as well.

TARGETED ONCOLOGY:What are the take-home messages for community physicians?

Govindan:

In general, we hope our partners in the community understand the rapidly evolving science in this area. You cannot divorce the science from clinical practice anymore. This is a very scientifically driven clinical practice today. Getting that message across to what we are doing in the lab—what we are doing in research—and how we can translate that in the clinic is an important thing.