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Optimal Sequencing in EGFR-Mutant NSCLC Remains a Work in Progress

Gina Columbus @ginacolumbusonc
Published: Monday, May 15, 2017

Ramaswamy Govindan, MD

Ramaswamy Govindan, MD

As researchers continue to debate optimal sequencing in EGFR-positive non–small cell lung cancer (NSCLC), results from the ongoing BEVERLY trial—if positive—would add another wrinkle to the discussion.

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). During the 2017 OncLive® State of the Science Summit on Advanced Non–Small Cell Lung Cancer, Ramaswamy Govindan, MD, professor, Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in St. Louis, lectured on the EGFR-mutant landscape in NSCLC. In an interview, Govindan, who also co-chaired the meeting, spoke to the rapid therapeutic changes and sequencing questions physicians are currently asking.

OncLive: 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 of EGFR mutations. 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. 

What are some of these newer strategies?

The first thing is in the frontline setting. At the moment, the issue is, what can we do? Should we really look at the EGFR genotype 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. 

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

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.

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