Investigating EGFR Resistance Leads to New Therapies, Advances in NSCLC

Roman Perez-Soler, MD

While resistance to EGFR-targeted therapies in non—small cell lung cancer (NSCLC) presents a major challenge, there is a silver lining, according to Roman Perez-Soler, MD.

“The story is evolving in a very fascinating way,” said Perez-Soler, chief of the Division of Medical Oncology at Montefiore Medical Center, Albert Einstein College of Medicine. “First of all, it is resulting in new therapies for patients, which is good. Secondly, it is resulting in new biological knowledge regarding, really, what these tumors are all about.”

OncLive: What do we currently understand about EGFR resistance?

In an interview with OncLive, Perez-Soler discussed mechanisms of EGFR resistance and novel agents, including osimertinib (Tagrisso), which have promise for overcoming resistance.Perez-Soler: What we are seeing basically is, as we treat these tumors, they react and try to survive by creating other mutations, activating other pathways, and by changing the type of cancer that they are. We are seeing big morphological changes. What appears to first be an adenocarcinoma can come back as a small cell lung cancer, or as a sarcomatoid lung cancer. It is interesting to see that this tumor really has a potential ability to present in different ways.

The tumor is a chameleon but, behind that costume and behind all of the masks it wears, the tumor is still obviously just 1 tumor. Therefore, what is behind all of these changes? Where is the command center? It seems that everything is pointing to a stem cell—a cell at the beginning that really controls these changes. As the tumor is attacked with our therapeutic interventions, that stem cell is able to use a toolbox and come back with a new mechanism.

How has this challenge impacted patients?

We are going to win the war, and we are corning the enemy and coming up with new weapons. These weapons work for a while. It is only a matter of time to identify the culprit, to unmask the real operative, and to find the Achilles’ heel. We are getting there, but it’s going to be a while. It is fascinating to see how tumors really become tumors and how a gene adapts to survive.The positive part for the patients is that we have identified some important mechanisms and we are able to create drugs that really kill cells with those mechanisms. This means the patients are getting 6, 7, or 8 more months of control. As a result of that, we are pushing tumor control out to 3 years. We are prolonging survival step by step.

Osimertinib is 1 agent that has been identified to overcome this resistance. What impact has it had so far?

What are your thoughts on studies exploring osimertinib in the first-line setting?

It seems that we are going in the right direction for doing this. The progress is real and it happens—not only in immunotherapy, which is the field that everyone is looking at—but also in the field of molecular therapeutics. Here, there is a tremendous amount of progress in terms of the nature of understanding the beast. We are coming up with smart ways of cornering the beast. We are cornering it—slowly— but we are going to win.It has had a great impact. Half of the patients develop these T790M mutations. This drug gets into the brain. It doesn’t cause the rash that some of the inhibitors do. It has very little cutaneous toxicity. The preliminary data show that these drugs will work from the very beginning better than the others. It is a tremendous advance. It is very good news for the patients; they live longer and their quality of life is better. We are going to win.There is a high chance that we will see at least the same outcome as we do starting with another inhibitor—such as erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif)— followed by osimertinib if you develop the T790M mutation. If, in addition, we don’t have the side effect of a rash, then we have a clear winner. This is based on the numbers that we have. It looks very promising, but we have seen promising before and it isn’t always confirmed. We have to be cautious. We will be disappointed if osimertinib does not become the first-line choice.