Expert Discusses Targetable Mutations and New Agents in Lung Cancer

With the influx of FDA approvals of targeted agents and immunotherapy, lung cancer treatment is drastically different than it was years ago. Advances are also being made in the diagnostic arena as well, as more targetable mutations have been identified through plasma-based assays.

Most recently, in October 2016, the FDA approved the PD-1 inhibitor Keytruda (pembrolizumab) for the frontline treatment of patients with metastatic non—small cell lung cancer whose tumors have at least 50 percent PD-L1 expression and who do not harbor EGFR or ALK aberrations. This was an update from Keytruda’s initial approval in the second-line setting in October 2015.

Keytruda is joined by two other FDA-approved checkpoint inhibitors Opdivo (nivolumab) and Tecentriq (atezolizumab).

Numerous targeted agents have also been approved aimed at patients with EGFR and ALK mutations or abnormalities. For patients with EGFR-mutant tumors, Gilotrif (afatinib), Tarceva (erlotinib) and Iressa (gefitinib) are on hand, along with Tagrisso (osimertinib), a drug able to target the resistance mutation T790M. With ALK-positive patients, Xalkori (crizotinib), Zykadia (ceritinib) and Alecensa (alectinib) have been approved as targeted therapies, too.

These are just a handful of the advancements highlighted by Mark G. Kris, M.D.

What are these advancements that have shaped therapy?

In an interview with CURE, Kris, a medical oncologist at Memorial Sloan Kettering Cancer Center, shares his thoughts on the prominent advancements in the field of lung cancer, how liquid biopsies are shaping treatment decisions, and his predictions for the years ahead.First, we have an evolution in how the targets [for targeted therapies] are found. There is more comprehensive mutational tissue testing and more available tissue testing. Now, in addition to tissue, you have the ability to detect these relevant mutations in blood—both individual ones like T790M or EGFR in next-generation sequencing (NGS) panels of mutations where you can assay what options are available for individual patients. That is something that is rapidly becoming a standard of care here in the United States.

What sequencing challenges are we facing now?

More information is available, as well, about new drugs, such as Tagrisso at time of acquired resistance and also as initial therapy. Xalkori is here with its use in MET exon 14 skipping mutation, and with Cabomeytx (cabozantinib) and its use in RET—all these topics are being discussed. Now, the great opportunity that we have with these multiple agents is how do we select which one to give first, and how do we decide which one to give second? What information is there to make these choices? The marketplace and individual institution initiatives in the area of testing are just going to move this field so quickly. The problem is which option to choose and not having availability. Many of the insurance carriers have said that when a result is needed, they are agnostic as to the way it is obtained, as long as it is done in a clean setting. A lot of the barriers are gone. The cost barriers are virtually gone. It’s going to get cheaper and cheaper, and more and more available.

We've been hearing buzz about liquid biopsies a lot this year. Will that trend continue?

The issue is, do you test blood or tissue? What do you do when you have chosen to use tissue until the tissue results are available? We have heard a range of different options. Some patients have blood-based tests for specific genes; others, like at my institution, use immunohistochemistry (IHC)-based tests. The beautiful thing about them is that they are part of the flow of pathology departments today, and it’s very easy for them to do that in any patient with a suspicion of lung cancer. This is because they’re already doing other IHC tests, so to add an additional one is very easy and sometimes the quickest way to do it.For those patients that, for some reason, cannot have a tissue biopsy, it is going to be standard of care. I would say that, today, it is the standard of care. If you can’t do a biopsy, then you need that information. There are some issues there that the technology of interrogating hundreds of genes in a blood sample is a bit more daunting, because the amount of DNA that you get is variable. People with very limited spread of cancer often don’t have a lot of DNA; they might not be good candidates for that testing.

There has been an explosion of agents — both targeted and immunotherapeutic — over the last couple of years. Will they compete with one another?

As time goes on though, there isn’t going to be a single answer to that. It depends on your healthcare environment—the availability of tissue and of doctors providing tissue. If you are still doing a biopsy, then why not get all you can get out of that biopsy? Even using a blood-based test is kind of unnecessary if you have the tissue that you need.If you take traditional cytotoxic chemotherapy, immunotherapy and targeted therapy for those patients who have targets they are, in many ways, all relevant. There is not any firm evidence today that the success or failure with one or another predicts success or failure with the next one. If anything, they are parallel, likely sequential, and likely to derive benefit. EGFR is a good example. No matter when you get an EGFR inhibitor — if you have a cancer that is wired that way — it’s going to work. That is going to continue and nothing is going to replace anything. The order of treatment will change but as people live longer, we are going to have the need for more treatments. My guess is that people are going to get them all at some point.

In one year from now, what would you like to see accomplished?

As we have seen in the last year, though, our ability to see or predict for whom these drugs are going to work is going to improve. With the selections that we make, the first choice will ideally be the one with the greatest chance of benefit for the patient. That is what we are going to see going forward.We have an array of treatments. We should not get locked in the idea that there is any one treatment. Even ideas that were radical, such as operating on metastatic deposits on individuals with widely metastatic lung cancers, was considered totally inappropriate 10 years ago. Now, in the right patient, it’s the standard of care.

With each and every patient, we should put on our thinking caps — often with limited data available — to decide which approach to use first, what to choose as an alternative, and what is the alternative after that. That is the message today, and that is going to be the message for the next five years.

We are trying to figure all of this out. It is going to be tough, but they’re not going to be randomized trials that say, “do this” or “do that.” The field is moving too fast, and to wait 5 years to do a randomized trial is not going to happen anymore.