Advances in Biomarker-Driven Therapy for Advanced NSCLC - Episode 3

NSCLC: Targeted Therapy Landscape

Briana Contreras

Paul K. Paik, MD

Paul K. Paik, MD, discusses currently available targeted therapies for patients with NSCLC.

Briana Contreras: How has the availability of targeted therapies changed the overall survival rate of patients with advanced non–small cell lung cancer?

Paul K. Paik, MD: At this point, it’s fair to say that targeted therapies have led to a dramatic extension in overall survival rates for our patients with stage IV lung cancers. There’s a signal that’s beginning to emerge, where we think this is going to be present in our patients with early-stage lung cancer who have been treated with EGFR-directed therapies. I say “at this point” because in earlier days and earlier trials, it was hard to differentiate whether the survival signal we were seeing was because of the therapy or just the natural history of that disease. It could have been that these alterations led to a better prognosis, but it’s evident that they do lead to an improvement in overall survival, because we have treated these patients against other standard-of-care treatments like chemotherapy. The overall survival in some cases is much longer. We’re talking about overall survival rates for some of these patients being in excess of 4 years for the median; these are dramatic differences, and arguably some of the most powerful therapies that we have had to offer patients with these diseases.

Briana Contreras: When should targeted therapy be considered for a patient with advanced non–small cell lung cancer?

Paul K. Paik, MD: There are 2 ways to answer this. One way is from a cold, data-driven perspective, which is to say we have a set of therapies available for patients, so we’re going to do a series of trials to tease apart whether these treatments are better than one another in different settings. The thing we’re going to look for is how great the response is and how long patients live. That has been the traditional way to do these studies. They require large, randomized phase 3 trials and many patients, with half those patients getting 1 treatment and half the other. That has been the gold standard—and to some extent still is—but those trials take awhile to accrue, and the signals we’re seeing with targeted therapy trials in the earlier-phase settings are so high that we’re beginning to incorporate these things into standard practice even before these phase 3 trials.

Then we get to the second way of thinking about when to introduce these, which is a very patient-specific way. A good example of this would be for MET-directed therapy for patients who have exon 14 skipping. These patients are a lot older than our average patients with lung cancer, so they’re not represented in the standard-of-care trials that we have. There are other considerations and concerns when we treat them, particularly with how toxic the regimen might be and what other comorbid conditions they have. Here, we’ll take a more personalized approach, with large, targeted therapies—they come out as the treatments to give at the time of diagnosis because of how effective they are and about how well tolerated they are.

Briana Contreras: How do targeted therapies compare with other therapies in terms of the mechanism of action? How did this relate to their toxicity profiles?

Paul K. Paik, MD: All therapies that we give have specific mechanisms of action, so 1 common misnomer is to think that chemotherapy is indiscriminate in terms of how it works, so targeted therapies are better from that standpoint. That’s true to an extent, but it’s also a misunderstanding of how chemotherapy works in a very specific biological mechanism. Targeted therapies are referred to as targeted because there’s a specific change that we’ve identified in the cancer that we’re using to prescribe these medications, which then target these changes. That’s not really the case with chemotherapy. We give everyone chemotherapy, but there’s no biomarker that we look for, and that’s really the big difference between those 2 treatments. This gets at that second part: toxicity profiles. Since the targeted therapy is specific as to how it works in terms of the biological process, often these treatments are better tolerated than standard chemotherapy, and that’s reflected in the toxicity profiles that we see.

Briana Contreras: What are some of the more recent targeted therapies that have become available? What are some common biomarkers or alterations for which treatments are in late-stage clinical development?

Paul K. Paik, MD: The most recent targeted therapies in the treatment of non–small cell lung cancer—they boil down to 3. One of them is MET exon 14 skipping as a biomarker, for which we now have selective MET inhibitors that are FDA approved. Another has to do with 2 biomarkers, for which we do not have FDA-approved indications, but I think we will soon, and that’s targeted therapy against KRAS G12C. There is also targeted therapy against HER2 [human epidermal growth factor receptor 2] mutations. These have shown very good, promising signals—good enough to receive actual approval—so they’ll be approved next, and they fall under that most recent targeted therapy availability.

In terms of those that are in late-stage clinical development, at this point a lot of the emphasis is on earlier-phase studies, signals that we see in phase 2 studies. That’s where a lot of the excitement is because that’s when we begin to see the first glimpse of real efficacy. That’s often used by the FDA to provide an accelerated approval, which is of course the first mechanism by which patients can receive these therapies. There’s less emphasis nowadays on these late-stage phase 3 clinical trials because of that.

Transcript edited for clarity.