Targeted Genomic Therapies Have a Growing Impact on Lung Cancer

The discovery of oncogenic drivers in lung cancer — and subsequently, the targeted therapies used to treat them – have transformed the therapeutic landscape of the disease in recent years. But there is still room for improvement, said Dr. Corey J. Langer, director of thoracic oncology at the Abramson Cancer Center at the University of Pennsylvania.

CURE’s sister publication, OncLive, recently sat down with Langer at their Precision Medicine Symposium to learn more about his work in the field and how the advent of targeted therapies and immunotherapy have helped patients with non-small cell lung cancer.

OncLive: Where does lung cancer stand when compared with other cancers, as far as the precision medicine approach is concerned?

Langer: Lung cancer is really ahead of the pack, to some extent, which is sort of ironic. Historically, lung cancer has been considered a resistant illness and chemotherapy didn’t work too well. But in the last 10 to 15 years, there have been four actionable oncogenic drivers. EGFR was the first, then ALK, and more recently ROS1 and BRAF. Very few other cancers have that array of potential oncogenic drivers.

And now we’ve seen other drivers like HER2 and MET 14 skipping mutations, all of which are actionable. This is still a minority of patients, but it’s a significant number. Lung cancer affects 225,000 to 250,000 individuals yearly in the United States. Non-squamous is the most common histology, with at least 30% or perhaps 35% of patients with non-squamous disease that will have some sort of oncogenic driver.

How have targeted therapies transformed the way patients are treated?

Targeted therapies have irrevocably transformed the therapeutic landscape, at least for those with oncogenic drivers. So, for EGFR mutant patients, in the past we would have given them chemotherapy alone or chemo plus bevacizumab (Avastin). Response rates were about 30%, with progression-free survival at best six months and overall survival medians were around 12 to 14 months.

Now, with the advent of (Lorbrena [lorlatinib]), (Mekinist [trametinib]), (Gilotrib [afatinib]), and most recently (Tagrisso [osimertinib]), response rates are 70%. Progression-free survival with (Tagrisso) is nearly 19 months, and median survival in many of these studies has not been reached at three or even four years; in fact, the median survival overall of this population is clearly north of four years. In some studies, it looks like it will be about five years, and remember we are seeing some long-term survivors. I don’t fool myself for a moment that they’re cured, but as long as they stay on therapy, sometimes at reduced doses, they’re doing well.

We’ve seen even more astounding success with ALK. The number of patients with ALK translocations is a smaller proportion. Unlike EGFR which is about 10% to 15%, ALK is seen in perhaps 3% to 8% of advanced non-small cell non-squamous patients. But the drugs work exceedingly well. (Alecensa [alectinib]) and (Alunbrig [brigatinib]) are now the frontline agents of choice, with response rates in the 70% to 75% range and (progression-free survival), at least in the ALEX trial, at about three years. We’ve never seen that before. We were happy to see survivors at three years; this is a median progression-free survival of three years. And then, overall survival, at least in ALK and probably in ROS1 as well, it looks to be about six or even seven years.

Growing up in this field, finishing my fellowship as a junior faculty, I couldn’t envision what we’re experiencing now. It has completely transformed the therapeutic landscape. But it’s still only a minority of patients, about a third of patients.

Based on all this, what does a lung cancer diagnosis mean today versus a decade ago?

It’s still a bad diagnosis. Nobody wants lung cancer, and certainly nobody wants metastatic lung cancer. But it is a lot more hopeful.

When I started out, I finished my fellowship in 1987 - we’re talking 32 years ago - and it was bleak. Median survival was six to eight months. In the early aughts we moved to about a year, maybe 14 months, and now all of a sudden, we’re seeing trials with single-agent, non-cisplatin, non-chemotherapeutic approaches where the median survival is 20 months or 30 months. I hadn’t dreamt that anything of that sort would happen.

And you can color me, at least up until three or four years ago, an immune skeptic. I had prior experience with interleukin-2 and with beta-interferon, highly toxic treatments that purported to manipulate the immune system, where we certainly saw a lot of side effects, but we didn’t see much benefit.

And overnight, seemingly, certainly within a year or two, the checkpoint inhibitors have completely, irrevocably altered the therapeutic landscape. Things are a lot more hopeful, but unfortunately the vast majority of these folks will still die within three to five years. So, we need to do better.

The therapeutic approaches are clearly improving but we need a lot more to go on.