Lung Cancer: Novel Combinations

Roy S. Herbst, MD, PhD: I’ve been leading a trial with investigators from around the world on ramucirumab and pembrolizumab together. We started doing this in refractory disease—actually, in lung cancer, bladder cancer, and gastric cancer. I’ve reported recently on the arm in lung cancer refractory disease, where we’ve seen responses. As you would expect, you see that with pembrolizumab alone, but also in PD-L1-high, PD-L1-low, and PD-L1-negative patients. So, I think it’s quite compelling that we’re seeing that.

We’re also seeing—in this group of very heavily pretreated patients, second- to fourth-line patients—a PFS of almost 9 months at the median, which for that refractory lung cancer is quite high. So, I think that there’s something there and that it needs to go to a randomized phase II or a phase III trial. There are theoretical reasons as to why a VEGF inhibitor might increase T cell proliferation into the immune microenvironment. It might also help with antigen presentation.

Right now, there are so many unmet needs for clinical investigation. We’re at the tip of the iceberg in what we understand with immune therapies. They work—1 out of 5 patients is getting some benefit. Maybe 1 out of 10 or 1 out of 15, has that long-term benefit and is approaching a cure. So, we have proof of concept. We know it works, but we have to figure out in a personalized way who it works best in. Many patients have primary resistance, meaning that the tumor doesn’t have T cells, so is it inflamed and won’t respond? The tumor might have other checkpoints in play, such as an immune checkpoint or other regulatory mechanisms. We have to figure that out because many patients might need combinations of these drugs in frontline therapy.

And then, we’re seeing that many patients do well, but only for so long, and we don’t know how long we should treat. Is there a specific dose that’s needed to maintain the treatment? Why do patients become resistant? What happens? How do the tumors evolve? So, that’s going to become a major area as well. I would see sensitivity and resistance as the major area, and then, of course, integrating the immune therapies and this new paradigm into the entire continuum of lung cancer treatment.