Rationale for Anti-Angiogenesis in Lung Cancer

Roy S. Herbst, MD, PhD: Any tumor, as it grows, is going to require energy, oxygen, and that’s going to occur by bringing new blood vessels to bear on the tumor. So, you have blocking blood vessels, inhibiting the new formation of blood vessels—angiogenesis—which is quite an exciting thought for how to treat cancers. We’ve known for many years now that bevacizumab, an antibody against vascular endothelial growth factor, or VEGF, does in fact have an effect and improves survival with chemotherapy versus chemotherapy alone. The ECOG 4599 trial showed that the hazard ratio is about 0.8—so some benefit. Interestingly, no biomarker was ever developed to tell us who benefits more than less. We have been using anti-angiogenesis therapy in lung cancer for quite some time.

There are differences in action between ramucirumab and bevacizumab. Ramucirumab is an antibody against VEGF receptor 2. So, it directly targets the receptor, whereas bevacizumab is an antibody against the ligand VEGF. You can either trap up all the ligand with bevacizumab or go directly for the receptor. The 2 drugs are both approved in lung cancer—bevacizumab up front in combination with chemotherapy, the original trial being with carboplatin and paclitaxel. Though, people do use it with carboplatin and pemetrexed as well, usually for nonsquamous tumors because of the risk of bleeding in squamous cell disease.

Ramucirumab is approved in the second-line setting with docetaxel, interestingly both in squamous and nonsquamous cancers. It had a benefit. The benefit wasn’t dramatic, but it was real: a hazard ratio in the mid-0.8 range in the second-line setting. So, it’s an option if you’re using docetaxel in that setting to include ramucirumab. I’m quite excited about it, because I think VEGF is involved in inhibiting antigen presentation and having effects in the immune microenvironment, allowing T cell trafficking near the tumor.

We’re actually doing some trials now with ramucirumab, the VEGFR2 antibody, plus pembrolizumab, the PD-1 inhibitor. Those trials—actually we’ve presented at several of the major meetings this year—are quite exciting because they show that the combination, albeit in a phase I setting where you don’t have a control arm, is producing responses in PD-L1-positive and PD-L1-negative patients in the second—and more—line lung cancer setting. Meaning that, in patients with second-, third-, fourth-, or fifth-line lung cancer, we’re seeing a progression-free survival in the 8- to 9-month range, which I think is quite high. Again, randomized trials will be key.