Corey J. Langer, MD, FACP: Angiogenesis inhibitors can upregulate VEGF and can recruit high concentrations of T-suppressor cells, other elements that may work immunologically against the tumor. When I say against, I mean that they reduce the efficacy. Combining immunotherapy with VEGF inhibitors may help nullify those modes of resistance. This has possibly panned out clinically, based on phase I/phase II trials combining ramucirumab with pembrolizumab. But the door is open to other VEGF inhibitors. Certainly, bevacizumab is being looked at in this setting. Some of the TKIs are also being looked at. It’s certainly not standard yet.
IMpower150 is really the only frontline trial that I’m aware of that looks at frontline combination VEGF inhibition—in this case, bevacizumab with paclitaxel/carboplatin—comparing that regimen with the same triplet with atezolizumab. The trial was strikingly positive. We see a survival advantage in the range of 4.5 to 5 months. That advantage is seen in individuals who have oncogenic drivers—molecular aberrations such as EGFR and ALK. The control arm had a median survival of 17 months, and the investigational arm has not been reached yet. We’re also seeing the opposite end of the spectrum—patients with visceral-dominant disease, such as liver metastases. In fact, in those 2 groups, the hazard ratios are better than the larger, less selected population.
So, the role of combination angiogenesis inhibition and immunotherapy is real. It’s in the here and now. If we go back to that trial and look at the curves, specifically at the progression-free survival curves, they seem to separate more over time after the chemotherapy is completed. This strongly suggests that, in fact, there may be some special synergy between bevacizumab and atezolizumab.
There have been a number of trials in individuals with molecular aberrations, particularly EGFR mutations, comparing erlotinib alone to erlotinib in combination with bevacizumab. Those trials have shown significant improvements in progression-free survival—a 5-, 6-, 7-month advantage for the combination. Unfortunately, as presented at the 2018 ASCO Annual Meeting, that has not yet translated into an overall survival benefit. This is a shame because I truly think that beyond survival, we need to consider quality of life and duration of response.
These individuals, though, if they’re on a TKI, it’s a pill. They don’t need to come into the hospital or into the clinic often. Once you put them on an angiogenesis inhibitor, such as ramucirumab or bevacizumab, they’re tied to the clinic every 3 weeks. That’s the major disadvantage. On the other hand, if I were a patient and had an EGFR mutation, I might opt for the combination, simply to extend my progression-free interval. This will be explored further. There are similar studies looking a osimertinib and ALK inhibitors with angiogenesis inhibition, but those haven’t been reported out yet.