Breakthroughs in Treating NSCLC

Benjamin P. Levy, MD: I don’t think we really know mechanisms of resistance for VEGF inhibition. This is a very hot area of research. Why would patients initially respond to either bevacizumab or ramucirumab and do well for a long period of time, and then their tumor grows? I think this is something we need more work with. We know very little about some of the mechanisms of resistance to chemotherapy, alone, immunotherapy, and antiangiogenic drugs. We know more about targeted therapy mechanisms of resistance. But very little is known. This is an area where we need to do more work, so that we can come up with rational strategies to address these mechanisms of resistance that can translate into meaningful improvements and outcomes for patients.

I think the nice thing about antiangiogenic strategies is that they may partner well with a lot of different novel agents. I think VEGF is at the underpinning of a lot of tumor growth, whether it’s an EGFR-mutant lung cancer case, an ALK-rearranged lung cancer case, or a patient without an actionable mutation.

There’s a lot of rationale for using an antiangiogenic drug with a checkpoint inhibitor. VEGF is immunosuppressive. It upregulates to regulatory T cells, which are immunosuppressive. It upregulates myeloid-derived suppressor cells, which are immunosuppressive. It decreases T-cell trafficking. By inhibiting VEGF with an antiangiogenic drug, you may reverse that immunosuppression that may allow the checkpoint inhibitor to work better—essentially augmenting the responses with immunotherapy. There is a lot of preclinical rationale for why using checkpoint inhibitors with antiangiogenic drugs may be very beneficial. We have very little data on this. We do have some data with the IMpower150 trial, but we’re going to learn more and more with this clinical immunotherapy blitz that’s coming out. Many of these strategies are looking at antiangiogenesis, or anti-VEGF, with a checkpoint inhibitor—either a PD-1 or PD-L1 drug.

There’s a lot of preclinical rationale for why adding an antiangiogenic drug, or an anti-VEGF drug, may work with an EGFR TKI. These drugs, at least clinically in the data that we have so far, have synergy. Adding bevacizumab to erlotinib improves progression-free survival in every single study that we’ve seen. While it may not improve overall survival, we think that there is potential synergy in looking at a VEGF or EGFR pathway, and in looking at TKIs and antiangiogenic drugs, again, that may enhance tumor responses and lead to better outcomes for patients.

While I’m not a fan of just combining antiangiogenic drugs with more chemotherapy, I think targeted therapy combinations and immunotherapy combinations are really exciting. The preclinical data that we have supporting this is strong. The clinical observations that we’ve seen have also been meaningful. So, we’ll have to see. If you ask me this next year at the ASCO Annual Meeting, I think I would have a different answer. I think there will be updated information that will tell us whether these drugs work or not in combination with targeted therapy or immunotherapy.