H. Jack West, MD: At this point, I would say that there really is not a great understanding of a mechanism of action for how and why patients and their tumors become resistant to antiangiogenic agents. That really still needs to be elucidated.
One of the things that is also being looked at is the potential benefit of continuing an antiangiogenic agent beyond progression, and perhaps switching out the chemotherapy given with it. At this point, this is a study of clinical inquiry. It is the subject of some studies, but it’s not widely practiced at this point. It’s just an open question right now. It’s a provocative one, with some hints from retrospective work that patients may benefit by continuing an antiangiogenic agent beyond the point of progression, keeping that going while changing out the agents given with it.
There are several different agents that can work by antiangiogenic mechanisms. There are monoclonal antibodies. There are oral VEGF inhibitors. We need to do more to evaluate the potential benefit of sequencing these. What we can say is that in the REVEL trial, which looked at ramucirumab in combination with docetaxel after patients had already received first-line chemotherapy-based treatment, the subset who had received bevacizumab, another antiangiogenic agent, still received the same relative benefit with the addition of ramucirumab as the broader population. This suggests that there is not so much cross resistance that you can’t potentially benefit from sequencing antiangiogenic therapy. The fact that there are other antiangiogenic agents, including oral VEGF inhibitors, leaves that option open as well, but this really needs to be studied further. There are studies that are beginning to look at this, and I look forward to seeing clinical data to help guide my decisions and potentially lead to an approval of an agent for this. Right now, it’s still an open question.
We don’t yet know whether antiangiogenic agents in combination with immunotherapy will lead to a significant improvement in clinical outcomes. Preclinical data suggest that could be a fruitful approach. What we have seen actually comes from the IMpower150 trial, which looks at the chemotherapy backbone of carboplatin and paclitaxel with bevacizumab, with or without atezolizumab. What we’ve seen is a significant improvement in the arm that got atezolizumab. In this trial, we’ve also seen a benefit in the subset of patients with an EGFR mutation or ALK rearrangement. What we don’t know is whether that is specific for the chemotherapy regimen—which I doubt—the checkpoint inhibitor—maybe—or, potentially, if there is some particularly effective role for the combination of an antiangiogenic agent with immunotherapy.
We need to study this more. We really don’t have any trials that directly test this. That would be very attractive because one of the challenges with trials combining immunotherapy and chemotherapy is that while the efficacy is good, we don’t know if it’s clearly better than everyone getting a sequential approach. One of the hopes and promises of immunotherapy, initially, was that we would be able to avoid the chemotherapy side effects and practical challenges of administering it for months to years in patients who could benefit.
If we could improve the clinical outcomes and the range of patients who benefit from immunotherapy by giving an antiangiogenic in combination with immunotherapy, we could achieve that clinical benefit and avoid chemotherapy in patients who don’t necessarily need it.
Preclinical data have demonstrated that the EGFR mutation and ALK rearrangement is associated with a greater sensitivity or delay of resistance if these targeted agents against that driver are administered with antiangiogenic therapy. We’ve also seen clinical data in the EGFR mutation setting that has fairly consistently shown a benefit in terms of progression-free survival. There are also some suggestions of modest improvement in overall survival when antiangiogenic agents are administered concurrently with an EGFR inhibitor.
We haven’t seen as much with ALK rearrangements, but a lot of times we’ve seen that the patterns we see with EGFR apply to ALK, and vice versa. It will be extremely valuable to see a clinical trial result that addresses this question of a combination regimen of an antiangiogenic agent with a very effective ALK inhibitor.