Insights From: Bruce Cheson, MD, Lombardi Comprehensive Cancer Center; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Anas Younes, MD: There are multiple agents emerging in clinical trials and being tested in follicular lymphomas that may have future therapeutic value in this disease. But none of them are giving us this high response rate. An example is the BTK inhibitor, ibrutinib, where the average response rate is about 20%. That doesn’t mean that it’s not going to be useful. It is probably going to be useful in combination strategies. We can still combine it with other active agents, like the PI3 kinase inhibitors, but by itself it doesn’t seem to be a home run. Second is venetoclax, which is surprising. Venetoclax is a drug that targets BCL-2, and BCL-2 especially is a hallmark of follicular lymphoma, because of the translocation between the chromosomes 14 and 18. So, they have very high levels of BCL-2, yet a BCL-2-targeted agent like venetoclax is not very effective in this disease. And the reason why is because there are other mechanisms that can predict resistance and compensate for BCL-2 inhibition. But then again, that doesn’t mean that this drug will not have a role. It probably will have a role, but in combination with other agents. There are Syk inhibitors, but, again, it’s too early to call. At least there are a couple of them being tested in the context of phase I or early phase II trials. Same story—it’s not going to be a homerun, but probably pretty good for combination strategies.
There are multiple anti-CD20 antibodies being tested; a couple of them are approved for different indications. So, ofatumumab and obinutuzumab. Again, there’s indication that one or the other may be slightly better than the old-fashioned rituximab. They’re being combined with chemotherapy: the most recent trial combining obinutuzumab with CHOP, bendamustine, and CVP. So, there’s at least clinical evidence that an obinutuzumab-based combination would be better than a rituximab-based combination in terms of progression-free survival. We’ll see how this will work in the clinical practice, whether it will be widely used or not, because there’s concern that there’s also slightly added toxicity when you combine obinutuzumab with chemotherapy. But some patients may be better fitted for this regimen. So, we’ll see how it will play out in clinical practice.
Bruce Cheson, MD: Few of these novel agents are going to achieve what we want them to achieve, as single agents and combinations are critical. We are at a loss right now. We don’t have biomarkers that tell us what combinations are likely to be more effective and less toxic than other combinations. So, right now, we’re just doing it totally empirically. Who can give us the drugs to combine with other drugs? It’s not optimal. Combinations are what we need to search for, ones that will get us not only responses but also more complete responses, so that we have a chance of a longer time to progression, a longer survival, and perhaps with a shorter duration of therapy. Because the goal is eradication of the disease, we’d like to use regimens up front, which is the goal to get. Your best shot is your first shot, but what we have learned over the last few years developing combinations is that we’ve run into trouble. We’ve tested a number of doublets and triplets of drugs that by themselves are very well tolerated, but when you put them together, you can lead to disastrous, fatal outcomes in patients. So, one needs to be extremely careful putting drugs together, even though they may seem very well tolerated—particularly in the frontline setting, where you have the most to gain but you also have the most to lose.