Combination Therapy Values and Future Outlook in CLL

John Fox, MD, MHA: There is an inherent danger in doing indirect comparisons in clinical trials, but 1 question that’s always asked is, is monotherapy better than combination therapy? I think our experiences that combination therapy targets multiple different elements of a pathway may be more effective but carries with it toxicities. For example, in 17p deletion patients, 1-year survival with ibrutinib monotherapy was 85%. In that same patient population treated with venetoclax plus Rituxan—so, combination therapy—the 2-year survival, meaning progression-free survival, was 85%. So, we got the same median progression-free survival: 85% at 1 year with ibrutinib versus 2 years’ progression-free survival with the combination therapy.

So, that’s just 1 indirect comparison. There are lots of challenges with that, but it does appear that combination therapy may be the direction we’re heading, and that’s supported by all the clinical trials. If you look at the clinical trials that are ongoing today, the vast majority are combination therapies and not monotherapies.

So, where is all of this going? I know given the clinical trials that are being done, combination therapy with multiple different agents, with multiple different mechanisms of action, is likely to become the standard in the future, if not already. I know that there are going to be toxicities associated with that, and there is going to be a plethora of choices for clinicians and patients to make regarding the efficacy of the therapy, the risk factors that contribute in their decision, and the toxicities—financial and drug related.

Just like with non—small cell lung cancer, where we used to have just chemotherapy but now we have a plethora of choices, I think the same thing is happening in CLL. Historically, we’d just had chemotherapy, then we had chemotherapy plus anti-CD20, and now we’ve got the kitchen sink, where we’ve got a host of different mechanisms of action that could substantially improve outcomes—but at a cost.