Published on July 22, 2016
Would combining inhibitors with monoclonal antibodies improve complete response rates? Dr. Philip Thompson of MD Anderson Cancer Center answers this question from a Patient Power member. With several new treatments in development, Dr. Thompson explores the safety and efficacy issues associated with various treatment combinations.
Sponsored through an educational grant from the Patient Empowerment Network, which received support from AbbVie Inc. and Genentech Inc.
Transcript | Could Antibodies and Inhibitors Be Combined to Improve Response Rates?
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Great. Given the great ACP196 data with its high percentage of partial responses, is there still a role for second- and third-generation antibodies to be used in combination therapy with the idea that, in combination, they would improve the complete response rates?
That’s a really good question. I guess these kinase inhibitors, like ACP196 and ibrutinib (Imbruvica) before it, they’ve changed the treatment goals in CLL somewhat in that, previously, when we were treating patients with, chemotherapy, like FCR, essentially, if you got a complete remission, you would have a long remission. If you got a partial remission, it would be very brief. I guess that’s because you were giving all the therapy and then stopping. And then if there was disease left over, it would come back.
These oral medications are taken continuously, and so they will suppress the CLL. So you can be in a long-term stable partial remission, which is a new phenomenon. I guess the downside of this is that you’re stuck on medication. These medications are very expensive, and they also have side effects in some patients. Now, many patients tolerate them very well, and they’re certainly easier to take than chemotherapy. But some patients have significant side effects like, you can have an irregular heartbeat, you can have an increased risk of bleeding. Some patients have some joint pains and some diarrhea, which can be problematic. I guess from a doctor’s point of view—and I think patients are keen for this, too—I would like to be able to get my patients into a complete remission where I can’t find any CLL. And then I can get them off all therapy and observe them, and I think patients ultimately want this as well.
Now, you have to be able to do this without causing too much toxicity. Now, antibodies like rituximab (Rituxan), and there are some newer ones like Gazyva or obinutuzumab, they certainly are capable of improving responses when they’re added to other therapies, and there are a number of studies that are looking at ibrutinib in combination with obinutuzumab, which is a newer antibody but targets the same protein as rituximab, and also looking at ACP196 in combination with obinutuzumab.
The way obinutuzumab and other antibodies work is they get the immune system to kill the CLL cells. In the lab, it looks like ibrutinib may impair the ability of the immune cells to kill the CLL cells in response to one of these antibodies.
In the lab, it looks like ACP196 does not do that to the same extent or does so to a much lesser extent, in fact. Now, whether this will bear out in patients is not clear. And certainly, we’ve had a study where we’ve looked at rituximab in combination with ibrutinib, and it certainly gets the white cell count down faster, and it’s too early to tell whether the responses are better, but we’ll know that in the coming months to years. I actually think that we’ll see more potent combinations. For example, I think the combination of venetoclax (Venclexta), and ibrutinib is definitely going to be tested. In the lab, this looks amazing, and I think it will be more potent than a combination of an antibody with a BTK inhibitor.
Now, whether adding an antibody to that two-drug combination will make it even better, I’m not sure. But certainly, we’re working on a number of ways of combining things with these new kinase inhibitors so that we can achieve really deep responses and get the patients off the medication.