Davids Discusses Frontline CLL Combo of Ibrutinib Plus Chemoimmunotherapy

Matthew S. Davids, MD

Data presented at the 2017 ASH Annual Meeting by Matthew S. Davids, MD, showed that combining ibrutinib (Imbruvica) with standard frontline chemoimmunotherapy induced negative minimum residual disease (MRD) status in bone marrow for 83% of fit, younger patients with chronic lymphocytic leukemia (CLL).

The phase II study evaluated ibrutinib combined with fludarabine-cyclophosphamide-rituximab (FCR) chemoimmunotherapy. The objective response rate was 100%, including a rate of complete response (CR) with or without hematologic recovery of 40%. Thirty-seven percent of patients had CR in association with MRD negativity. Thirty-one patients initiated ibrutinib maintenance after FCR. There were no new safety signals for ibrutinib or FCR.

OncLive: What was the rationale for creating this type of clinical trial?

In an interview with OncLive, Davids, associate director of the Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute, highlighted the key results of the research and discussed other emerging combinations in CLL.Davids: What we have learned over the last few years is that patients can get very durable benefit from FCR alone; there were a number of publications showing that patients, particularly who have this IGHV-mutated form of CLL, have curative potential with FCR. This is based on data that are showing remissions of 12 to 15 years in some of these patients who are probably cured of the disease. We have several newer drugs that have come along, such as ibrutinib and other novel agents, and some have made the leap to put these novel drugs together and abandon chemotherapy.

While it is certainly a promising strategy to do a chemotherapy-free approach, our strategy is a little bit different—which was to build up on the curative experience from chemotherapy by adding the new drugs to chemotherapy and trying to increase that cure rate. That was the rationale from that perspective.

We also know that ibrutinib and similar drugs that target the B-cell receptor can actually move CLL cells out from the lymph nodes and bone marrow and into the blood, where they are more susceptible to being killed by chemotherapy; it is a chemotherapy-sensitization strategy.

Can you comment on the specific findings from the trial?

Then, the final piece was that we treated 3 patients at Dana-Farber Cancer Institute on this regimen as part of a different study, and all 3 patients had deep, durable remissions. All of the factors together were the inspiration to develop this study.The first thing is that anytime we put multiple drugs together, we want to make sure they are tolerable. In the initial safety lead-in with the first 10 patients, we didn’t see any unexpected toxicities and we were able to proceed and accrue the full 35 patients on the phase II study as originally conceived. In terms of the toxicity profile for the full cohort, the ibrutinib plus FCR (iFCR) regimen has generally been well-tolerated. One thing to note is that we require the routine use of growth factor and antimicrobial prophylaxis; by following this protocol, iFCR has been proven to be a safe regimen for these younger, fit patients.

What has been even more exciting are the efficacy data. The overall response rate was 100% and the primary endpoint of the study was quite stringent: patients had to get into a CR in terms of the scans and bone marrow, and patients also had to achieve MRD negativity in the bone marrow—we call that rate of CR with bone marrow MRD negativity.

If you look back at studies of FCR alone, that rate was somewhere around 20% and, in our study, it’s about 37%, so it nearly doubled that rate. One of the things that this study also incorporated was after finishing the iFCR combination, patients then continued on ibrutinib maintenance as a monotherapy for a couple of years. What we saw is that the rates of MRD negativity increased quite dramatically over time. When we looked at the rate of best bone marrow negativity, it was actually 83%.

As you compare across some of the different studies, including some of the ones presented at the 2017 ASH Annual Meeting—and if you are looking at studies of frontline therapy for CLL that included all-comers in terms of risk categories, including those with ultra high risk del(17p) disease—our rate of 83% is the highest rate of bone marrow MRD negativity that has ever been achieved in the frontline setting for CLL. We are pretty excited about that.

The reason that is important is that if you want to develop a curative regimen, then by prerequisite we have to get to MRD negativity first to eradicate every cell.

Those are the key findings, and then based on those promising efficacy data…we were able to expand the study to accrue an additional 50 patients. Therefore, we are going to have a total of 85 on this study by the time it finishes. However, one of the key changes and new amendments to the study is rather than keeping patients on indefinite ibrutinib after the chemotherapy portion, we are now doing only 2 years of ibrutinib maintenance. Those patients who are MRD negative in the marrow after 2 years of ibrutinib maintenance then stop all therapy, with the idea being that, hopefully, if these patients are cured then they are not going to need ongoing ibrutinib.

To me, that is a critical thing in the field right now; we have lots of promising regimens. Which of these regimens are going to provide durable enough response that they can be time limited? We have seen some of the novel agents, such as CD20-directed antibodies, in combination with novel agents, and so far, the MRD-negativity rates look promising. However, we don’t know what the long-term outcomes are going to be like for those novel agent—based approaches. It is possible that patients are just barely hitting MRD and 1 or 2 years later these patients may relapse; we just don’t know yet.

As I mentioned, we do know that with FCR; if we can get to MRD negativity, then we see long term survival rates of up to 15 years or longer in some cases. It is hard to know which of these regimens is going to end up being better in the end. Only time will tell, really. But in terms of the data we have on hand right now, we are certainly enthusiastic about this approach with chemotherapy plus novel agents.

Please expand on that point. Who might be the best patients to receive the ibrutinib plus FCR regimen?

You mentioned there was a good safety profile with this combination. What toxicities should physicians take note of that were observed?

This is obviously an exciting combination. Are there others with ibrutinib that also have potential? Or novel agents in combination with FCR?

Our regimen is geared toward the youngest and fittest patient with CLL, so we restricted our study to age 65 or younger. The majority of patients with CLL are older and frailer and not necessarily candidates for our approach, so that is important to highlight. The chemotherapy free based approaches are likely to be better for the more typical CLL population that is older.We had 4 patients on that first cohort of 35 patients who had a 17p deletion and, even though they all did respond, the depth of response is not as good as it was in the other patients. When we opened up the new cohort up of 50 patients, we decided to exclude patients with 17p deletion, as we do not think that the chemotherapy was adding much compared with ibrutinib alone. Based on our data, those patients who have 17p deletion—even if they’re young and fit—they are better served by either ibrutinib alone or ibrutinib with a different novel agent, but not with our chemotherapy backbone.The way they can think of it, based on our experience, is you have to be mindful of the risks of either regimen alone. We did have a case of atrial fibrillation on ibrutinib and we had 3 cases of minor bleeding issues—so typical ibrutinib toxicities. With FCR, we did have a couple cases of pneumonia and febrile neutropenia, which are typical toxicities. The overall message is that, basically, we saw the typical toxicities of both regimens but nothing more than that.Yes. One other thing is that, in parallel with the ibrutinib/FCR study, we have been running a study of FCR with duvelisib (dFCR), which is a new PI3k-δ and -γ inhibitor. We've also seen very nice results with that combination. It is always good for patients to have options, and there are some patients who are not great ibrutinib candidates, based on cardiac risk factors, for example, and bleeding history. We believe dFCR is also a promising new approach.

What are some looking-forward thoughts as this 50-patient expansion trial accrues?

As I mentioned, these chemotherapy-free approaches are going to be options for the frailer, older populations. For the older, frailer populations, there were a couple ibrutinib combinations presented at the 2017 ASH Annual Meeting that peaked my interest in particular. The most promising of these are ibrutinib/ venetoclax (Venclexta) and venetoclax with obinutuzumab (Gazyva), both of which look promising.When our study is fully accrued, we will have a good-sized phase II experience of 85 patients and that will be informative and, hopefully, enough data to reassure people about the efficacy and safety of the regimen. A challenge in our field, in CLL research in general, is that we have a lot of these promising phase II studies coming along; how are we going to compare across these populations and decide what is best for which patient?

There are other ongoing studies in Europe that are randomized phase III studies comparing similar regimens. For example, the FLAIR study in the United Kingdom and then also a study called CLL13 in Germany; although, neither of those trials are using the ibrutinib/FCR regimen specifically.

I am hopeful that we will be able to explore iFCR in the randomized phase III setting because, ultimately, that will be the best way to answer the question about which regimen is best. We would love to be able to compare ibrutinib/FCR with other combinations in a cooperative group setting. There are efforts underway to get that going.

Davids MS, Kim HT, Brander DM, et al. A multicenter, phase II study of ibrutinib plus FCR (iFCR) as frontline therapy for younger CLL patients. In: Proceedings from the American Society of Hematology 59th Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA. Abstract 496.