Matthew S. Davids, MD, MMSc

​​​​​​The introduction of novel agents such as ibrutinib (Imbruvica), idelalisib (Zydelig), venetoclax (Venclexta), and duvelisib (Copiktra), though not curative, are showing potential for deep remissions both as monotherapy and in combination in patients with chronic lymphocytic leukemia (CLL), explained Matthew S. Davids, MD, MMSc.

“There have been several exciting advances,” said Davids, associate director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute. “Over the last 5 years, we've had several different drugs approved, typically, as monotherapies. These are drugs like ibrutinib, idelalisib, and venetoclax. More recently, the excitement has surrounded some of the data with combining these drugs together.”

Initial enthusiasm stemmed from the use of ibrutinib as monotherapy and in combination with rituximab (Rituxan) in the Alliance North American Intergroup Study A041202. In this trial, older treatment-naïve patients randomized to the BTK inhibitor either alone or plus rituximab experienced a significant improvement in progression-free survival (PFS) compared with the historical standard of bendamustine and rituximab (BR). Specifically, investigators observed PFS rates of 87% (95% CI, 81%-92%) with the monotherapy, 88% (95% CI, 81%-92%) with ibrutinib plus rituximab, and 74% (95% CI, 66%-80%) with BR.1

Following these data, results from the phase II ECOG E1912 study showed that the combination of ibrutinib and rituximab resulted in a 65% reduction in the risk of progression or death versus fludarabine, cyclophosphamide, and rituximab (FCR) in younger treatment-naïve patients with CLL (HR, 0.35; 95% CI, 0.22-0.50; P <.00001). In patients with IGHV-unmutated disease, the risk reduction was even higher at 74% (HR, 0.262; 95% CI, 0.137-0.498; P <.0001).2

“Figuring out what the optimal combinations are for individual patients is going to be key,” added Davids. “That type of individualized therapy is only going to get better in the future for CLL patients.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Davids, who is also an assistant professor of medicine at Harvard Medical School, discussed recent shifts in the paradigm with the use of novel therapies and the need to increase personalized treatment with these agents.

OncLive®: What novel combinations are being explored in CLL?

Davids: One particularly promising combination is ibrutinib and venetoclax. That combination showed very encouraging preclinical data in our lab. Several groups had seen this as well, so there is a strong scientific rationale for this combination. There are now a number of different studies around the world that are looking at the combination. The CAPTIVATE study in particular is looking at the combination in patients under the age of 70 years in the frontline setting. Patients are given 3 months of induction therapy with ibrutinib followed by the combination for a total of 15 months of therapy.

For certain patients who get to an undetectable minimal residual disease state, they can discontinue treatment. This is exciting because it allows for the prospect of deep remissions and time-limited therapy. Moreover, there is very good tolerability for patients who have other medical issues and may not tolerate chemotherapy-based approaches as well.

How do the toxicity profiles of these novel agents compare with those of chemotherapy-based regimens?

In general, the toxicity profiles of the novel agent-based regimens are better compared with chemotherapy. In particular, we see lower rates of cytopenias, so we tend to see less serious bacterial infections. With chemoimmunotherapy, we might see late effects of second malignancies, in particular myelodysplastic syndrome or acute myeloid leukemia. Although the novel agents have their own risks and adverse events, in general, we're finding them to be very well tolerated—especially in the older CLL population.

What are the next steps for research?

We're going to have some great phase II data for regimens, such as ibrutinib and venetoclax, but we're not going to have comparative data against the current standards of care for quite a while. Fortunately, there are some ongoing studies in Europe that are looking at combinations of novel agents compared with chemoimmunotherapy. These [ongoing] studies include the GAIA (CLL13) study as well as the FLAIR trial; they are either nearing full accrual or are now fully accrued. The data will take a little time to mature, but eventually we'll have the answer of how these new regimens compare with current standards of care.

Could you expand on the use of these BTK inhibitors and how ibrutinib compares with acalabrutinib (Calquence)?

Ibrutinib has become a standard of care for patients. At the 2018 ASH Annual Meeting, we saw a couple of really important presentations, one of which was subsequently published in the New England Journal of Medicine. That was the Alliance North American Intergroup Study A041202, which looked at older patients over the age of 65 and randomized them to receive either an ibrutinib-based regimen or BR, which is a frontline standard of care. Results showed a very dramatic benefit in PFS, particularly for patients with unmutated IGHV. Those data established ibrutinib as a great standard for those patients in the frontline setting.

We also saw data from ECOG E1912, which looked at younger patients under the age of 70 and compared the combination of ibrutinib and rituximab with our current standard of care, FCR. Surprisingly, there was a benefit in overall survival with the ibrutinib-based regimen due to the progression events in the patients who received FCR. By IGHV mutation status, the benefit seems to be restricted to the patients without IGHV mutations. For that group, it has changed the standard of care. We're using ibrutinib a lot more in that group, even when they're young. For patients with IGHV mutations, it's still controversial. Some will still use ibrutinib. Personally, I like the idea that there's a potential for functional cure for these patients who have mutated IGHV with a 6-month course of FCR, particularly in a young patient who is willing to tolerate chemotherapy.

We also have acalabrutinib. Although it’s not yet approved in CLL, it's approved in mantle cell lymphoma, so we do have some access to it off-label. We've seen very exciting data. John C. Byrd, MD, of Ohio State University, presented an update of the frontline study with acalabrutinib in about 100 patients at the 2018 ASH Annual Meeting. There were very few progression events and very low discontinuation rates [with acalabrutinib].

One of the things that may distinguish acalabrutinib from ibrutinib is its toxicity profile. Across studies, we're seeing somewhat lower rates of grade 3/4 atrial fibrillation, and lower rates of major bleeding. Some of the other toxicities that we can see with ibrutinib, such as rash or pneumonitis, seem to be less frequent with acalabrutinib. We have not seen any significant issues with ventricular dysrhythmias as have been reported with ibrutinib. There is a lot of optimism about acalabrutinib. However, I would caution that we have longer follow-up with ibrutinib, which is a strength of the molecule. We also don't have comparative data yet. Fortunately, we have the ELEVATE-TN study, which is maturing; this is a head-to-head study in the relapsed setting. That's going to be helpful in settling this question of which BTK inhibitor is better for our patients.

Are there other novel agents you want to highlight?

Another novel agent that is very attractive is duvelisib (Copiktra), which was recently FDA approved based on the phase III DUO trial. In the trial, patients in the relapsed setting were randomized to receive duvelisib or ofatumumab (Arzerra). Seventy-five percent of patients in the duvelisib arm had a response, including about 85% who experienced a lymph node response. The median PFS was in the range of 13 to 15 months depending on the number of lines of prior therapy. It’s a nice option for patients, and it’s good to have more options.

We have patients who have had significant cardiac issues. They may be on anticoagulation. We may be nervous about using BTK inhibitors. Thus far, with PI3K inhibitors like duvelisib, we haven't seen any cardiac issues. It really speaks to the individualization that we need for patients. There are certain patients who may be great candidates for duvelisib. Other patients may be better for ibrutinib. Since none of these novel therapies are curative, most patients are going to make their way to different therapies.

What are some of the challenges that still need to be addressed in CLL?

One of the challenges is going to be how we pay for these medications. These are expensive drugs on their own, and now we're talking about combining 2, and in some studies, even 3 agents together. If patients can achieve get deep remissions with time-limited therapy, it may [justify] the year of expenses, if they go into remission for several years as opposed to using a single novel agent for 9 years in a row.

Educational efforts are important because there are many new drugs in the CLL space. For community doctors who are seeing many different types of patients, it is getting harder to keep up. Efforts such as OncLive that bring experts into communities is important to get the word out about the new drugs and how to use them. We're certainly excited about all the new tools we have for our patients.

What is the outlook for the field of CLL?

The future of CLL is going to be surrounding these combinations. Are there particular characteristics of certain patients that make them more prone to respond to particular combinations? Are there predictive biomarkers we can use to identify those patients rather than just treating everyone and seeing how they do? We need to get a little bit smarter about how we're applying these novel agents. There are many genomic and functional assays in development to help us assess that.

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