Jeffrey Jones, MD, discusses exciting data with venetoclax, the role it is likely to have in the treatment paradigm of CLL, and what role it may have alongside ibrutinib and idelalisib.
Jeffrey A. Jones, MD, MPH
As a single agent, the Bcl-2 inhibitor venetoclax (ABT-199/GDC-0199) was shown to demonstrate early efficacy in patients with chronic lymphocytic leukemia (CLL) who relapse on therapy with ibrutinib and/or idelalisib, according to preliminary results of a phase II study.1
In the open-label study, which was presented during the 2015 ASH Annual Meeting, patients who previously received ibrutinib (Imbruvica; arm A, n = 22) and idelalisib (Zydelig; arm B, n = 6) received venetoclax monotherapy starting at 20 mg followed by a 5-step weekly ramp-up to a final daily dose of 400 mg.
Fifteen patients in arm A and 6 in arm B underwent an 8-week assessment. In arm A, 53% (n = 8) had a partial response (PR), 40% (n = 6) had stable disease, and 1 patient was inevaluable. In arm B, 2 patients achieved a PR, 1 had stable disease, and 1 had progressive disease prior to first assessment. These data suggest that venetoclax, as a single agent, is active in these patients who previously failed on ibrutinib and idelalisib.
Venetoclax has already been granted a priority review by the FDA for use in adults with CLL, including patients with a 17p deletion, following at least 1 prior therapy. The review is based on findings from the phase II M13-982 study,2 in which venetoclax elicited responses in nearly 80% of patients, many of whom were refractory to fludarabine and bendamustine therapy.
The agent is also gaining traction in combination. In January 2016, venetoclax received an FDA breakthrough therapy designation for use in combination with rituximab (Rituxan) to treat patients with relapsed/refractory CLL. The designation is based on findings from the phase Ib M13-365 study,3 in which the combination had an overall response rate of 86%, with deep and durable responses in patients.
In an interview with OncLive, Jeffrey Jones, MD, assistant professor of Internal Medicine, Division of Hematology, Department of Internal Medicine, Ohio State University Wexner Medical Center, discusses these exciting data, the role venetoclax is likely to have in the treatment paradigm of CLL, and what role it may have alongside ibrutinib and idelalisib. Jones: The most remarkable news in CLL over the last 2 years is the advent of small-molecule inhibitors of B-cell receptor signaling, and both idelalisib and ibrutinib have been highly effective in the majority of patients with relapsed/refractory CLL. However, there is still a fraction of patients for whom these drugs are less effective, either because of high-risk genetic features or because of the adverse events associated with either drug. In that group of patients, outcomes are particularly poor after discontinuing ibrutinib or idelalisib.
A totally different way of addressing the problem in CLL is to not only stop the growth, but also restore the death instinct. Bcl-2 inhibitors, such as venetoclax, work on that opposite end of the spectrum. This agent has been the subject of a number of ongoing investigations.
This study examined a group of about 50 patients now, the majority of whom have received prior therapy with ibrutinib and a smaller number who have received treatment with idelalisib. The overall response rate with 36 weeks of follow-up has been 61% in the group of patients receiving prior therapy with ibrutinib, and about 50% in patients receiving prior therapy with idelalisib.
This is still early on, and the responses are continuing to deepen with the expectation that a larger number of patients will ultimately respond, and the number of patients achieving a deep response—a complete remission—will increase with continued therapy.
With respect to toxicities, since that’s a concern not only for investigators but also for patients, venetoclax seems to be very well tolerated. The spectrum of adverse events in patients receiving the drug, in this context, is very similar to what’s been observed in previous studies of venetoclax.
We’ve also seen a very careful, upward dose titration over the first weeks of treatment. Patients can safely tolerate it without an unacceptable risk of tumor lysis syndrome, which was problematic in the initial phases of studying this drug. I think the question that arises a lot for us is, “What do we know now about sequencing all these highly effective agents?” Drugs like ibrutinib and idelalisib reached the market first, so we’re beginning to understand the relative merits of sequencing them.
But now, with the expected approval of venetoclax in 2016, it’s really not clear whether it is a drug better utilized in the first-, second-, or third-line setting. That’s probably going to take more investigation to settle out.
The most important thing for physicians to understand is that we now do have highly effective alternatives available, most of which appear to work without the addition of cytotoxic chemotherapy.
It will be very important, at least for the foreseeable future, that we continue to treat patients in a kind of “buy-and-hold” manner. When we’re used to treating patients with chemotherapy, we think of episodic care. Now, we are taking that same group of patients, and their physicians—who have their own expectations—and giving them drugs that require continuous treatment. The RESONATE-2 trial is the first randomized comparison of ibrutinib to standard of care therapy in the frontline setting for CLL. That data is expected to lead to approval of ibrutinib for first-line therapy for patients with previously untreated CLL.
The relative merits of ibrutinib versus, for example, fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab, which are more commonly used in the United States and Europe as frontline therapy, won’t be settled until data from ongoing randomized studies are available.
On the other hand, there are now second-generation BTK inhibitors that have potential pharmacologic benefits compared with ibrutinib. One drug in particular that we helped investigate at Ohio State University was acalabrutinib, formerly ACP-196. It’s a second-generation molecule targeting BTK in a very similar way to ibrutinib, but it’s far more specific. The most extensive program in venetoclax combinations has been a combination with monoclonal antibodies. We have previously seen preliminary data presented with rituximab and venetoclax, and it looks like the overall and complete response rates are improved when venetoclax is given in combination with an anti-CD20 monoclonal antibody.
Promising findings are also reported from another study I’m a co-investigator on, which combined venetoclax with obinutuzumab (Gazyva), the second-generation anti-CD20 that is engineered for greater potency in CLL. You’ve asked kind of the million-dollar question, particularly for the companies involved and their patients. It may ultimately depend on the patient. There may be a 78-year-old patient who has comorbidities and may need CLL to not be a problem. Therefore, treatment with a single agent that controls the disease, cytopenia, and symptoms that could be continued indefinitely, is very reasonable.
However, for a patient my age or someone even younger, the prospect of taking a pill for the rest of their life is less satisfying. The idea that you could take combinations of treatment that would result in a deeper remission that could allow discontinuation of therapy all together is very appealing.
I don’t know if it’s necessarily an “either or.” It may be that, with the advent of highly effective therapies, we will have greater flexibility in our goals of treatment, which cytotoxic chemotherapy doesn’t really lend itself to now.