CLL and MCL Survival Benefit From Umbralisib Plus Ibrutinib Holds Up in 4-Year Follow-Up

Matthew Davids, MD, MMSc

Initial results for the combination of umbralisib plus ibrutinib (Imbruvica) showed high rates of response in early 2019, but longer-term follow-up presented during the 2020 European Hematology Association (EHA) Congress demonstrated that complete responses increased over time in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).

For patients with MCL, the median progression-free survival (PFS) was around 11 months, and the overall survival (OS) was around 2.5 years, which is not much different than what has been observed with ibrutinib monotherapy. However, in the CLL cohort, the 4-year PFS rate was 80%, and the 4-year OS rate was 90%, which was a big difference compared with historical controls.

Many patients are still receiving treatment with ibrutinib and umbralisib on the study, but this dataset highlights the continued efficacy and safety of dual B-cell receptor blockade. Umbralisib remains an investigational agent at this time, but more positive findings for this agent were recently presented from the phase 3 UNITY-CLL trial, which evaluated umbralisib in combination with ublituximab (TGTX-1101) in patients with CLL.

In an interview with Targeted Oncology, Matthew Davids, MD, MMSc, an associate director with the Center for Chronic Lymphocytic Leukemia; director of clinical research, Lymphoma Program; and medical oncologist, Dana-Farber Cancer Institute and an assistant professor of medicine with Harvard Medical School, discussed the long-term follow-up results of ibrutinib in combination with umbralisib as treatment of patients with CLL and MCL.

TARGETED ONCOLOGY: For patients with CLL and MCL, could you discuss the prognosis we see in this relapsed/refractory patient population?

Davids: With the advent of the BTK inhibitor ibrutinib, the outlook for patients with relapsed/refractory CLL and MCL certainly improved quite a bit. The drug is very active, and yet, particularly for high-risk patients and for CLL that means, especially patients with TP53 dysfunction, the durability of these responses is usually relatively short, so in that CLL high-risk population, looking at median PFS of only about 2 to 3 years in the relapsed setting with ibrutinib as a monotherapy. In MCL, even though the response rates are high, actually, the PFS is only a little over one year with a bruit nib as a monotherapy. That provided a rationale to try to develop combination approaches for this population, and there's a number of them that are being evaluated right now.

The 1 combination that we focused on was looking at dual blockade of the B-cell receptor pathway. We know that the CLL cells and MCL cells depend heavily on this B-cell receptor pathway for survival and that there's actually another arm of the pathway that has Pi3K as a key node. We were really interested in going after this other arm of the pathway to see if we could try to prevent resistance to ibrutinib as a monotherapy agent. That was the rationale for the study design.

TARGETED ONCOLOGY: What were the methods of design used for this study, and what did the patient population look like?

Davids: One of the challenges with this study is that there was a previous study that combined a SICK inhibitor drug with a Pi3K inhibitor and showed significant toxicity. That was the first time that there was a dual targeting of the B-cell receptor pathway, so we decided to take a different approach and rather than targeting SICK to target BTK, and rather than using an older delta-specific inhibitor of Pi3K, we used a newer molecule called umbralisib, which is a selective Pi3K inhibitor. It also targets casein kinase 2.

The idea here was to use 2 very well-tolerated drugs to target these 2 different parts of the pathway and try to prove that this could be a safe and effective strategy. We were able to accrue 42 patients to the study, 21 with CLL and 21 with MCL. These were all relapsed/refractory patients, generally with at least 1 to 2 lines of prior therapy. Few of them had had prior ibrutinib as mono therapy, but they weren't refractory to ibrutinib; they had maybe started it but were still in the first few months of treatment. It was a pretty high-risk population as well, about 70% of the CLL patients had the unmutated IGhV and about 20% of the CLL patients had deletion 17p or TP53 mutation. This is generally quite a high-risk population. Many of the MCL patients had also relapsed already after autologous stem cell transplantation and were in desperate need of effective treatment options.

TARGETED ONCOLOGY: What were the results from this study?

Davids: We had published the initial results of this study early last year with around 2 years of follow up, and we did find the high rates of response in both CLL and MCL. We saw very good tolerability. We were able to identify the recommended phase 2 dose of umbralisib drug as 800 mg in combination with standard dose ibrutinib. The challenge with that early report was that the follow up was quite short, and so really the idea with our update at the EHA meeting is now with around closer to 4 years of follow up, looking at the progression-free and open overall survival for these very high-risk patients.

The other thing that we looked at actually was the rates of complete remission, which did increase a bit over time as we've seen with B-cell receptor pathway inhibitors. That was the case in our study as well. What we thought were the key updates from this poster were the PFS and OS data. Now with MCL, these didn't change too much. The median PFS was only around 11 months in this very high-risk population, although the median OS was about 2 and a half years. To us, this didn't look too different from ibrutinib a monotherapy, so it was hard to know if there's a difference there. Where we are really seeing a difference is with the CLL patients. Obviously, we're comparing to historical controls. There's no there's no randomized comparator here, but we did see a 4-year PFS in this high-risk CLL population of close to 80% and a 4-year OS of 90% in the CLL population with many patients still on the to drug combination, doing very well. Our data set here really highlights both the efficacy and the safety of dual B-cell receptor blockade, and I think this really does warrant further study.

TARGETED ONCOLOGY: Now that we've seen these promising results in the relapsed/refractory setting, is their evidence you think just for moving this up in the treatment landscape or in another patient population?

Davids: I think 1 patient population where this could be a useful approach is in the post-venetoclax (Venclexta) setting. Particularly in CLL, now we're using venetoclax in earlier lines of therapy, including in the frontline setting. This type of approach might be very useful to use, for example, in the second-line setting; I think that needs to be explored. I think there have been challenges with moving other Pi3K inhibitor drugs into the frontline setting. We've seen more immune-mediated toxicities in those studies, but I do think with umbralisib being a very well-tolerated Pi3K inhibitor drug and ibrutinib being such a popular regimen for frontline CLL, certainly this type of approach could be studied in the frontline setting prospectively.

TARGETED ONCOLOGY: How do you see this combination potentially impacting the treatment landscape for CLL and MCL?

Davids: As of right now, umbralisib remains an investigational agent, although we did recently hear a press release about a positive result in the CLL UNITY study. I think that this is a drug that's headed toward a label in CLL and possibly in MCL as well. Although right now, this is not a regimen that could be utilized, I do think it's potentially a regimen that could be utilized off label in the future for a select group of patients. However, I would feel more comfortable as there's more data accumulating in larger datasets to make this as more of a recommendation for patients. I think we need larger studies and ideally, a randomized study where we can compare a doublet like this to perhaps singlet therapy with ibrutinib.

Nonetheless, I think our study is the first time that we've shown the feasibility of combining a BTK inhibitor with a Pi3K inhibitor. We showed it in these 2 non-Hodgkin lymphomas, but I think this is the type of approach that could also be studied in other non-Hodgkin lymphomas and may be promising there as well.

TARGETED ONCOLOGY: Are there any next steps planned right now?

Davids: For this study, as I mentioned, we have lots of patients still on the drug, particularly in the CLL cohort, so we'll continue to follow them over time and see what their survival outcomes look like. We don't have any specific plans to expand this particular study, but I do hope that the initial results that we've presented, and this longer-term follow-up will support the development of future studies of this combination.

TARGETED ONCOLOGY: What are your key takeaways from this study right now?

Davids: I think the key takeaways from this update with longer-term results is that the initial results we saw are holding up for the CLL patients where we're seeing really good durability of these responses that we've seen. We saw higher rates of complete remission than we'd expect from ibrutinib on its own. You know, there's an argument in the field right now about whether complete remission matters in patients who are on a continuous therapy. I think our data are supportive of the possibility that getting into these deeper remissions can sustain the remissions for longer as we're seeing very impressive PFS and OS data, but we need even longer-term follow-up to know and eventually comparative studies to answer that question more definitively.