Novel Triplet Regimen Induces Promising Early Activity in Relapsed/Refractory CLL

Paul M. Barr, MD

Paul M. Barr, MD

The triplet combination of umbralisib and ublituximab (U2) plus venetoclax (Venclexta) demonstrated a tolerable toxicity profile in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in a phase I/II clinical trial, which was presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

Inthis study of U2 plus venetoclax, 27 patients were evaluable at the time of analysis for safety and 23 for efficacy. Patients received 3 28-day cycles of U2 followed by 9 additional cycles of venetoclax in this study. Although the data is still early, the triplet regimen led to promising responses and outcomes in patients with relapsed/refractory CLL.

At the end of the 12 cycles, the objective response rate (ORR) was 100% with a complete response (CR) rate of 44%. All patients had undetectable minimal residual disease (uMRD) at the time of assessment in the peripheral blood, and 78% of patients had uMRD in the bone marrow versus 22% of patients who were MRD intermediate. No patients had progressed at a median follow-up of 6.4 months (range, 0.7-19.0+).

The most common all-cause grade 3/4 adverse events (AEs) included neutropenia (19%), leukopenia (15%), infusion reaction (7%), deep vein thrombosis (7%), anemia (4%), diarrhea (4%), rash (4%), lower GI bleed (4%), supraventricular tachycardia (4%), anxiety (4%), hypophosphatemia (4%), and dyspnea (4%). No cases of clinical or laboratory tumor lysis syndrome (TLS) were observed, and no patients developed grade 3/4 liver function test elevations.

In an interview withTargeted Oncology,Paul M. Barr, MD, Wilmot Cancer Institute, University of Rochester, discussed the rationale and preliminary findings for the phase I/II study evaluating U2 plus venetoclax in patients with relapsed/refractory CLL. He also explained how the role of combination therapy continues to evolve in this space.

TARGETED ONCOLOGY: What was the rationale for evaluating this combination in CLL?

Barr:This study was developed based on the interesting responses we saw early on with venetoclax. It’s an orally administered agent that is providing very deep remissions compared to a lot of the other single agents we are using. The thought was can we do better, can we build on that, and can we use a novel class of drugs that don’t get a lot of use right now, such as PI3K inhibitors?

Umbralisib is a PI3K delta inhibitor that seems to be better tolerated than others in its class. The whole thought process was to use umbralisib and its partner CD20 antibody ublituximab to debulk patients and protect them with venetoclax-associated TLS, then we add in venetoclax. We hypothesized that this 3-drug regimen would provide deep uMRD remissions with using a relatively short duration of therapy.

TARGETED ONCOLOGY: What were the methods of design for this study?

Barr:Patients initially received a 3-cycle initiation of U2. They underwent tumor lysis evaluations before and after that. Venetoclax was ramped up in this typical fashion, and then patients received 9 additional cycles of venetoclax and umbralisib, so it’s 3 plus 9 total cycles in just under a year. At the end of treatment, we do full response assessments, including CT scans, bone marrow biopsies, and MRD testing.

TARGETED ONCOLOGY: What data were presented at the 2019 ASH Meeting for this trial?

Barr:We focused on the phase I group, the 9 patients that completed 12 months on treatment in the phase I cohort. We presented preliminary data for the phase II patients we have enrolled so far. We found that, overall, the regimen was very well tolerated. There are, like with most treatments, some adverse events that were noticed, but they were relatively low-grade. The gastrointestinal effects were low-grade, the cytopenias were mild for the most part, and we didn’t see any tumor lysis events, not even TLS or laboratory TLS as a result of the patients being adequately debulked. It looks tolerable.

We were encouraged by the early efficacy. The first 9 patients have completed the 12 cycles, and in the end, 4 out of 9 were in a CR. The MRD testing in the peripheral blood showed that MRD was undetectable in all 9 patients. Seven out of 9 patients were undetectable in the bone marrow. It is still early, but this is promising.

No patients have progressed to date, which I think is probably the most important end point for patients. We are encouraged. We are continuing to treat and enroll CLL patients, and we have expanded the study further to test the regimen in patients with Richter’s transformation, as well as mantle cell lymphoma.

TARGETED ONCOLOGY: In your opinion, what are the implications of these positive findings be?

Barr:It is promising, but we still need to follow patients further. We hope this could build on venetoclax when used in the relapsed/refractory setting. If we do see in a larger number of patients, uMRD remissions that last for years, I think it could become a standard regimen for patients who have failed or progressed through BTK inhibitors.

Based on what we see, further discussion will help dictate where this should be tested further, whether it should be in other lines or the first-line. That remains to be seen, but it is looking promising for us in this specific population of relapsed/refractory patients.

TARGETED ONCOLOGY: How does this analysis shed light on the use of MRD?

Barr:There is a lot of work to do on using MRD. I primarily consider it a research tool at this point, not something we want to use across the board outside of a clinical trial setting. In this study, we used the European Consortium’s standard flow cytometry with a sensitivity of 10^-4. For most studies, that is the technique we are getting the most data from. Nonetheless, next-generation testing is promising in providing deeper levels of sensitivity. I think this is a first look at what this regimen can do using the standard flow cytometry-based assay. However, more work needs to be done before this is an accepted standard.

TARGETED ONCOLOGY: Is there anything from these data you would like to highlight?

Barr:I would emphasize that as venetoclax is becoming part of the standard treatment algorithm and based on other data, we expect U2 will be approved in the months or year to come. I think it is possible that this combination could warrant further use depending on what the long-term outcomes look like. I would also highlight that a second larger study will be investigating the 3-drug regimen in a national trial, termed the ULTRA-V (NCT03901525) study. That is currently open and accruing now, so we will see a lot more data to come with this regimen.

TARGETED ONCOLOGY: We are seeing other triplet therapies in CLL. Could you expand on those data?

Barr:We certainly are seeing an abundance of combinations with all of these new agents and rightfully so. Where we are seeing the largest amount of data is the same strategy we used in our study, combining an inhibitor of BCR signaling inhibition with a BCL2 plus a CD20 antibody. There are a variety of trials investigating ibrutinib (Imbruvica) plus venetoclax and a CD20 like obinutuzumab (Gazyva). We are also just seeing first glimpses of data from acalabrutinib (Calquence) and venetoclax plus obinutuzumab. I think to date, what we have seen are responses in the MRD results at the end of the treatment period. Some of these studies are set up so there is a defined treatment period, and some are asking an MRD question; can MRD be used to direct therapy?

So far, we are seeing a high level of CRs and uMRD disease. The question is what is the progression-free survival? What is the duration of disease control? It is too early to say right now, but I think as these studies mature, we will have a better idea of which doublets or triplets will change practice and which patients will be best served with the combination therapy? Given the responses we are seeing, it is very encouraging.

TARGETED ONCOLOGY: Would it be fair to say that CLL is taking the same direction as multiple myeloma with the development of all these combinations?

Barr:It is a fair analogy. In the old days, multiple myeloma was treated heavily with chemotherapy, and novel agents have demonstrated better tolerability and better efficacy. Now we have an abundance of novel agents being combined in different ways. CLL is making a similar transition; however, the chemotherapy worked very well, and it is still fair to say patients are served well with [chemotherapy]. Based on recent randomized studies, we are seeing better outcomes in terms of tolerability, disease control, and even overall survival with the novel agents. It is like starting from scratch to build novel combinations similar to myeloma.

Reference:

Venetoclax (U2-Ven) in Patients with Relapsed/Refractory CLL. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 360.