Ibrutinib, Venetoclax, and Obinutuzumab Triplet Safe, Effective as Initial CLL Therapy

Kerry A. Rogers, MD

The regimen of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta) can be safely given as initial therapy for chronic lymphocytic leukemia (CLL), according to preliminary results of a phase II trial of treatment-naïve patients.

This triplet produced objective responses, including minimal residual disease (MRD)-negative complete responses in all patients to date, noted investigators. Of 24 evaluable patients at the time of reporting, the complete remission (CR) rate, including CR with incomplete marrow recovery, was 50% (n = 12). MRD-negative status in the blood and bone marrow was observed in 14 patients (58%).

Adverse events (AEs) were consistent with what was seen in the phase Ib study in relapsed/refractory patients, says principal investigator Kerry A. Rogers, MD. Overall, this regimen has been shown to be tolerable in treatment-naïve patients.

OncLive: Can you discuss the initial results of the phase II treatment-naïve cohort?

In an interview with OncLive, Rogers, assistant professor of internal medicine in the Division of Hematology at The Ohio State University Comprehensive Cancer Center, discussed the promise of the obinutuzumab, ibrutinib, and venetoclax triplet as a first-line treatment for patients with CLL.Rogers: This phase Ib/II study of obinutuzumab, ibrutinib, and venetoclax in CLL is a way to study a chemotherapy-free combination. Generally, combination treatment in CLL has a very long tradition of success, including combinations with chemotherapy and CD20-targeted monoclonal antibodies, leading to very high rates of durable response. However, the side effects of chemotherapy are very difficult for a lot of patients, and there are some long-term side effects.

Now that there are some newer agents, we can combine 3 agents that have very different mechanisms and toxicity profiles that do not overlap. The dosing scheme for this study starts each agent over the first 3 cycles to mitigate the side effect of tumor lysis syndrome with venetoclax. The phase Ib portion reported at the 2016 ASH Annual Meeting established the recommended phase II dose of venetoclax as 400 mg, which is the approved dose in CLL as a single agent.

Since we had a dose that was tolerated, we moved into 2 cohorts that accrued parallel phase II studies. This is a cohort of previously untreated patients, so it is really exciting as it offers patients who have never been treated the opportunity to receive what we believe to be a highly effective therapy while completely avoiding chemotherapy. Thus far, we have gotten halfway through the study, and the midpoint response assessment has shown a very high response rate. One patient discontinued treatment before the midpoint so, in the intent-to-treat analysis, that was considered a treatment failure. However, everyone who made it to that point had a response, so it is very effective.

The most impressive finding was the very high rate of negativity for MRD, which means that there was no detectable CLL by flow cytometry in either the blood or the bone marrow. By this traditional measure of MRD, we could not find any CLL cells—and that was in over half of patients who were assessed at this midpoint. These findings show that while avoiding chemotherapy, we were still able to achieve very high rates of elimination of all detectable CLL.

Were there any toxicities that should be noted?

Important things that we have yet to see out of this study are the primary endpoint, which is the rate of MRD-negative CR after treatment. This is a time-limited treatment strategy of 14 months, similar to some chemoimmunotherapy regimens. It will be exciting to see what all of the end-of-treatment responses are, because that is when patients have stopped taking the drugs. The progression-free survival will also be very important. Most of the toxicities were consistent with what has already been reported with the 3 individual drugs. The most common nonhematologic AE was infusion-related reactions from obinutuzumab. Then, we saw bruising, arthralgia, hypertension, and side effects that are known for ibrutinib. The main higher-grade AEs were hematologic, with a lot of high-grade neutropenia. That is probably because all of the drugs in the study can cause neutropenia, so those are more specific to the combination.

In the treatment-naïve patients, which was what this cohort was, we actually did not see a lot of complications with neutropenia. We did have 1 person who got neutropenic colitis and bowel perforation that discontinued treatment, and subsequently died months later of late complications. It is a regimen that had substantial toxicity for at least 1 individual.

However, it is actually less than what you would expect to see with chemoimmunotherapy. In general, it is more tolerable than regimens that include traditional cytotoxic agents. Also, when we look at the relapsed/refractory cohort, I expect there to be more treatment-related complications and probably more infections in pretreated patients.

At this point in time, what would you say is the significance of these results?

The upshot is that this regimen is very tolerable, and definitely more tolerable than chemoimmunotherapy. We have no surprising AEs, but it is still possible to have serious toxicities with this regimen.It is very exciting to know that [this triplet] can offer patients an opportunity to have very good elimination of their residual CLL down to undetectable in many cases without taking any chemotherapy. [This regimen] is a lot easier on the lifestyle and side effects than chemotherapy with similar results.

Moving forward, what are the next steps?

Is there anything else that you would like to highlight?

However, the most important thing that we have yet to learn is how long these remissions are going to last. Once we see that, there is a possibility that this regimen could replace chemoimmunotherapy. In many cases, especially for those trying to avoid chemotherapy because of the long-term side effects, something like this regimen should replace chemoimmunotherapy. For this study, we need to get everyone through the end-of-treatment response and look at the PFS, because what happens after people stop treatment is vital for knowing what to do next. This regimen should be assessed in a larger study comparing it with standard-of-care regimens, such as randomized phase III study.This is time limited; it specifies 14 months of treatment. Both ibrutinib and venetoclax alone get very good responses, but they are [not] necessarily as deep as what we have seen with this combination. This is especially true with ibrutinib, where you do not really get a lot of patients who have no detectable CLL left. The label for both ibrutinib and venetoclax is to take them indefinitely until disease progression or intolerance.

One of the really exciting things about a strategy like this is that you get control of the CLL, high response rates, and elimination of any detectable CLL by flow cytometry with only 14 months of treatment. This means that you are not committing people to long-term side effects of continuing on treatment indefinitely, and you are not exposing them to treatment burden or pill burden of other regimens.

Patients and the healthcare system should be worried about the financial impact of continuing these targeted agents on an indefinite basis. It is a lot nicer to have a time-limited treatment strategy for many reasons. This is a treatment paradigm that is closer to the chemoimmunotherapy experience, where treatment is done for a defined time period.

Rogers KA, Huang Y, Stark A, et al. Initial results of the phase 2 treatment naive cohort in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in chronic lymphocytic leukemia. In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 431.