Assessing Fixed-Duration Obinutuzumab, Ibrutinib, and Venetoclax in CLL: A 7-Year Follow-Up

In this interview, Kerry Rogers, MD, The Ohio State University, discusses her study titled “7-Year Update on a Phase 2 Trial of Fixed-Duration Obinutuzumab, Ibrutinib, and Venetoclax for CLL,” which was presented at the 2024 European Hematology Association Congress. She also shares her thoughts on what the future holds for combination therapy in the treatment of chronic lymphocytic leukemia (CLL).

Please introduce yourself by stating your name, title, organization, and relevant professional experience.

I'm Kerry Rogers, and I'm an associate professor in the division of hematology at The Ohio State University. I'm a practicing hematologist and a physician scientist, and I'm the principal investigator on the study that I'm going to be talking about.

Can you give some background about your study, and what prompted you to undertake it.

The study is a phase 2 study of combination ibrutinib, venetoclax, and obinutuzumab that is given for a fixed duration of a little over a year. It is 14 cycles, around a year of treatment. The study started at Ohio State around 2014, so it is rather long term follow up. In CLL we have some successful and effective targeted agents. The two main classes are BTK inhibitors, ibrutinib, and venetoclax, which is an inhibitor of BCL2. We have now seen that they can be safely combined, and this study includes an anti-CD20 antibody, obinutuzumab.

Back when this study started, it was actually the first to combine a BTK inhibitor and a BCL2 inhibitor, and especially with the addition of the antibody. We're presenting long-term follow up because there has been a lot of investigation on these fixed duration combination regimens. Since we have the kind of longest follow up on this type of study, we wanted to share the results.

The initial rationale for the study was to combine our three most effective agents in CLL to have a fixed duration treatment, with the hope of affecting very durable remissions, which we did in fact, see. This is a 7-year follow up of the study.

What were the methods of the study?

This study had a phase 1b portion that found the appropriate dose of venetoclax for combination with the licensed dose of ibrutinib and obinutuzumab on a schedule. This is of the more studied administration schedule. And then it had a phase 2 study that enrolled three cohorts. There were two concurrently enrolled cohorts of 25 patients. Initially after the phase 1b portion, one was previously treated relapsed refractory patients with CLL, and one was treatment-naive patients. We then subsequently enrolled a third phase 2 cohort that was just treatment-naive patients. In total, at this time the study includes 25 patients with previously treated CLL and 50 patients who are taking this as a first treatment for CLL.

The drugs were given in combination for a little over a year for 14 cycles. The first cycle is just obinutuzumab, with the dosing scheme of a split dose over the first 2 days, then days 8 and 15. Ibrutinib is added to obinutuzumab in cycle 2, and venetoclax ramp up over cycle 3. The obinutuzumab is continued monthly through cycle 8, and then the ibrutinib and venetoclax are continued in combination through cycle 14. Venetoclax and ibrutinib are both given at their currently licensed doses. That is the dose that has been commonly used in other combination studies with these agents. Patients were assessed for response 2 months after the completion of treatment. They were followed for progression and survival events after that.

Can you summarize the main findings of your study?

We have previously reported responses in the study which were quite good, including the rate of complete remission with undetectable, measurable residual disease. So, I want to remind everybody what some of those results are.

The overall response rate for relapsed refractory patients was 88% and for treatment-naive patients it was 90%. And that is an intention-to-treat analysis for end of therapy, so that patients who didn't complete the whole 14 cycles were considered as non-responders. Everyone had a biologic response to this for as long as they were able to take the therapy.

The rates of undetectable residual disease were quite reasonable. People who were not considered measurable residual disease (MRD) undetectable unless they had no detectable leukemia in both the blood and the marrow. This was assessed at the 2-month mark after treatment by flow cytometry with a cutoff of <1x10-4. All in all, 44% of relapsed refractory patients and 58% of treatment-naive patients achieved this minimal or measurable residual disease, undetectable status after treatment.

The main findings I presented at the European Hematology Association (EHA) Meeting this year was the progression-free survival in this study. So, we know that responses to these targeted agents are quite good, but the question is, how long does it keep people in remission, or what is the durable benefit?

Prior to this there had not been any reported results for progression-free survival of a study with these combination agents where the median had been reached. We reached the median progression-free survival in the first cohort of relapsed refractory and treatment-naive patients on both the original two phase 2 cohorts. The median progression-free survival for previously treated patients with CLL was 81.8 months and for treatment-naive patients in that first cohort was 88.5 months. Again, for the third treatment cohort, it was not reached because there was shorter follow up.

These results are for over 7 years of medium progression-free survival for patients participating in this study. I think it is an outstanding result and less than the expectation with continuous ibrutinib monotherapy, where a median was reached in a study called RESONATE-2 that Dr Berger presented at the same EHA meeting. That is 8.9 years, but that does mean that patients are taking ibrutinib continuously during that time and risk their CLL becoming resistant to it at the time they experience disease progression.

We have seen across studies, including in this one, that patients who progress after completing a fixed duration therapy with their CLL can take either BTK inhibitors and venetoclax again and expect a response to re-treatment. So, this good progression-free survival really supports that this is a good strategy to give a fixed duration BTK inhibitor-venetoclax combination, and then re-treat at time of disease progression, even though the progression-free survival might be slightly shorter for the initial therapy. With the strategy, the overall scheme might be better for patients.

What key improvements in patient outcomes were observed over the 7 years, and how do these findings compare to previous treatment regimens?

The key improvement is that we are seeing durable remissions in people who are not taking treatment. Over 10 years ago when chemo-immunotherapy was the standard, patients with CLL would expect to take a 6-month chemo-immunotherapy course and then enjoy time in remission, not on treatment. BTK inhibitors by their nature are continuous dose therapies for years and years. So, for patients this increases side effects because they are taking pills continuously, and they experience financial toxicity or costs of care burdens for taking highly expensive prescription drugs for multiple years in a row.

These combination regimens of BTK inhibitors and BCL2 inhibitors— this being a three-drug combination with the addition of the anti-CD20 monoclonal antibody—have allowed patients to take a treatment, complete it, and then again enjoy time in remission, not on treatment. That is the biggest kind of paradigm shift with these types of regimens.

However, there are a few unanswered questions, including if the anti-CD20 monoclonal antibody is necessary. There is a randomized phase 3 study called AMPLIFY, which will help answer that question in part. This is a study comparing acalabrutinib, venetoclax, obinutuzumab to a chemo-immunotherapy as a standard, so it was not designed to compare with or without obinutuzumab. But we will get some information from the AMPLIFY study. Overall, this study supports that it is a useful strategy for patients to take a combination regimen and stop taking it.

The combination of ibrutinib and venetoclax is approved by the European Medicines Agency, so it is used in Europe as a standard. It was also approved by Health Canada. However, it was not approved by the US Food and Drug Adminsitration (FDA), so we cannot currently implement either this regimen or those like it as a standard currently in the United States. Hopefully, as we get phase 3 studies such as AMPLIFY reported, we will have an option for patients in the future that is a fixed duration BTK inhibitor and venetoclax.

There are several advantages to this approach. The current fixed duration option for an initial therapy for patients with CLL is venetoclax-obinutuzumab, but that requires infusion of obinutuzumab, which includes visits, infusion chair time, and side effects of an anti-CD20 which are not always desirable for all patients. This is a three-drug combination, but hopefully some of these two-drug combinations will be approved that could be all oral. And whether or not it is a BTK inhibitor-venetoclax, or BTK inhibitor-obinutuzumab combination doing a treatment for a year, and then enjoying what looks like a median of 6 additional years not on treatment is huge for patients.

From a cost perspective, while these are highly expensive drugs and costly to give all three of them upfront, you have to factor in the additional years when patients are not taking expensive medications. So, it is actually cost effective to pay for all of three drugs in one year and then not have medications to treat CLL be needed vs having to pay for one of these drugs for 7 years. That is an important perspective on this. The majority of patients, although not all of them, prefer being in remission and not needing treatment.

How do the results from the 7-year update influence the current treatment protocols for patients with CLL?

With this study, given that this regimen is not approved and there are still questions about whether or not the anti-CD20 is necessary to get the same results, is not going to be immediately practice changing for patients. Certainly, I would not propose that we make this a standard based on this phase 2 study.

However, a regimen similar to this regimen is now in phase 3 testing. Regimens with the newer BTK inhibitors like acalabrutinib and zanubrutinib that have less cardiac toxicity in combination with BCL2 inhibitors are likely to be in standard use at some point and are now being highly investigated.

What this follow up really adds is support that we should continue to investigate these BTK inhibitor-venetoclax combinations. Now that we have one of these studies, which is the first to have a medium progression-free survival reach that is quite good, also shows that these regimens are an excellent way to achieve durable remission after a fixed duration therapy.