Expert Explains Expanding Post-Ibrutinib Options in CLL

Jacqueline C. Barrientos, MD, MS

The armamentarium for patients with chronic lymphocytic leukemia (CLL) who progress following ibrutinib (Imbruvica) is rapidly expanding with a batch of exciting agents, according to Jacqueline C. Barrientos, MD, MS.

The BLC2 inhibitor venetoclax (Venclexta) has shown strong promise after ibrutinib failure in patients with CLL. Venetoclax is approved by the FDA for patients with CLL with or without 17p deletion who have received at least 1 prior therapy, as well as for use combined with rituximab (Rituxan) in the same patient population.

The second-generation BTK inhibitor acalabrutinib (Calquence) has also shown post-ibrutinib promise. The drug is being explored in a head-to-head comparison against ibrutinib in a phase III trial of patients with previously treated, high-risk (del17p or del11q) CLL (NCT02477696).

The PI3K inhibitor duvelisib (Copiktra) is approved for relapsed/refractory CLL in patients who have received ≥2 prior therapies. Additional agents moving through the pipeline include umbralisib and ublituximab, among several others.

In an interview with OncLive, Barrientos, associate professor, The Feinstein Institute for Medical Research, Northwell Health, highlighted emerging agents in the post-ibrutinib landscape and overall next steps for advancing the field of CLL.

OncLive: What are the latest advances that are important in the CLL treatment landscape?

Barrientos: There are several new emerging agents in our armamentarium right now that are commercially available, but there are also more in the pipeline. One of the first new agents that is currently available in the market but not yet approved for CLL is acalabrutinib, a second generation BTK inhibitor. It has been shown to have activity in patients that are intolerant to ibrutinib and also in patients for the frontline and in the relapsed/refractory setting. This is currently in phase III trials against ibrutinib in high-risk disease, del17p and del11q patients. The data are still maturing; we don’t have the results yet, but it is very interesting. Hopefully, it’s another option for our patients who are unable to tolerate ibrutinib.

In terms of PI3K inhibitors, we have the new agent duvelisib recently approved to the market after 2 prior lines of therapy in patients with relapsed/refractory CLL; this also has activity in del17p patients. It’s really good, because we always need therapies for those patients. They are always the first to relapse.

There’s another PI3K-delta inhibitor in the pipeline called umbralisib (TGR-1202). It has activity not only in CLL and follicular lymphoma, but it has also shown some clinical activity in diffuse large B-cell lymphoma, so there are studies ongoing in Richter’s transformation for combination strategies. PI3K-delta inhibitors still have the issue of the colitis and diarrhea, so it’s important to remember that these are issues that your patients should tell you about for you to stop the drug the moment that it happens, so it doesn’t get to a grade 3 or 4 that is severe.

Umbralisib was also tried and tested in patients who are intolerant of TKIs. It had a very good response rate and very good progression-free survival, so that’s another strategy for that drug. Umbralisib in combination with ublituximab (TG-1101), a bioengineered monoclonal antibody targeting CD20, is being studied in a phase III trial, the UNITY-CLL trial, being compared against obinutuzumab in combination with chlorambucil in the frontline and the relapsed/refractory setting.

The last safety data information came up around September 2018 stating that there were over 300 patients treated with umbralisib for over a period of 2 years on the same therapy and It’s well tolerated, so we are very excited to have more information on this drug. We’re very excited and looking forward to more information on this drug.

Additionally, there are several novel BTK inhibitors besides acalabrutinib that I should mention: vecabrutinib (SNS-062), zanubrutinib (BGB-311), and tirabrutinib (GS-4059/ONO-4059). They are in clinical trials right now. Some of them are actually in phase III trials, so it’s very nice to see that the field is trying to improve upon what we have been able to achieve with ibrutinib.

In terms of venetoclax (Venclexta), a new drug in the armamentarium, this was first approved for patients with relapsed/refractory del17p as monotherapy, but now based on the MURANO data, you can use it in combination with rituximab for fixed-duration dosing of 2 years. There are excellent responses, and longer follow-up at ASH showed that patients are still in remission if they achieved MRD-negative state. We also are learning more on the mechanisms of resistance in some patients developing mutations in the BCL2.

I think the future is combination strategies with all the new agents, but additionally, we also need to mention the role of CAR T-cell therapy, which has been amazing in acute lymphocytic leukemia, but in CLL we had issues with responses. The thinking is that it may be the T cell dysfunction from the CLL patients.

There was a trial that was presented at ASH 2018, the TRANSCEND CLL-004 trial. It was presented for a very small number of patients, about 16 patients. They had previously been treated with ibrutinib and developed an intolerance, toxicity, or progression on ibrutinib. Many of them, the majority, had del17p or complex carrier type or TP53 mutations. These were very high-risk patients. The response rates were really high in the 80% range with several of them achieving complete remission (CR) after longer follow-up. We are also very excited now that the phase I study has been presented. There is a phase II expansion cohort accruing, and that’s another drug in the pipeline that I think is necessary since our patients unfortunately continue to have issues with being on the drug if they carry certain mutations such as del17p.

Yes, we do have drugs for them. We have idelalisib, duvelisib, ibrutinib, and venetoclax. All of them are available and have activity in del17p, but unfortunately, at the same time, these are the patients that tend to relapse sooner. We still need more therapies, and CAR T is a novel treatment strategy that can help us.

What do you see in the future for the treatment of patients with CLL?

The future may include combination strategies in certain patients, particularly in high-risk disease. There are several new treatment strategies including ibrutinib in combination with venetoclax both in the relapsed/refractory setting. That was presented at ASH 2018 with excellent response rates. Many of the patients achieved MRD-negativity or undetectable state so they were able to get off the study drug. The CAPTIVATE study, a frontline study for an ibrutinib/venetoclax combination, has also shown they were able to achieve CRs and undetectable MRD in the patients. That’s one of the strategies.

Another strategy is intergroup studies including obinutuzumab (Gazyva). It would be ibrutinib with obinutuzumab plus or minus venetoclax in both frail and elderly or fit and young. Both are done by intergroup studies, groups including the ALLIANCE and ECOG. With that, we are very excited and encourage physicians and patients to consider participating in clinical trials.

What challenges still need to be addressed in the CLL space?

For sequencing strategies, we still don’t have much data on what will happen for a patient that has been exposed only to venetoclax. Can they be salvaged by ibrutinib or idelalisib? We don’t have any data on that.

The other challenge is that as of right now, TKIs such as ibrutinib or idelalisib, are supposed to be used all the way until you develop a toxicity or progression of the disease. This wouldn’t really matter if you are in your 70s or 80s, but if you are in your 40s and you consider the prospect of being on a drug for the next couple of decades, it has a lot of potential toxicities that could come like hypertension, arrhythmias, arthritis, and many other things that can happen over time. We are trying to develop strategies for young, fit patients so that they don’t have to be exposed to a drug continuously, hence the combination studies that are accruing now in clinical trials.

What do you hope for oncologists to take away from all of this?

I would love for oncologists to consider sending their patients to clinical trials, particularly patients with del17p or TP53 mutation. It’s very important to say to the community oncology doctors or any physician that sees CLL patients is to test for 2 things: TP53 mutation and del17p. That’s one. The other thing is the status of IGHV mutations because if you have a patient that is young, fit with mutated, because if you have a patient who is young and fit with a gene rearrangement, that patient could, in theory, be free of any disease recurrence 10 to 15 years after getting 6 cycles of FCR [fludarabine, cyclophosphamide, and rituximab] if they achieve an MRD-negative state.

Those are the patients that would benefit still from chemoimmunotherapy approaches, and that’s a reason. The other reason to test for del17p and TP53 mutations is that these are the patients that will relapse sooner to ibrutinib. You need to know, because these patients should be monitored more closely and potentially considered for clinical trials because you know these are the patients that are going to relapse sooner.

The other issue is combination strategies. Once you use 2 good drugs frontline, let’s say you use venetoclax plus ibrutinib, for example, how do you then salvage those patients? Will they respond to a PI3K-delta inhibitor or will they respond to CAR T? We know that chemotherapy is now no longer widely used based on all these recent studies, but the problem is what do we salvage these patients with if they become refractory to these novel agents? What would be the best therapy to then use? That’s another challenge.