CLL Expert Discusses Venetoclax, Promising Next-Generation Agents

Jennifer R. Brown, MD, PhD

The PI3K inhibitor idelalisib (Zydelig) and the BTK inhibitor ibrutinib (Imbruvica) made a dramatic impact on the field of chronic lymphocytic leukemia (CLL) when they were approved in 2013 and 2014, respectively.

Since then, several next-generation PI3K and BTK inhibitors, including duvelisib (IPI-145), TGR-1202, ONO-4059, and ACP-196, have built on the success of their predecessors, demonstrating promising data in early trials.

In addition, the novel Bcl-2 inhibitor, venetoclax (ABT-199), which received breakthrough therapy designation from the FDA for patients with 17p deletion CLL in May 2015, has also shown potential. In a phase II study for patients with relapsed or refractory CLL harboring the 17p deletion, venetoclax met its primary endpoint for overall response rate (ORR). Full study results have not been presented; however, previous studies have shown an ORR of 79% with venetoclax in CLL, with 26% of patients experiencing a complete response, and 53% of patients experiencing a partial response.

OncLive: What is on the horizon for CLL?

To gain a better understanding of the future of CLL treatment, OncLive spoke with Jennifer R. Brown, MD, PhD, director, Chronic Lymphocytic Leukemia Center, senior physician, associate professor of Medicine, Harvard Medical School and Dana Farber Cancer Institute.Brown: The next inhibitor that is likely to be approved is venetoclax (ABT-199), which is a Bcl-2 inhibitor. This drug is in very advanced clinical development and has shown excellent response rates in the order of 80% to 90% in relapsed refractory CLL. Complete remission rates from 25% to 40% were observed in the combination study with rituximab. It is somewhat unique in its ability to induce complete remissions compared to other Bcl-2 inhibitors. It is in a number of registration trials, as well as combination therapy trials.

I am very excited about ABT-199 as a novel class of inhibitors that affects Bcl-2, particularly because some of its mode of action suggest that it may be synergistic with and work well in combination with ibrutinib. This could perhaps form the backbone for a potential combination therapy that is free of chemotherapy.

Of the next-generation PI3K inhibitors, which agents have the most potential?

There are also next-generation PI3K inhibitors and next-generation BTK inhibitors, which are the drugs that are being developed in the wake of the approvals of ibrutinib and idelalisib.There is duvelisib (IPI-145), which is also an inhibitor of the delta isoforms of PI3K. Unlike idelalisib, it also inhibits the gamma isoform. The impact of inhibiting the gamma is not entirely clear. It is expressed in CLL cells, so there could be enhanced efficacy. However, there may also be effects because gamma is in T cells and neutrophils. This may modulate microenvironment stimuli to the CLL cells which could help with efficacy, but it may also enhance toxicity because of the effects on these other immune cells. The data with duvelisib looks quite good so far. In the follow-up of the phase I story, approximately 66% were still in remission at 2-years PFS. That drug is in registration trials that are ongoing.

The other PI3K inhibitor is TGR-1202, which is a delta-specific inhibitor. That is a next-generation molecule with a different structure, which we hope might reduce some of the hepatotoxicity that is seen with other PI3K inhibitors. Efficacy data is still early and relatively immature, but the response rates with that drug in CLL look promising.

Which BTK inhibitors do you see potential for?

Interestingly, the toxicity data also look better in the sense that there is less hepatotoxicity and less colitis, as we have seen so far. It is unclear whether this will hold up because their data suggest that delta-inhibition may affect regulatory T cells and that may be the basis for some of the toxicities we see with PI3K inhibition. If that were the case, it would be an on-targeted effect and we would expect to see it with all of the delta inhibitors. That is something we will be keeping our eyes on as the data matures.In terms of next-generation BTK inhibitors, there are two on the horizon. One is ONO-4059, which had very promising phase I data a couple of years ago, and we are now awaiting additional trials. The other is ACP-196. Unfortunately, no clinical data has been reported on that drug. However, it has a very extensive trial portfolio, including two phase III studies designed for potential registration that have been initiated. Notably, they are doing a head-to-head trial of ACP-196 versus ibrutinib in patients with relapsed CLL. It will be very interesting to see how these registration trials for this additional inhibitors develop over the next few years.

Do any of this novel agents have particularly concerning toxicities that may need to be managed?

ACP-196 also looks very promising as a more specific BTK inhibitor compared with ibrutinib, but we will actually get head-to-head data assessing that down the line.The adverse events of the drugs in each class are somewhat distinct. For example, the Bcl-2 inhibitor actually causes tumor lysis, which can be severe and, in the early studies, led to some deaths. The drug has to be given over a slow, ramped-up dosing schedule with very careful monitoring. That is something that has actually been worked out fairly well to date in the clinical trials, but it did initially slow the development. That will need to move into clinical practice once the drug gets approved.

The PI3K inhibitors have a pretty classic adverse event profile, which involved transaminitis that can occur in the second month of therapy, pneumonitis, which tends to build over the first few months and then peak at about 4 months. Patients can also develop immune-mediated colitis, which can involve severe diarrhea. We typically treat the colitis and the pneumonitis with steroids, which usually does resolve the problem. However, one has to have a very low threshold in suspecting that these may be drug-related so that one can jump in, withhold the drug, and introduce steroids early on. We do need more research to better understand this adverse event profile and potentially to mitigate it.

For BTK inhibitors, the main problems have involved bleeding with ibrutinib. This is relatively poorly understood. We do know that BTK is important for platelet aggregation in response to collagen, but we are unsure whether this is solely responsible for the bleeding. More research is needed to determine if the next-generation agents will have similar side effects.