CLL Landscape Continues to Expand With Addition of Venetoclax

Javier A. Pinilla-Ibarz, MD, PhD

The field of chronic lymphocytic leukemia (CLL) has experienced a number of therapeutic advances, with multiple new agents approved and even more being explored in clinical trials. According to Javier A. Pinilla-Ibarz, MD, PhD, combinations may be the future of frontline treatment.

Phase II findings from the CAPTIVATE trial showed that the front-line combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) demonstrated a 100% objective response rate for patients with CLL. Notably, 77% of patients tested negative for minimal residual disease (MRD). Venetoclax was granted a full approval by the FDA in June 2018 for the treatment of patients with CLL with or without 17p deletion, following at least 1 prior therapy.

In September 2018, the FDA added MRD data from the phase III MURANO trial to the label for venetoclax for its approved use in combination with rituximab (Rituxan) for previously treated patients with CLL. Looking ahead, the CLL14 study (NCT02242942) is evaluating the combination of obinutuzumab (Gazyva) plus venetoclax in patients with CLL. The phase III, randomized, open-label, multicenter study is designed to compare the safety and efficacy of obinutu- zumab plus venetoclax with obinutuzumab plus chlorambucil.

OncLive^®: How would you describe the current CLL treatment landscape?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Pinilla-Ibarz, a senior member of Moffitt Cancer Center, discussed updates in the treatment of patients with CLL.Pinilla-Ibarz: We are quite excited in the world of CLL, and we are so lucky to have so many drugs coming down the pike. The highlight of my talk was the combination of ibrutinib plus venetoclax, data of which were presented at the 2018 ASCO Annual Meeting and 2018 EHA Congress in the CAPTIVATE trial. This trial looked at the frontline combination of these 2 very important drugs, which were recently approved for the treatment of patients with CLL. The data were quite remarkable in terms of complete remission, and more importantly, MRD negativity. We know that these outcomes are associated with very long progression-free survival (PFS). However, we do not have all the data yet. We need to follow those trials for a long period of time. The hope is to have a limited therapy of 1 year to 15 months in the frontline setting or 2 years in the relapsed/refractory setting.

What does this mean for the role of chemotherapy?

We have a very exciting combination coming up with the CLL14 study, which is evaluating obinutuzumab plus venetoclax compared with obinutuzumab plus chlorambucil. No doubt, there is a plethora of second-generation BTK inhibitors that are entering the phase I and early phase II trials. Most of these drugs are trying to address this area of BTK resistance or secondary mutations. C481S is becoming the classical mutation, in which patients on long-term ibrutinib with high-risk features stop responding or relapse.There is no doubt that chemotherapy continues to fade away. Very soon, we are going to have data for the ALLIANCE study, which is investigating the use of ibrutinib versus ibrutinib plus rituximab (Rituxan) versus bendamustine plus rituximab (BR) in the frontline setting for patients with CLL who are over the age of 65. This is a very important trial; everyone is looking forward to it.

What is the status of umbralisib?

In general, we see chemotherapy having less and less of a role as a frontline option for CLL. In most of the guidelines, the combi- nation of chemotherapy in the form of fludarabine-cyclophosphamide-rituximab (FCR) is only indicated for patients younger than 65 with IGHV-mutated surface immunoglobulin. We have data showing the long-term benefit, and even possible cure [with FCR]. BR is still an option for older patients, but there is no doubt that the advantage of limited therapy is something we should discuss with our patients when we are offering different types of frontline therapy.The oral PI3K-delta inhibitors have not shown much progress since idelalisib (Zydelig). Idelalisib is a great drug; however, it has been shown through trials that there is a high discontinuation rate due to autoimmune adverse events (AEs). Duvelisib, which is due to be approved soon, is a PI3K-gamma/delta inhibitor, and is likely to follow the same steps as idelalisib in terms of long-term toxicity.

We are very excited about umbralisib. Umbralisib is a PI3K-delta inhibitor, but it very interestingly has the activity of another kinase that is unknown to many people—casein kinase 1 isoform epsilon, or CK1-epsilon. This may compensate the autoimmune AEs. What we see with these drugs is similar efficacy with any oth- er PI3K-delta or gamma/-delta, but with significantly less grade 3/4 AEs, such as pneumonitis, colitis, and hepatitis.

How has the approval of venetoclax has impacted the landscape?

We are waiting for the results of further trials in the first- and second-line settings in combination with ublituximab, a CD20-targeted monoclonal anybody. We are really looking forward to seeing these data, because it may indicate a resurgence of the PI3K-delta inhibitor. It may be an interesting drug to combine with BCL-2 inhibitors or other monoclonal antibodies.Venetoclax has completely revolutionized the second-line treatment of patients with CLL. There is no doubt that the possibility of having a limited duration of therapy, and the high rate of MRD-negative disease in the bone marrow, with or without complete response, is bringing a lot of hope to our patients. It is definitely something that everyone is quite excited about.

Looking ahead, what will be the optimal sequencing for these emerging agents?

In combination with rituximab, and in the future with other mono- clonal antibodies or ibrutinib, [venetoclax] is going to be more pres- ent in the treatment of patients with relapsed/refractory CLL, as well as in the frontline setting.There is no doubt that in the field of CLL, we try to combine everything. We have learned that 1 drug is good, 2 is better, and 3 may be even better. However, we need to be cautious about this. Recent data with the combination of obinutuzumab, venetoclax, and ibrutinib are quite good, but we start to see an increase in AEs that may be the limiting factor in combining them all together.

Therefore, what will be seen in the next few years in terms of clinical trials? Following many other trials, [we will see] induction with a bendamustine regimen for 1 or 2 cycles, an introduction of a monoclonal antibody—obinutuzumab or ofatumumab (Arzerra)— with a BCL-2 inhibitor or a PI3K-gamma inhibitor. [These are all] early data, but we will know how to combine everything together, how to sequence each drug optimally, and increase outcomes to bring more patients to MRD-negativity and very long PFS.

Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol. 2018;36(suppl; abstr 7502).