Combos Explored to Enhance CLL Outcomes

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Partner | Cancer Centers | <b>Moffitt Cancer Center</b>

Julio Chavez, MD, discusses the current state of CLL and emerging regimens moving through the pipeline.

The success of ibrutinib (Imbruvica) has had a significant impact across several populations of patients with chronic lymphocytic leukemia (CLL). However, not all patients respond, and ibrutinib combinations and other novel regimens are being explored to improve outcomes, said Julio Chavez, MD.

For example, findings from the phase III GENUINE trial, which were presented at the 2017 ASCO Annual Meeting, showed that the combination of ublituximab (TG-1101) and ibrutinib demonstrated an objective response rate of 78% for patients with previously treated high-risk CLL.

A separate ongoing, multicenter, open-label, prospective phase III study is exploring the efficacy and safety of obinutuzumab (Gazyva) plus venetoclax (Venclexta) versus obinutuzumab and chlorambucil in patients with CLL (NCT02242942). If positive, Chavez adds, it could lead to another frontline treatment option for patients.

OncLive: What did you focus on in your lecture on CLL?

What game-changing results have we seen with ibrutinib? Also, what do you do when patients fail on ibrutinib?

Chavez, who works in the Department of Malignant Hematology at Moffitt Cancer Center, discussed the current state of CLL and emerging regimens moving through the pipeline during the 2017 OncLive® State of the Science SummitTM on Hematologic Malignancies. In an interview at the meeting, he shared his insight on ibrutinib’s benefits and challenges, and emerging combinations in CLL.Chavez: CLL is the most common chronic leukemia in the United States. I focused on the new treatments available for this condition, including novel agents, and also on the efficacy and toxicity of potential combinations for future treatments on these patients. Ibrutinib has changed the landscape of treatment entirely for CLL. It is an oral agent that is generally well tolerated; however, there are some toxicities we should keep in mind, like increased bleeding, atrial fibrillation, or infections. Those are manageable, but we have to keep in mind that there are potential comorbidities.

The efficacy of ibrutinib is impressive in basically all settings—in high-risk patients, those with 17p deletion, elderly patients, those with treatment-naïve disease, and relapsed/refractory patients. The success has been remarkable in CLL.

However, there are some issues. As I mentioned before, the CR rates are low—less than 10%. It doesn’t increase with combination therapy, whether we add rituximab (Rituxan) or whether we had bendamustine and rituximab or chemotherapy. It doesn’t increase much of the CR rates. It has been noted that deeper remissions are associated with good outcomes in patients with CLL.

The other problem is that patients discontinue treatment on ibrutinib for several reasons. Whether it is because of toxicity or disease progression, the outcomes are not good. Especially for patients who have progression of disease in CLL, there are alternatives but we have to be careful what to choose.

What are your thoughts on the combination study with ibrutinib and venetoclax?

We saw data from the phase III GENUINE study at the 2017 ASCO Annual Meeting. What is your insight on this trial?

Looking forward to the next couple of years in this landscape, what do you hope we can tackle in CLL treatment?

What take-home points do you wish to provide for community oncologists?

Recent data show that if patients progress on ibrutinib, going back to chemotherapy or monoclonal antibodies is not more effective than going to kinase inhibitors, such as idelalisib (Zydelig) or venetoclax. If patients fail on ibrutinib, the next step should be venetoclax of the FDA-approved agents. Venetoclax will probably be the next step in those who fail ibrutinib. Sequential treatment is going to be the future—not only ibrutinib and venetoclax, but also monoclonal antibodies, such as obinutuzumab and venetoclax or other monoclonal antibodies in clinical trials. Ibrutinib and venetoclax is an interesting combination; it is an ongoing trial. We will expect some early results at the 2017 ASH Annual Meeting. The idea of trying to debulk patients from the burden of their disease and then trying to achieve a deep response with venetoclax is very appealing. We will achieve what we were looking for in patients with CLL: MRD negativity. To cure is the goal. Ublituximab is a monoclonal antibody that is similar to obinutuzumab. It has shown good activity as a single agent and also in combination with other drugs. Again, [we have found that] adding ibrutinib with a monoclonal antibody…could lead to better outcomes.Combinations of highly effective monoclonal antibodies with kinase inhibitors that have the property to lead patients to CR or MRD-negativity will be the future. We are looking forward to findings from a clinical trial that explore the combination of obinutuzumab and chlorambucil with venetoclax and obinutuzumab. If it’s a positive study, it probably will have a new frontline therapy approved of venetoclax and obinutuzumab. That is going to be pretty exciting. Assess the patient as a whole. There are several factors in CLL. We talk about the genetics; there are patients with poor prognosis, high-risk CLL with 17p deletion and TP53 mutations. Those are patients who are an area in need. Also, we need to focus on the patients, too. Not all patients are the same. There are patients who are fit and young and can handle intensive therapy, but there are others who are unfit. There are many comorbidities, so [if they have them], we can’t give them the kinase inhibitors such as ibrutinib.

Even though we are trying to move away from chemotherapy, we have to keep in mind that chemotherapy is effective in a subgroup of patients. Especially in younger patients and lower-risk patients, they can have long-term remissions.

We have new, exciting drugs and low-toxicity oral drugs. However, we have to choose what is best for the patient. [It is important not] to forget chemotherapy, because we have good success, high CR rates, and also MRD negativity.

Sharman JP, Brander DM, Mato AR, et al. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study. J Clin Oncol. 2017;35 (suppl; abstr 7504).