Kipps on Impact of Potential Venetoclax Approval and Other Novel CLL Agents

Thomas Kipps, MD, PhD

There have been significant advancements in chronic lymphocytic leukemia (CLL) in recent years, with new agents approved that are associated with increased survival for many patients.

Nevertheless, there is still much work to be done, says Thomas Kipps, MD, PhD, professor of Medicine in the Division of Hematology-Oncology, and deputy director for Research at the University of California San Diego Moores Cancer Center.

“We’ve done a lot, but there is still a lot going on,” he says. “Although patients have improved and we have more treatment options, we still haven’t closed the deal and achieved a curative strategy that works for all patients. Until that day comes, I think we need to work further to achieve that goal.”

Kipps has been involved in the investigation of venetoclax, a first-in-class Bcl-2 inhibitor, which received a priority review by the FDA in January 2016 for use in adults with CLL, including patients with a 17p deletion.

The review is primarily based on the phase II M13-982 study, in which venetoclax elicited responses in nearly 80% of relapsed/refractory patients with CLL who have a 17p deletion. The FDA is expected to make a decision on the agent within the next 6 months.

Venetoclax is also being investigated in combination with anti-CD20 monoclonal antibodies, including rituximab (Rituxan) and obinutuzumab (Gazyva).

In an interview with OncLive, Kipps provides insight on the potential impact of an FDA approval for venetoclax, the management of tumor lysis syndrome associated with venetoclax, and combination possibilities for the agent.

OncLive: What impact would an FDA approval for venetoclax in CLL have?

He also discusses other emerging agents he is excited about in CLL, including second- and third-generation PI3 kinase inhibitors, second-generation BTK inhibitors, and selective spleen tyrosine kinase (SYK) inhibitors. Kipps: It is a very effective drug that is orally active. It is active in patients who are resistant to standard chemotherapy drugs, and it has a different mechanism of action than some of the currently approved therapies.

What toxicities associated with venetoclax should oncologists be aware of? How can they be optimally managed?

From that standpoint, I think it will be used both as a single agent and in combination. There is a high likelihood that this will find its way into the treatment of patients with CLL because of its activity. The challenge with venetoclax is due to its effectiveness. Some patients do experience tumor lysis syndrome because the drug destroys tumor cells so quickly it can cause problems for the patient. That is a major side effect that we have encountered.

One way to prevent tumor lysis syndrome is to identify the patients who are higher risk. Patients who have bulky disease, very large lymph nodes, high white blood cell count, or high leukemic cell count are at a higher risk for tumor lysis syndrome. For patients who have poor kidney function, it can also be more complicated to treat tumor lysis syndrome because a lot of the electrolytes that are released from dying cells aren’t filtered and excreted properly.

The main way to prevent it is to follow patients very closely and monitor their blood frequently to see if tumor lysis syndrome is occurring. If it is, then practitioners can administer appropriate treatment immediately.

What combinations do you envision venetoclax being part of and showing the most potential with?

Once the patient gets started on the medicine, the risk of tumor lysis syndrome is no longer there if they maintain themselves on the same dose. Therefore, patients can get started on venetoclax, they can be monitored very closely, and if they don’t experience tumor lysis syndrome after receiving their established dose, they are safe to take the drug without tumor lysis syndrome complications. Venetoclax, when used alone, has produced a complete remission (CR) in about one-quarter of patients who have been treated so far. However, for patients who do not receive a complete response with venetoclax as a single agent, they may be able to benefit from it in combination.

When venetoclax has been added to rituximab or other anti-CD20 monoclonal antibodies, such as obinutuzumab, CR rates have been higher—approaching 50% or more depending on the trial. The combination of the antibody and venetoclax makes sense when the goal is to improve activity.

There is some discussion of mixing it with other drugs, such as some of the other approved kinase inhibitors. However, the potential for that still remains to be seen; both drugs are metabolized by the same pathway, so there may be some interference in the metabolism with the 2 drugs. Therefore, we need to determine if the combination of kinase inhibitors and venetoclax is going to be well tolerated and have activity.

What other emerging agents are you excited about in CLL?

Obviously, oncologists want to combine drugs for additional activity, but overlapping toxicities do need to be considered. There have been approvals of some other kinase inhibitors, including ibrutinib (Imbruvica). Another second-generation BTK inhibitor, acalabrutinib, is undergoing clinical testing based on early data from 61 patients who were treated in a phase I/II study. In that trial, patients had similar responses as they did with ibrutinib, but there may be different toxicities. It needs to be tested in clinical trials. Idelalisib (Zydelig) and other second- and third-generation drugs of that same category are also being investigated.

We are also very excited about antibodies against other antigens. We have had trials with CD19, which is another B-cell differentiation antigen. There is also a new agent—CC-122—that has an effect thought to be more specific than lenalidomide (Revlimid), which is interesting.

There are also some drugs that are being investigated that might target other pathways, such as SYK inhibitors. SYK is another enzyme inside the cell that can block signaling to a certain extent. That has been tried in combination with P13 kinase inhibitors. Unfortunately, patients had a lot of complications when these drugs were used in combination.