Upcoming Approvals, Combinations Will Transform CLL Treatment

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The treatment landscape for chronic lymphocytic leukemia (CLL) is about to undergo a significant transformation, says Victor Y. Yazbeck, MD, an assistant professor of Hematology-Oncology, Internal Medicine, at Virginia Commonwealth University (VCU) School of Medicine, VCU Massey Cancer Center.

Several new agents, especially as part of combinations regimens, have the potential to be practice-changing, he says. These include the combination of idelalisib (Zydelig) with bendamustine and rituximab (BR).

“This is a very active combination and it will most likely become a standard of care in the relapse setting,” says Yazbeck.

In a phase III trial, the combination of idelalisib and BR reduced the risk of progression or death by 67% compared with BR alone for patients with CLL.¹ After 12 months of follow-up, the median progression-free survival (PFS) with idelalisib was 23.1 months compared with 11.1 months for BR alone (HR, 0.33; 95% CI, 0.24-0.45; P <.0001).

Another exciting agent is the Bcl-2 inhibitor venetoclax, which received FDA priority review in January 2016 for use in adults with CLL, including patients with a 17p deletion following at least 1 prior therapy. The FDA will take action on the drug's application within 6 months.

Also in January, venetoclax received an FDA breakthrough therapy designation for use in combination with rituximab (Rituxan). This was based on data from the phase Ib M13-365 study, in which the combination demonstrated an overall response rate (ORR) of 86%, with deep and durable responses in patients with relapsed/refractory CLL.²

OncLive: Which recent studies are you most excited about in CLL?

In an interview with OncLive, Yazbeck discusses the potential for venetoclax and idelalisib, both as single agents and in combination with other agents, and what questions remain regarding both therapies in CLL. Yazbeck: Recently, phase II data was released on venetoclax for patients with CLL who harbor the 17p deletion. Single-agent venetoclax demonstrated an ORR of 80%, with a complete response rate of close to 7.5%.

What impact could these findings have on clinical practice?

In another study, venetoclax was combined with rituximab (Rituxan) in relapsed/refractory patients with CLL. This showed an ORR of close to 80% with a complete response (CR) rate of 44%. In the 17p deletion population, the ORR was over 80% and the CR was 33%. The PFS rates at 12 months and 24 months were 89% and 79% in the 17p deletion population, respectively, compared with 87% and 84% in all patients. The 12-month OS rate was 89% for patients with 17p deletion and 94% for all patients. Venetoclax targets Bcl-2, which is an anti-apoptotic protein, which prevents the cancer cell from undergoing apoptosis or cell death.

What are the biggest questions that still remain regarding venetoclax?

Thus far, no drug has been approved in this area. Venetoclax is the first one to be near approval—expected this year&mdash;and would be the first drug to be approved in this class. This will be an additional option for this population. Hopefully, once it is approved, other combinations with venetoclax will be investigated and approved to increase the benefit from this drug to patients. There are major questions that remain regarding venetoclax development. As a single agent, it is active but, obviously, the CR rate is limited. A lot of ongoing studies are trying to understand how to better combine it with other active agents, both in CLL and in other non-Hodgkin lymphomas.

What other agents are you excited about in CLL?

In this setting, at VCU Massey Cancer Center, we are working on a rational combination regimen with venetoclax and a PI3 kinase inhibitor that has preclinically shown a very synergistic interaction between the two. We hope that will lead to better clinical activity. One exciting combination is idelalisib and BR. Idelalisib and BR were investigated in a study in relapsed/refractory CLL presented at the 2015 ASH Annual Meeting.

What should a community oncologist take away from these findings?

In this study, it showed overwhelmingly positive results. The combination doubled PFS with a hazard ratio of 0.33, so it decreased the risk of progression and death by 67%. More importantly, it showed an improvement in OS, including in patients with 17p deletion who typically have a poor prognosis. This is a very active combination, and it will most likely become a standard of care in the relapse setting. In the HELIOS trial, the combination of ibrutinib (Imbruvica) and BR in CLL led to an improvement in PFS, but not OS. Now, with the idelalisib data, this will be the new standard of care for relapsed CLL.

I also think it will eventually be moved to the frontline setting. There are currently trials in CLL with BR and idelalisib versus BR alone in the frontline setting. We are currently also investigating idelalisib and BR in the frontline setting for indolent Hodgkin lymphoma.

References

1. Zelenetz AD, Robak T, Coiffier B, et al. Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia: results of a phase 3 randomized double-blind placebo-controlled study. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL; Abstract LBA-5.
2. Ma S, Brander DM, Seymour JM, et al. Deep and durable responses following venetoclax (ABT-199/GDC-0199) combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from a phase 1b study. Presented at: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 830.