Expanded Idelalisib Indication in CLL on Horizon After Positive Phase III Combo Trial With Ofatumumab

Jeffrey A. Jones, MD, MPH

Idelalisib (Zydelig) in combination with ofatumumab (Arzerra) more than doubled progression-free survival (PFS) compared with ofatumumab alone in patients with previously treated chronic lymphocytic leukemia (CLL), according to data presented at the 2015 ASCO Annual Meeting.

The phase III trial (Study 119) randomized 261 patients with CLL who progressed within 24 months from their last therapy to idelalisib plus ofatumumab (n = 174) or single-agent ofatumumab (n = 87). Patients were stratified based on relapsed versus refractory status, 17p deletion (del17p) and/or TP53 mutation status, and whether they harbored an IGHV mutation.

The combination reduced the risk of disease progression by 73% versus single-agent ofatumumab, with a medium PFS of 16.3 versus 8.0 months, respectively (HR = 0.27; P <.0001). In patients with del17p or TP53 mutations, the median PFS was 13.7 versus 5.8 months, respectively (HR = 0.33; P <.0001).

The overall response rate was 75.3% in the combination arm versus 18.4% in the ofatumumab alone arm (OR = 15.9; P <.0001). Medium overall survival was 20.9 months in the idelalisib/ofatumumab arm compared with 19.4 months in the ofatumumab arm (HR = 0.74; P = .27).

Based on results of Study 119, Gilead, the manufacturer of idelalisib, has filed an application with the FDA to expand the indication of the PI3K delta inhibitor to include use in combination with ofatumumab in patients with relapsed CLL.

Idelalisib was previously approved in combination with rituximab for use in the treatment of patients with relapsed CLL. The drug also has approved indications for follicular lymphoma and small lymphocytic lymphoma.

OncLive spoke with lead study author Jeffrey Jones, MD, MPH, assistant professor of Internal Medicine, section chief, CLL/HCL Clinical Research Program, Ohio State University, to better understand the Study 119 results, as well as the role idelalisib and other novel targeted agents will play in CLL going forward.

OncLive: Can you discuss the rationale, design, and findings of Study 119?

Dr Jones: The purpose of the trial was to determine if idelalisib and ofatumumab could improve PFS as compared to ofatumumab alone. This is because the number of agents that are traditionally available for patients with relapsed/refractory CLL is relatively limited. Efficacy is particularly limited in patients with high-risk disease, including those with del17p.

In the trial, patients were randomized 2:1 to the combination arm or the single-agent arm. They received 6 months of treatment with ofatumumab in both arms, and patients in the combination arm received idelalisib twice daily to be continued until disease progression or intolerable side effects.

What we found was that PFS was significantly improved in the patients treated with the combination arm. In secondary analyses, we saw that the overall response rate was also significantly improved among patients receiving the combination, with 75% versus 18% in the combination and single-agent arms, respectively. The likelihood of response was several times higher in the patients treated with the combination, as well. Overall, there was remarkable efficacy of the combination compared to the single-agent antibody.

What are the next steps in this research?

This data follows the previously reported trial of idelalisib in combination with rituximab, which led to an approval of the combination for the treatment of relapsed/refractory CLL in July 2014. What our latest trial did was provide additional details to confirm the efficacy of idelalisib, this time in combination with another anti-CD20 antibody, ofatumumab. It also further confirms its safety profile because most of the adverse events that were reported in this trial were similar to what has been recorded in prior trials that looked at idelalisib.

There is now discussion that the label indications of idelalisib could be broadened to include it in combination with ofatumumab. This would be very reasonable, based on this data.

Were there any concerning toxicities found with the combination of idelalisib and ofatumumab?

There were higher rates of low blood cell count in the combination arm. This is not really any different than what has been reported with idelalisib previously. Interestedly, the rate of infusion reactions, a common toxicity of monoclonal antibody therapy, appeared to be reduced in the combination arm. This suggests that idelalisib may be able to attenuate some of the infusion toxicities typically associated with monoclonal antibodies.

What did you see as the role of idelalisib in CLL treatment going forward?

Idelalisib has been studied in combination with monoclonal antibodies and chemotherapy, but most of the activity in this combination is from the drug itself. We’ve been prescribing it since its approval as a single agent. What we understand about kinase inhibitors, idelalisib included, is that sustained remission will require continued therapy. That has consequences for patients’ health in the long term, their financial health in the long term, and the financial health of our healthcare system. Many of us are interested in rational combinations that could result in higher response rates and allow discontinuation of therapy. For myself and other CLL investigators, we are excited to see which combinations develop, ideally with novel targeted therapies.

How have advances in novel targeted therapies impacted the treatment of CLL?

The survival advantage attributed to these novel agents is very apparent. We are making a profound impact in treating patients with relapsed disease, but we are interested in seeing if these drugs have increased utility when used earlier in the course of the disease. We might be able to alter the natural history of the disease and not allow it to evolve to the point where it becomes refractory in the way we see now.