Frontline Ibrutinib Benefit Sustained in Pivotal CLL Trial Update

Updated findings from the phase III RESONATE-2 trial presented at the 2016 ASH Annual Meeting showed that at 29 months’ follow-up, frontline ibrutinib (Imbruvica) reduced the risk of of progression or death by 88% versus chlorambucil in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

RESONATE-2 included 269 treatment-naïve patients aged ≥65 years with CLL or SLL. The study was the pivotal trial that led to the March 2016 approval of ibrutinib for the frontline treatment of patients with CLL/SLL.

The benefit with ibrutinib shown in the data presented at ASH extended across high-risk subgroups, such as patients with deletion 11q.

“This suggests that ibrutinib may be even more effective in these high-risk groups than what you would expect to see with any traditional chemotherapeutic regimen,” Danelle James, MD, said in an interview with OncLive at ASH.

In her interview with OncLive, James, an assistant adjunct professor in the Division of Hematology-Oncology at the Chronic Lymphocytic Leukemia Research Consortium and head of Oncology at Pharmacyclics (an AbbVie company), the manufacturer of ibrutinib, discussed the updated RESONATE-2 data and the next steps with ibrutinib in CLL.

OncLive: Please discuss the RESONATE-2 Trial.

James: The phase III RESONATE-2 trial explored ibrutinib versus chlorambucil for the frontline treatment of patients 65 or older with active CLL. The trial was originally reported at the 2015 ASH Annual Meeting and showed an impressive progression-free survival (PFS) benefit, overall survival benefit, and benefit for response and hematologic improvement over chlorambucil.

At ASH, we shared 29 months of follow up with these patients and it shows impressive continued tolerability of ibrutinib. Seventy-seven percent of these 70-year-old patients continue to take daily ibrutinib. What is even more impressive is the PFS. About 90% of the patients are now progression-free with over 2 years of follow up.

It is interesting because what we traditionally consider to be bad prognostic features in CLL—such as deletion 11q or immunoglobulin heavy-chain gene-mutational status­—did not confer any adverse outcomes with ibrutinib. It suggests that ibrutinib may be even more effective in these high-risk groups than what you would expect to see with any traditional chemotherapeutic regimen.

How could the findings with this agent impact the CLL community?

Ibrutinib is approved in all lines for CLL and SLL in the United States. It also has a broad approval outside the United States in the EU, so it is available as a single agent for patients to be treated in the frontline setting. The NCCN has given it several category 1 recommendations, including fairly large patient subsets in the frontline setting.

This updated data set will help bring physicians and patients more security and understanding of what the drug does over a long period of time. Interestingly, in addition to preventing disease progression, we see the quality of the responses get better over time. Therefore, we see patients who originally had a partial response now achieving complete responses to therapy.

What are the next steps?

For this study, we are going to continue to follow the patients. We haven’t even come close to establishing a median PFS in the frontline setting, so we really want to see what the true benefit is of ibrutinib by following those patients long term.

Right now, the program is also looking at ibrutinib in combination in the frontline setting and is looking at ibrutinib versus many other comparators. Basically, we want to review all of the standard comparators that you use to treat patients with CLL in the community, such as bendamustine and rituximab (Rituxan; BR), fludarabine, cyclophosphamide, and rituximab (FCR) and the obinutuzumab (Gazyva) and chlorambucil combination.

We have an ongoing study exploring ibrutinib in combination with obinutuzumab in terms of further developing the frontline program as well as 2 big studies looking at ibrutinib or ibrutinib/rituximab against FCR or bendamustine and rituximab.

What are the toxicity concerns with ibrutinib?

In addition to diarrhea, we usually see grade 1/2 fatigue. It is a small proportion of patients who will get arthralgias. We also usually see low-grade bleeding events, in about up to 50% of the patients and that’s consistent with our label. Atrial fibrillation is seen in patients treated with ibrutinib, and that tends to also be an AE that resolves. However, that is probably one of the adverse events that physicians pay the most attention to with ibrutinib.

What other details from ASH regarding ibrutinib are important mention?

Susan O’Brien, MD, presented the 5-year follow-up from our first pivotal study of single-agent ibrutinib, the PCYC-1102 trial. These are 130 patients who have been followed now for over 5 years. Again, we see good tolerability; about 65% of the patients who are aged 65 and up are still taking daily ibrutinib. It speaks to the tolerability of the agent when a patient can remain on treatment for so long. Additionally, we see enduring remissions throughout the high-risk subgroups within that phase II clinical study.

Barr PM, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 234.

The most frequent adverse events AEs with ibrutinib are traditionally grades 1/2. Diarrhea is one of our most common AEs. We have a safety poster that looks at a number of patients across the frontline setting, relapse setting, and long-term follow-up—establishing that ibrutinib has a nice tolerability profile. Most of the AEs are short-lived and resolved.