Pivotal Trial Finds That Imbruvica Shows Benefit in CLL and SLL

Imbruvica (ibrutinib) reduced the risk of progression or death by 88 percent compared to chlorambucil in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to the updated findings from the phase 3 RESONATE-2 that were presented at the 2016 American Society of Hematology (ASH) annual meeting.

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

The benefit with Imbruvica 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, M.D., said in an interview with CURE at ASH.

Can you dicuss the RESONATE-2 trial?

In her interview, 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 Imbruvica, discussed the updated RESONATE-2 data and the next steps with Imbruvica in CLL.The phase 3 RESONATE-2 trial explored Imbruvica 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 Imbruvica. Seventy-seven percent of these 70-year-old patients continue to take daily Imbruvica. What is even more impressive is the PFS. About 90 percent of the patients are now progression-free with over two years of follow up.

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

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 Imbruvica. It suggests that Imbruvica may be even more effective in these high-risk groups than what you would expect to see with any traditional chemotherapeutic regimen.Imbruvica 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.

What are the next steps?

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.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 Imbruvica by following those patients long term.

Right now, the program is also looking at Imbruvica in combination in the frontline setting and is looking at Imbruvica 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 Rituxan (rituximab; BR), fludarabine, cyclophosphamide and Rituxan (FCR) and the Gazyva (obinutuzumab) and chlorambucil combination.

What are the toxicity concerns with Imbruvica?

We have an ongoing study exploring Imbruvica in combination with Gazyva in terms of further developing the frontline program as well as two big studies looking at Imbruvica or Imbruvica/rituximab against FCR or bendamustine and Rituxan.The most frequent adverse events AEs with Imbruvica 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 Imbruvica has a nice tolerability profile. Most of the AEs are short-lived and resolved.

What other details from ASH regarding Imbruvica are important to mention?

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 percent of the patients and that’s consistent with our label. Atrial fibrillation is seen in patients treated with Imbruvica, 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 Imbruvica.Susan O’Brien, M.D., presented the five-year follow-up from our first pivotal study of single-agent Imbruvica, the PCYC-1102 trial. These are 130 patients who have been followed now for over five years. Again, we see good tolerability; about 65 percent of the patients who are aged 65 and up are still taking daily Imbruvica. 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 2 clinical study.