Asher Chanan-Khan, MD
In the phase III HELIOS study, combining ibrutinib (Imbruvica) with standard bendamustine and rituximab (BR) lowered the risk of disease progression by 80% in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to results presented at the 2015 ASCO Annual Meeting.
The trial looked at 578 previously treated patients with relapsed/refractory CLL/SLL. Half received BR plus ibrutinib (n = 289) and half received BR plus placebo (n = 289) The full 6 cycles of BR were completed by 83% of patients in the ibrutinib and 78% of patients in the placebo arms.
Overall response rate was 82.7% in the ibrutinib arm compared with 67.8% in the control group (P
<.0001). Complete response (CR) rates were 10.4% compared with 2.8% with ibrutinib versus placebo, respectively. The OS analysis showed a nonsignificant 37% reduction in the risk of death with ibrutinib (P
To better understand the significance of the HELIOS trial and ibrutinib’s role in CLL, OncLive
spoke with lead author Asher A. Chanan-Khan, MD, chair of the division of Hematology/Oncology at the Mayo Clinic in Jacksonville, Florida. OncLive: What were the goals of the HELIOS study?Dr Chanan-Khan
: This study was designed as a randomized, placebo-controlled, one-on-one international study. It has all the bells and whistles that are required to answer a clinical question in the most rigorous way. Over 578 patients were enrolled in two arms. The study was designed to give 6 cycles of BR with or without BR or placebo. At the time of the completion of the 6 cycles, patients were allowed to continue with ibrutinib or placebo. The primary endpoint of this study was PFS. CLL is an incurable cancer. The management strategy of CLL is to first get patients in remission and then try and maintain that remission for as long as possible. We wanted to investigate if we could add to the existing advantage that BR brings. Would you consider this study practice changing?
Absolutely. This is a practice-changing moment in CLL indeed. We found amazing results. They are spectacular, and they will change how we treat CLL going forward from today. The PFS assessed at the median of 17.2 months showed that those patients that were in the ibrutinib arm have not reached their median PFS. Those who were in the placebo-controlled arm had a 13.3 PFS of months. The hazard ratio suggested that the risk of progression is significantly decreased by 80% among patients who have received ibrutinib. That is impressive. That piece by itself is practice-changing data.Were there any significant toxicities found with ibrutinib?
Its safety profile and its ease of administration to the patient is remarkable because we did not see any safety signal between the control arm and the ibrutinib arm that would deter us from going forward in this regimen. That is really great. It is a practical regimen that can be given anywhere.What is the potential for ibrutinib to be a platform or backbone agent in CLL?
Stepping back and looking at the two large conclusive studies that have been done, the RESONATE study and the HELIOS study, it is very clear in the relapsed setting that ibrutinib makes a huge impact on a patient’s ability to go into remission and to stay in remission. There is no doubt, at the end of these two studies, that ibrutinib is a backbone agent for all patients with CLL.
Can you explain the benefits of combining ibrutinib with BR from a mechanism of action point of view?
This is, again, a very unique perspective where three drugs with different mechanisms are used together. For a long time, bendamustine has had an impact in CLL treatment. The second drug, rituximab, is an immunotherapy with known benefits for patients with CLL, and that is a whole other mechanism of action. Then, we have a targeted therapy that specifically goes and inhibits the signal that is delivered to the cancer cells to survive longer. Therefore, you have three different ways of targeting the cell and, clearly, when you do that there is benefit to the patient. It is not just science—it is clinically meaningful.
Is there a curative potential with the HELIOS combination?
I wish I could say that there is curative potential, but it is too early to make that determination. We will have to see how the data matures over time.
Do you think the optimal use of ibrutinib will emerge as a combination?
As we saw from the HELIOS study, when you target the cancer from three different ways, the clinical impact is major. There are certainly opportunities for us to continue to investigate ibrutinib as a backbone, and bring in other newer and older drugs to study that could fit well with this backbone to deliver the maximum impact to patients.