Dr Cheung Discusses Ibrutinib-Based Regimens Versus Standard CIT for CLL

Matthew Cheung, MD, FRCPC, SM, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Canada, discusses a phase 3 trial comparing bendamustine-rituximab with ibrutinib-based regimens in untreated patients with chronic lymphocytic leukemia (CLL).

Transcript

Hello, my name is Matthew Cheung. I am a hematologist at Sunnybrook/Odette Cancer Centre in Toronto, Canada. I am also an investigator at the Canadian Cancer Trials Group.

Our group collaborated originally with the Alliance Cooperative Group to conduct an economic analysis of their study called the Alliance A041202 study. In Canada, we called that study CLC-2. 

This was a randomized phase 3 trial that was designed to show the superiority of ibrutinib-based regimens over standard chemo-immunotherapy, bendamustine and rituximab specifically, in patients with CLL who were 65 and older and requiring front-line therapy. 

That original study met its primary endpoint, which demonstrated a progression-free survival (PFS) benefit with ibrutinib alone or ibrutinib in combination with rituximab over the standard chemoimmunotherapy (CIT), which was bendamustine and rituximab.

In that original study, there was no survival advantage seen with ibrutinib at the time of their primary analysis, which took place at 2 years. We felt that there were likely some tradeoffs in terms of whether or not we would want to use ibrutinib for front-line management. 

So for example, there might be more non-hematologic adverse events seen with ibrutinib therapy. As well, ibrutinib therapy has to be given continuously or on an ongoing basis as compared to chemoimmunotherapy, which can be given as a fixed shorter duration. As well, we believed that the cost of ibrutinib, especially in the US, was quite considerable when given on an ongoing basis. 

We conceived of this economic analysis along with the Alliance Group at the time of their study design. We hypothesized that ibrutinib-based therapies were going to be more costly, but we were hopeful that these costs might be offset by less toxicity with ibrutinib as well as, hopefully, improved quality of life.

We completed a prospective trial-based economic analysis to study the direct medical costs and quality-adjusted benefits, including quality-adjusted survival associated with the ibrutinib-based therapy compared to bendamustine and rituximab in specifically Canadian patients that were enrolled in the Alliance A041202 study.

What we found was that the direct medical costs associated with ibrutinib-based therapy was substantially higher than the costs associated with chemoimmunotherapy. In fact, they were close to $200,000 over the 2-year study period, and that was about four-fold higher than the chemoimmunotherapy approach for management of front-line CLL.

The majority of these costs, or the key cost driver, was associated with the cost of acquiring or paying for the ibrutinib therapy itself. We were also unable to find any improvements in quality-adjusted survival for patients receiving ibrutinib or ibrutinib and rituximab compared to bendamustine and rituximab.

I would say that was perhaps our biggest surprise with this study. We anticipated that with ibrutinib you would be getting an oral therapy, that it would be perhaps easier to tolerate. As well, the study did find a PFS benefit with ibrutinib.

We thought all of those would lead to at least some sort of quality-adjusted benefit with ibrutinib therapy compared to bendamustine and rituximab, but we didn't find that in our study.

As such, we see that there are substantial costs associated with ibrutinib-based therapy but, so far, not a lot of value from at least the standpoint of quality-adjusted survival benefits.

Our study is based in the Canadian context. We have a public healthcare system, and these costs are essentially born by society in terms of payers deciding whether to cover these costs or the benefits that are gained by society. 

At least in the Canadian context, there is a bit of an argument about whether or not the benefits that you see with ibrutinib, at this point specifically a PFS benefit, are worth the opportunity cost that you have to invest into paying for these therapies.

Right now, based on these findings in our study, there would have to be a little bit of a debate in terms of whether those benefits are worth substantial costs that have to be covered. From a standpoint of this study, it is still an early analysis.

It's important for us to continue follow-up for survival outcomes from this actual study. If there are later on survival benefits or quality-adjusted survival benefits, then those calculations and the benefits that you might gain with ibrutinib-based therapy, might be very different from what we're finding right now in this earlier time frame.

We are interested in the longer-term follow-up data. We are going to look out for long-term survival data and again, looking for whether or not there might be a quality-adjusted survival benefit detected later on. 

Overall, our group is very committed to understanding generally the value of therapies and looking at not just the classic outcomes that we see in clinical trials like survival benefits, PFS benefits, but also looking at quality of life and quality-adjusted survival. Then balancing those with the opportunity costs and specifically direct medical costs that patients might have to bear in terms of out-of-pocket costs as well as productivity impact at work.

Those are outcomes that our group is very interested in more broadly in cancer research and clinical trial research, not just related to this study today.

I do practice in the Canadian setting. Again, with our public system, it generally is a bit more of an equitable access to novel therapies in CLL. I would worry a little bit about other jurisdictions in which there isn't that more universal coverage. 

When this cost of therapy is so high, I would worry a little bit about patients in other settings outside of Canada perhaps having difficulty accessing treatments that might offer some benefit. 

Again, our study did raise the question about whether or not there is a lot of value with getting access to ibrutinib when compared to something like chemo-immunotherapy. Overall, I worry about the high costs of these therapies that are emerging not just in CLL but a lot of our hematologic malignancies.

In Canada, we're all part of a network called the Canadian Cancer Trials Group. A majority of our hospitals, small and large, are part of this group that tries to uniformly enroll patients in certain disease sites into clinical trials. I think it's the right model on our national basis, but we can certainly still do better. 

We still know that a lot of our patients, particularly in rural areas, or may not have access to larger centers like my hospital, may still not be getting enrolled in trials, may not even ever hear about them. It's a goal that universally we all need to be invested in at this point in time.

These data are still quite early in terms of the results, even the trial results from the Alliance study itself. We do appreciate that things might change over time. We felt it was important to get this information out early, especially for our Canadian context where decisions around drug funding are based on these types of value decisions, considering both the costs and the clinical benefits.

It's an early look and things might change, but we thought it was important to get out there right now.