Brian T. Hill, MD, PhD, and Matthew S. Davids, MD, MMSc, address the role of study design in CLL to highlight the importance of patient-reported QOL outcomes and matching-adjusted indirect treatment comparisons (MAICs).
Anthony R. Mato, MD, MSCE: Brian, I want you to talk about a topic that I have to say is a particular weakness of mine in terms of interpretation, and that's patient-reported outcomes (PROs) and health-related quality of life outcomes data. There were data from [the] ELEVATE-TN (NCT02475681) and RESONATE-2 (NCT01722487) [clinical trials]. Paolo Ghia, MD, PhD, of the Università Vita-Salute San Raffaele in Milan, Italy, presented data, [and] the ALPINE trial (NCT03734016) was presented on these PRO data. Can you comment or summarize what you got out of those presentations and what we should walk away with?
Brian T. Hill, MD, PhD: Yes, so [this is] not an area of my expertise either, but it is nice to see that these data are being collected when we have these large data sets. Many of the trials that we're talking about don't change overall survival. They just change PFS (progression-free survival), and when you're talking about the potential for long, indefinite therapy for years and years and years, it's important to know the impact on PROs and [patients’] experiences. I would summarize by saying that if you look at the RESONATE-2 trial, which compared ibrutinib with chlorambucil, even though ibrutinib has its warts, as you might say, there were definitely better PROs when you compared ibrutinib with chlorambucil. I think that was probably more likely to be the result of better disease control, not necessarily differences in the toxicities of the drugs, because chlorambucil actually has pretty minimal toxicities. There have also been other comparisons. For instance, [with] zanubrutinib vs bendamustine rituximab in treatment-naïve patients, compared with chemotherapy with bendamustine rituximab, we saw, unsurprisingly, that the zanubrutinib had much better PROs. I like this trend. I think we probably need to start to use these really robust data in our decision-making when we're dealing with chronic illnesses.
Anthony R. Mato, MD, MSCE: One other follow-up question to add a little more controversy to it: PROs always tend to be these secondary or tertiary outcomes that we hear about 3 years after the trial [data] are presented. Do you think these should be more incorporated into the primary end points for a clinical trial?
Brian T. Hill, MD, PhD: Yes, I think that's a great idea. With CLL now, there [are] so many different ways to approach patients that are unlikely to lead to changes in overall survival, so I think other factors are important. The cost of the treatment, the duration, and the PROs should all be coming into play when we make these decisions.
Anthony R. Mato, MD, MSCE: I'll editorialize for a second. I spent 30 minutes in-clinic on Monday trying to help a patient turn on an iPad to report a PRO. If these [efforts] are going to be realistic for older [or] frail patients with CLL who may not be particularly computer savvy, I think we need to come up with some better ways to collect these data. [For] that particular patient, [we] didn't collect the PRO because I couldn't figure out how to get the iPad to actually work for them. So [that’s] 1 editorial [comment] when we think about interpreting these data.
Speaking of modeling, Matt, I want to switch to you. You presented a MAIC at [the] 2021 ASH (American Society of Hematology) [Annual Meeting & Exposition]. Number 1, what the heck is that, and number 2, what did you find? What did we learn about sequencing from that, particularly with the BTK (Bruton tyrosine kinase) inhibitors?
Matthew S. Davids, MD, MMSc: So we have these great prospective head-to-head clinical trials now of BTK inhibitors, for example, in the relapse setting. One of the problems, though, is that we don't have prospective trials in the frontline setting. The idea behind this was actually to try to compare across trials in a systematic way in the frontline setting to see if there were differences that emerged between acalabrutinib and ibrutinib. We also looked at venetoclax/obinutuzumab because that's a popular frontline regimen as well. This is a way to basically compare across the studies and match in every way possible based on various prognostic variables to try to get the patient populations to be as similar as possible. This study included a number of different trials, particularly the ELEVATE-TN trial and some of the frontline ibrutinib trials. The ALLIANCE study (NCT03737981), for example, had pretty long follow-up with close to 4 years of follow-up.
In general, I would say there were more similarities than differences between the trials, but some of the themes that we've seen in the relapse setting do emerge from the MAIC analysis, such as improved tolerability of acalabrutinib compared with ibrutinib. We actually start to see also some of the advantages around PFS (progression-free survival) with acalabrutinib/obinutuzumab compared with ibrutinib-based therapy or even venetoclax/obinutuzumab in this study. I think it's thought-provoking, [but] I don't necessarily consider it practice-changing. I don't think we're going to see prospective trials of these types of comparisons any time soon in the frontline setting, so it fills in that data gap while we're awaiting that data.
Transcript has been edited for clarity.