VIDEO: CLL clinical trial updates focus on combination therapy, long-term follow-up data

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So, there's been a lot of exciting data coming up from CLL. I think one of the more exciting studies was an update from the UK FLAIR study, and this was a study looking at combination ibrutinib [Imbruvica; Pharmacyclics/AbbVie, Janssen] and venetoclax [Venclexta; Genentech, AbbVie] in the front-line setting using a MRD-, or minimal residual disease-guided approach. And so, we've had a lot of data looking at combination ibrutinib and venetoclax, either in a phase 2 study or even phase 3 compared to chemoimmunotherapy, the GLOW study, the CAPTIVATE study. This study was designed a little bit differently where they looked at the time it took for a patient who was getting ibrutinib and venetoclax until the time that they achieved undetectable disease on their peripheral blood and confirmed on bone marrow biopsy that guided how long they would be on a combination of venetoclax and ibrutinib. And then the control arm was [fludarabine, cyclophosphamide, rituximab (FCR)]. This study was conducted in Europe and what's really exciting is that, you know, even after 5 years of therapy, these patients with the targeted agent regimen had very deep rates of undetectable disease. So, at 5-year fault, 93% of those patients still had undetectable MRD in the blood and 66% had undetectable MRD in the bone marrow. So that's really exciting data. They also showed fewer deaths in secondary cancers using this regimen vs. FCR. And, you know, compared to other fixed duration ibrutinib and venetoclax combinations across, looking at different trials, of course they had different inclusion criteria, but we saw some of the deepest responses with this type of approach. And so, to me this is really exciting because it showed us that really personalizing therapies for our patients is kind of the wave of the future and it's paving the way for other MRD-guided treatment approaches for patients.

So, we had some preliminary data from a phase 1 study looking at a novel BCL-2 inhibitor, sonrotoclax [BeiGene], combined with second generation BTK inhibitor, zanubrutinib [Brukinsa, BeiGene]. And so, sonrotoclax and zanubrutinib are now being studied in the front-line setting in head-to-head comparison with obinutuzumab [Gazyva, Genentech] and venetoclax in a phase 3 study. So, we'll have that data hopefully in a couple years to help guide how to use these novel agents in a more safe fashion and hopefully achieve deeper responses. I think these are the studies that are helping us figure out, you know, maybe a QR for CLL potentially, in a population of patients. We also had a lot of data, you know, longer term follow-up data for some of the studies we've been keeping an eye on, like the Elevate study, which looked at acalabrutinib [Calquence, AstraZeneca] vs. chemoimmunotherapy. We had longer follow-up data comparing the zanubrutinib vs. ibrutinib in the Alpine study. And so, they basically confirmed that even with longer term follow-up, we're seeing really wonderful responses with these targeted agents. And the second-generation BTK inhibitors continue to show improvement over front-line ibrutinib and chemoimmunotherapy. So, the side effect profiles are really wonderful — lower cardiac complication risks and even patients with higher risk cytogenetics at longer term follow up are doing really well with these drugs. So that's exciting.

We also have some options in the relapse/refractory setting, which are really important because as I mentioned with the BRUIN study, pirtobrutinib [Jaypirca, Eli Lilly &Co.] is fantastic. We're not seeing years of response with these patients. So, we're hopeful to see how pirtobrutinib will do when we move it up potentially into earlier lines of therapies or as a combination regimen. But, you know, we do still need good regimens in the relapse/refractory setting since chemotherapy really isn't effective in that setting. So, there's the study looking at [chimeric antigen receptor T cell] CAR-T therapy. There’s some data presented from liso-cel [lisocabtagene maraleucel; Breynazi, Bristol Myers Squibb], which showed a pretty sustained response in a subset of patients who had kind of that tail of a curve response that we hope to see. We also saw some data from a bispecific therapy targeting ROR1, so that's also pretty exciting. And then, we also got some exciting data from the BRUIN study looking a bit deeper dive into patients who develop resistance to pirtobrutinib.