Marc S. Hoffmann, MD, discusses data for sonrotoclax plus zanubrutinib and unmet needs in the mantle cell lymphoma treatment paradigm.
With sonrotoclax (Beqalzi) plus zanubrutinib (Brukinsa) demonstrating impressive safety and efficacy data on the heels of the recent FDA approval of sonrotoclax for patients with mantle cell lymphoma (MCL), a chemotherapy-free future is becoming increasingly possible, according to Marc S. Hoffmann, MD.1
Data from the
In an exclusive interview with OncLive®, Hoffmann discussed data from the trial, why BTK and BCL2 inhibition is effective, and how these data move the field closer to being chemotherapy-free.
Hoffmann is an associate professor of hematologic malignancies and cellular therapeutics, as well as the medical director of Lean and Quality Improvement and the Lymphoma Program at The University of Kansas Medical Center in Kansas City.
Hoffmann: There are a couple different pieces to this puzzle that are worthwhile to highlight. The first is that it’s been a struggle for BCL2 inhibitors in the management of MCL. Venetoclax [Venclexta] has been developed in that space for a number of years, and the 5-year data from the phase 3 SYMPATICO study [NCT03112174] were published in the British Journal of Haematology [in July 2026]. We’ve known about BCL2 inhibition for a long time, and there’s a demonstrable progression-free survival [PFS] benefit with ibrutinib [Imbruvica] and venetoclax compared with ibrutinib plus placebo.
At the same token, the uptake [of these regimens in clinical practice] has been low. It’s been challenging to get approvals in MCL. The MCL indication for ibrutinib was voluntarily withdrawn. [The MCL field has] been a bit complicated and unwieldy, and there are a number of factors behind that, some of which have to do with the approvals we just discussed, and some of which have to do with ramp-up schedule and the experience that some of us may have [with these agents] in chronic lymphocytic leukemia, where the risks of tumor lysis syndrome [TLS] are a bit higher. We did not see those same risks of TLS in MCL with ibrutinib and venetoclax, but there’s been a bit of a struggle in getting a drug class that we know is effective out into clinics.
Sonrotoclax was developed as a monotherapy. Those data have been presented and published, and [in May 2026], sonrotoclax got FDA approved as monotherapy for the management of relapsed/refractory MCL. The future of sonrotoclax is not going to be as monotherapy, but [as part of a] combination. Since [BeOne Medicines] owns both sonrotoclax and zanubrutinib, it made combining these agents easier, and that [contributed to] the rationale behind [the BGB-11417-101] study.
From a biological standpoint, there are a number of reasons why [zanubrutinib plus sonrotoclax] makes sense. Zanubrutinib tends to disrupt the tumor microenvironment, increase immune function in these patients, and be more of a disease-modulatory agent rather than leading to cell death. It seems that there’s some degree of synergy between zanubrutinib and BTK inhibitors/BCL2 inhibitors in general in a number of diseases. Given that the BCL2 inhibitors are apoptotic, you get some degree of more effective cell death along with microenvironmental modification, increased immune function, and some degree of pathway inhibition. [BCL2 inhibitors combined with BTK inhibitors is] targeting 2 different spaces.
Additionally, the volume of distribution and efficacy are a bit different [between sonrotoclax and venetoclax]. Zanubrutinib and BTK inhibitors tend to be more effective in lymph node compartments, whereas venetoclax and sonrotoclax tend to be more effective in marrow and splenic compartments. There appears to be some synergy [between BTK inhibitors and BCL2 inhibitors], and that’s the basis of why this study was conducted.
This trial was looking at zanubrutinib plus and sonrotoclax across a wide variety of different states of malignancies. This MCL cohort was just one of them. It included relapsed and refractory patients, who in general were BTK inhibitor naive. That’s the population we were looking at, but the study is a much larger basket study, and there are a number of other various abstracts that have come off of that protocol.
From a safety standpoint, we did not see any significant toxicities that were unexpected [with sonrotoclax and zanubrutinib]; it was in general a well-tolerated regimen. The rates of TLS were extremely low, and patients did not have any clinical events, although there were a couple laboratory events. We did not have significant rates of hematologic toxicity, and they were all manageable. This is a drug combination that is safe in this patient population, and the primary outcome of the study was figuring out the RP2D for the combination.
Sonrotoclax Plus Zanubrutinib in MCL: Take-Home Points
We also saw impressive efficacy. The efficacy rates among those who were responsive were high. We saw a significant CR rate, and [87.5]% of these patients attained a CR and went on to have durable disease control. One of the limitations of the study was that it was designed with a zanubrutinib lead-in period. There were some patients who ended up refractory to a single-agent BTK inhibitor who were not included in the subsequent analysis because they never ramped up the protocol dose, but they were included in an intent-to-treat analysis.
With these safety data, one of the things we can start thinking about is: Do we need that lead-in period? Can we shorten it and make it either a couple weeks or maybe a month rather than 2 months? Can we just start [the 2 agents] concurrently, which is what was done in SYMPATICO? By the time we did SYMPATICO, we knew that there was a lack of significant TLS, and thus we started these drugs concomitantly on day 1. Moving forward, there will be some degree of trying to get this [regimen started] a little earlier so patients who may have some reduced sensitivity to BTK inhibition will not lose the opportunity to have a BCL-2 inhibitor in the combination strategy.
You have to crawl before you can walk. This was the crawl study, where we demonstrated safety and efficacy. The true walking study would be a phase 3 efficacy study. This is a promising strategy, and it reinvigorates the role of BCL-2 inhibition in the management of MCL, not just in combination with zanubrutinib, but potentially in a lot of other combinations. When this disease becomes refractory, it is often challenging to manage, and we lack a lot of high-quality randomized data. We’re often choosing regimens based upon personal preference or what’s available for a certain scenario.
At EHA 2026, [I participated in] an advisory panel, and I was working with a number of colleagues throughout Europe. What’s available in each member state is quite different. You’re often just cobbling things together based upon what you can do. The real take-home here is that this drug combination has a future. This drug combination with obinutuzumab [Gazyva] will be done in the frontline setting. We’re moving toward less chemotherapy in MCL, not that chemotherapy doesn’t work, but we’re moving toward a strategy of seeing if we [can give] less chemotherapy. Can we start to give targeted therapy combinations and have that lead to durable efficacy with an acceptable safety profile?
This is just the first step in that direction and shows some ongoing promising activity. Is [zanubrutinib plus sonrotoclax] going to be better than ibrutinib and venetoclax? That’s a bit hard to know. We have some cross-trial comparison data and then some other data from other contexts that suggest that each of those partner drugs may be best in class. Therefore, combining 2 best-in-class agents, zanubrutinib and sonrotoclax, may be a bit better than ibrutinib plus venetoclax. We’ll see, but I think the drugs are going to end up being widely available.
The question is whether we’re going to be able to get them in combination and whether this would be sufficient enough to get a compendium listing. [Regulatory agencies are] going to require a lot more data to give approvals, but there might be a strong enough argument, if these data appear to show durable PFS, that we might be able to get a listing in the compendium for patients with relapsed/refractory MCL.
There is a patient perception that chemotherapy causes a lot of problems, and that’s not unfounded, although there are also long-term toxicities associated with specific drugs. Bendamustine is one of the core drugs that we use for the management of MCL, and that is associated with a nonnegligible rate of long-term myelosuppression, and patients also have long-term immune impairment. [Bendamustine also] sometimes impairs the efficacy of subsequent T-cell re-engaging therapy. Whether you give a bispecific antibody or CAR [chimeric antigen receptor] T-cell therapy with recent bendamustine exposure, the quality of the autologous CAR T-cell therapy appears to be diminished, and that’s a problem. There are also risks of myelodysplasia on a longer-term basis [with bendamustine]. [These toxicities and challenges] are what we want to avoid.
The targeted therapy combinations have their own toxicities. They are associated with a number of infections, and there are cytopenias with these regimens that are quite real, require treatment, and generally need to be aggressively prophylaxed. [There is going to be] a learning curve about how to [address these cytopenias], because usually with targeted therapy combinations, you can treat through the cytopenias and give growth factor support without stopping, whereas with chemotherapy, you generally have to interrupt the treatment.
My goal is not necessarily to get rid of chemotherapy in MCL. My goal is to maximize efficacy and durable disease control among patients with MCL with the least amount of toxicity that we possibly can. We’ve already gotten rid of transplant for the vast majority of patients. Only approximately 20% of patients who have detectable minimal residual disease after induction go to transplant. We’re getting rid of a large quantity of toxicity there. Now the question is: Do we get targeted therapy combinations? Do we get immune therapy combinations that may outperform chemotherapy and have more favorable short- and long-term toxicity profiles? In 10 years, it's not unreasonable to think [that MCL treatments may be in a place where] all patients are getting some sort of targeted therapy combination in the frontline setting.
We need to be cognizant of resources because a lot of those combinations are going to be quite pricey. It’s not like bendamustine plus rituximab [Rituxan] doesn’t work. We’ve been using bendamustine plus rituximab for a long time, among both transplant-eligible and non–transplant [eligible] candidates, and we see good results in the vast majority of patients, particularly those who do not carry aberrant P53 status. [Moving away from chemotherapy in MCL] becomes a question of: Do we hit the bar where we’re improving efficacy and reducing toxicity? It’s a complicated answer, but would be great to be chemotherapy free.
It’s an exciting time to be involved in this field. We’re developing a lot of new compounds and new drugs. As we continue to do this, I’m happy to see the reinvigoration of BCL2 inhibition in MCL. It’s been challenging a lot of times to get BCL2 inhibitors into patients with MCL, except under specific circumstances. Hopefully this trial and the recent approval of sonrotoclax will start to move that in the right direction.
