BeiGene’s Mehrdad Mobasher, MD, MPH, Discusses CLL Data, Pipeline Following ASH 2024

Some time ago, officials at BeiGene started looking at data for their Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) in years, not months. Still, sharing 5-year follow-up data for the SEQUOIA study (NCT03336333)¹ at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, which took place from December 7 to 10, 2024, in San Diego, California, was a big milestone for a company that had several in 2024—from opening its $800 million US flagship facility in Hopewell, New Jersey,² to announcing plans to change the company’s name to BeOne Medicines Ltd.³

(The company will change its Nasdaq ticker symbol to ONC today, according to a press release issued December 23, 2024.)

Data from SEQUOIA showed zanubrutinib reduced the risk of progression or death in newly diagnosed patients with chronic lymphocytic leukemia (CLL) by 71% compared with bendamustine and rituximab (HR, 0.29; 95% CI, 0.21-0.40; P < .0001).¹ CLL is the most common type of leukemia worldwide, diagnosed in 103,467 patients worldwide in 2019, which is a 150% increase over the past 30 years.⁴

ASH 2024 also brought data from a phase 1/1b study (NCT04277637) for sonrotoclax, BeiGene’s second-generation BCL2 inhibitor, in combination with zanubrutinib in CLL.⁵ The combination is showing potential as a fixed-duration regimen with less toxicity in treatment-naive CLL at a time when there is increased interest in this approach from patients and from payers. At week 48, a standard dose of zanubrutinib plus 160 mg or 320 mg sonrotoclax yielded an overall response for 100% of patients. The 160-mg dose of sonrotoclax brought 60% partial responses (PR) and 40% complete responses (CR) or CR with incomplete count recovery (CRi). The 320-mg dose yielded PR in 58% of patients and 42% with CR/CRi. Minimal residual disease (MRD) negativity was rapidly achieved, with 59% and 78% at the 160-mg and 320-mg doses, respectively, reaching undetectable levels at 10^–4 by week 24.⁵

Mehrdad Mobasher, MD, MPH | Image credit: BeiGene

This combination is being evaluated in the phase 3 fixed-duration study, CELESTIAL-TNCLL (NCT06073821), comparing the zanubrutinib-sonrotoclax combination with venetoclax-obinutuzumab.⁵

Finally, results for the investigational BTK degrader BGB-16673 showed promise in both CLL and for B-cell malignancies.^6,7

For insights on the data presented at ASH 2024, The American Journal of Managed Care® (AJMC®) spoke with Mehrdad Mobasher, MD, MPH, chief medical officer for hematology at BeiGene.

This interview has been edited for length and clarity.

AJMC: When zanubrutinib came on the scene after ibrutinib, much of what we heard about this second-generation BTK inhibitor was not only improved efficacy but also better safety—lower toxicity, fewer cardiac effects. As we learn more about sonrotoclax, the second-generation BCL2 inhibitor, will the story be similar in terms of a leap in safety over the current BCL2 inhibitor venetoclax?

Mobasher: Sonrotoclax was designed to have higher potency, and that can lead to better efficacy. It’s very specific, and that can have [a] better safety profile. And importantly, it has a [different] PK [pharmacokinetic] profile, meaning that it has a shorter half-life compared with venetoclax and it doesn’t accumulate in the peripheral blood. Venetoclax, in fact, has a long half-life of 26 hours and accumulates in the blood; specifically, what this means is that there are some known short-term and long-term adverse events associated with venetoclax.

From the long-term perspective, in particular, there is the risk of tumor lysis syndrome. With venetoclax, there is of course a ramp-up, but there’s also pretty labor-intensive laboratory monitoring with associated ramp-up. And by that, I mean there is a laboratory check at hour 8; that is the next day in earlier doses. Every time patients come in for the ramp-up, they need to check the blood to make sure the patient doesn’t have any signs of tumor lysis syndrome, and that’s because of that longer half-life that stays in the body for a little while, and this [creates] long-term toxicity as it accumulates in blood. We know that venetoclax treatment is associated with neutropenia, for example, and it has some adverse events that bother patients a lot; physicians and we in the industry sometimes don’t pay as much attention as we should, but there are also [gastrointestinal] toxicities, such as diarrhea, but we were well aware of those issues with venetoclax.

We try to design a medicine that specifically addresses efficacy, safety, and feasibility of how this medicine, a BCL2 inhibitor, can be given at any practice and to any patient because that is one of the barriers with venetoclax combinations. Not every practice is able to deliver them, and not every patient has the capacity to go back and forth or stay [in the clinic] for so many long hours. So that is how sonrotoclax was developed, and now we have enrolled more than 1300 patients across the overall clinical trial program. At ASH, we presented the data from the phase 1 study that is a combination of zanubrutinib and sonrotoclax.⁵

AJMC: There were results from a survey of community oncologists presented at ASH by John Burke, MD, of Rocky Mountain Cancer Centers in Colorado, that speak to some of these barriers with venetoclax.⁸ Fear of tumor lysis syndrome was one of the top concerns with administering venetoclax in community practice and was perhaps limiting uptake. Is this something that you’ve heard not just from patients but also from clinicians?

Mobasher: Absolutely. Thank you for mentioning that very important paper by Dr Burke. In fact, that is something that we have looked at, and we have carefully discussed this with a lot of folks…. We should put the wants of patients and what they really want at the center of our research. So, we ultimately develop treatments and tailor care to what exactly is important for them. As you mentioned, for patients [with] CLL, we are aware that it’s not just the efficacy that they care about. [It] is really safety that they want us to focus on, and with venetoclax, when any physician describes the potential for tumor lysis syndrome to the patient, it can be scary.

The fear of potentially developing tumor lysis syndrome is something that’s really big in patients’ minds. And as I mentioned, the feasibility for patients going back and forth is definitely part of the issue. For patients with a high risk of tumor lysis syndrome—those who have large lymph nodes or a very high lymphocyte count—they need to be hospitalized. That needs to be prearranged. And that becomes one of the barriers to the practice; every time they come to get their ramp-up, they need to get there at hour zero before they can take the medicine. Then if the laboratory [results] are normal, they take the medicine. Then there is an hour 8 laboratory check. When you add this up, think about a typical practice that might open [at] 8 AM or 9 AM. They check the laboratory [results]. They have to wait for normal laboratory [results to] give the patients the medicine. By the time [of] hour 8, is the clinic closed or closing? And somebody needs to monitor that laboratory result, and if there is an issue with a laboratory [result] abnormality, someone needs to correct it. So that hour 8 alone is a huge barrier; the patient will need to come back the next day before they can go home.

A lot of community physicians have issues doing this, and a lot of our patients are, of course, being treated at community centers. And even though academic centers have infusion centers with longer hours, this also adds a barrier to them too. So we certainly hear about this from physicians as well.

AJMC: Let’s go back to the phase 1 study you mentioned: the combination of zanubrutinib and sonrotoclax in treatment-naive patients.⁵ What can we look forward to in the phase 3 study?

Mobasher: The phase 1/1b study was a very well-received study in an oral presentation…. We enrolled all-comer patients with frontline CLL on 2 doses [of sonrotoclax], either 160 mg or 320 mg. We enrolled a total of 117 patients, so it’s a pretty large data set. We enrolled all patients, so even those patients with high-risk features, such as 17p deletion or TP53 mutation; about a quarter of the patients have those high-risk features.

This is a longer follow-up than we saw last year at ASH; the median follow-up was 19 months…. Now we see that it is translating in the clinic, particularly with this doublet. One thing that has grabbed people’s attention and has since the development of this drug is safety. We didn’t see a lot of those safety issues that we see with the venetoclax combinations, and a few of them I mentioned, for example, neutropenia—the higher rate of neutropenia that we see with venetoclax combinations—we didn’t see it here. We didn’t see any febrile neutropenia, and that’s a very important complication of neutropenia.

We didn’t see any ventricular toxicity—some of the venetoclax combinations, particularly with BTK inhibitors, have shown that—but knowing what we know about [zanubrutinib] having a very clean cardiac profile, we didn’t have any ventricular toxicity. Those ventricular toxicities are unacceptable for treatment-naive patients, because often they lead to death.

We also reported strikingly low MRD rates in this study; this is the rate of eradication of minimal residual disease, which is the best marker of showing how deep you are inducing these responses. This was consistent with what we saw last year, but this year, with a larger number of patients and a longer follow-up time, we saw a very high rate of uMRD [undetectable MRD] at what we call week 24. So [in] the way we describe the study, if you think about 1 year, this is the 6-month mark, and we see very high rates of uMRD—higher rates than have been reported with any doublets—but higher in the 320-mg dose compared with the 160-mg dose. In both cases, it deepens by the end of year to what we call the 48-week mark. In the 320-mg dose at this point, 91%, the vast majority of patients, [had] uMRD. So we are able to put almost everyone in a very deep remission and eradicate even minimal residual disease in their peripheral blood.

And so it is the 320-mg dose that we have taken to our phase 3. And I’m very happy that no patient [at that dose] had a primary progression, and in the 160-mg dose, there was a single case of progression that was actually a Richter transformation….

That was, as I mentioned, much higher than anything we had seen before. This and the safety data convinced us that we can develop a fixed-duration treatment—to seize treatment at 1 year for everyone—and that was the treatment we took to phase 3. That study, CELESTIAL-TNCLL, evaluates the fixed-duration zanubrutinib plus sonrotoclax at 320 mg vs venetoclax and obinutuzumab, which is currently the only globally approved fixed-duration treatment with good safety and very good efficacy….

That study started last year and is, in fact, enrolling and progressing very well.

AJMC: As we are talking about fixed-duration regimens, is the 24-week measure of undetectable MRD going to become more important?

Mobasher: To your point, we certainly want to put people in deeper remission, and we want to make sure they are in deep remission before we take them off treatment. So, they need that deep remission that I mentioned; MRD is relatively fast and much deeper than what we’re familiar with. The reason we continue to week 48 is to see when we would have almost everyone in the deepest remission and then take everyone off to make sure people don’t convert.

When we see evidence of uMRD conversion, patients progress quickly. So that was the importance of testing midtreatment and at the end of treatment. With these data, we took a 1-year treatment approach, and after that point, treatment will cease.

AJMC: BeiGene is marking some important milestones for zanubrutinib, and a lot of long-term data are coming out. If you walked into a clinician’s office and could only present a single long-term data point, what would it be?

Mobasher: The longer follow-up of our SEQUOIA study was by far one of the most important abstracts. We have presented SEQUOIA data before, but as you know, a hematologist-oncologist always wants longer follow-up for their consultations with their patients. In fact, just before ASH, we published a 42-month follow-up of ALPINE [NCT03734016], our relapsed/refractory study comparing zanubrutinib with ibrutinib. But with the 5-year follow-up for SEQUOIA, we showed that at a median of 61 months, both the superiority of zanubrutinib vs bendamustine-rituximab and the reduced toxicity are sustained. We show how patients do based on their IGVH status—whether [their status is] mutated or unmutated, the efficacy is the same. The safety continues to show really good, low rates of atrial fibrillation and infection, low rates of headaches….

So this gives us a lot of confidence to tell physicians, “These are important data to look at because the safety of these patients is protected and the treatment is tolerable.”

References

1. Shadman M, Munir T, Robak T, et al. Zanubrutinib versus bendamustine and rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: median 5-year follow-up of SEQUOIA. J Clin Oncol. Published online December 8, 2024. doi:10.1200/JCO-24-02265
2. Caffrey M. BeiGene opens $800M flagship US facility in New Jersey. Am J Manag Care. 2024;30(SP9):SP:SP719.
3. BeiGene unveils proposed name change to BeOne Medicines, reaffirming its mission to unite global community against cancer. News release. BeiGene. November 14, 2024. Accessed December 14, 2024. https://bit.ly/3DeCeN4
4. Tam C, Pinilla-Ibarz J, Castillo CG, et al. Results of VOICE: a global survey of disease-specific knowledge and perspectives of real-world patients with CLL. Blood Adv. 2023;7(22):6819-6828. doi:10.1182/bloodadvances.2023010879
5. Soumerai JD, Cheah CY, Anderson MA, et al. Sonrotoclax and zanubrutinib as frontline treatment for CLL demonstrates high MRD clearance rates with good tolerability: data from an ongoing phase 1/1b study BGB-11417-101. Blood. 2024;144(suppl 1):1012. doi:10.1182/blood-2024-199175
6. Thompson MC, Parrondo RD, Frustaci AM, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphoma: results from the phase 1 CaDAnCe-101 study. Abstract presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA. Abstract 885.
7. Seymour JF, Tam CS, Cheah CY, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory Waldenström macroglobulinemia: results from the phase 1 CaDAnCe-101 study. Abstract presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA. Abstract 860.
8. Jacobs R, Fletcher L, Rettew A, et al. Best practices to overcoming challenges in initiating venetoclax for patients with chronic lymphocytic leukemia: results from a United States community-based healthcare practitioner survey. Blood. 2024;144(suppl 1):2268. doi:10.1182/blood-2024-198466