How is rapid innovation in chronic lymphocytic leukemia treatment impacting clinical practice?

This article has been commissioned and funded by BeiGene

What key advancements have taken place in treating chronic lymphocytic leukemia and how have these translated into the clinic? Find out in this interview, where Prof. Stephan Stilgenbauer (Ulm University, Germany) and Mehrdad Mobasher (BeiGene, CA, USA) provide patient cases, physician learnings and takeaways from the recent ASCO and EHA medical conferences to help you navigate the complexities of decision-making in hematology practices.

Can you provide an overview of the current CLL treatment landscape and how it has evolved over the past several years?

Stephan Stilgenbauer: Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults and can serve as a role model in the transition from chemoimmunotherapy (CIT) to more targeted chemo-free treatments. Based on a better understanding of disease biology, several treatment options have been developed that target critical molecules or pathways of the disease. One of them is Bruton’s Tyrosine Kinase (BTK), a critical element in B-cell receptor signaling, maturation and survival of these cells. Not without a reason, therefore, pharmacologic targeting of BTK has proven clinically very successful.

The lead compound discovered here was ibrutinib, a specific inhibitor of BTK, which has truly transformed the treatment landscape of CLL. Over the years, there have been further developments, including second-generation BTK inhibitor (BTKi) acalabrutinib, and then next-generation BTKi zanubrutinib. These are more target-specific and have other beneficial pharmacologic properties. In head-to-head comparisons for relapsed/refractory CLL, zanubrutinib and acalabrutinib have shown to be better tolerated with acalabrutinib shown to be non-inferior (PFS, HR=1.0) to ibrutinib and zanubrutinib showing superior efficacy vs. ibrutinib (PFS, HR=0.65 in all-comers; HR=0.52 in patients with del(17p)/TP53 mutation).

Another treatment paradigm is targeting BCL-2, a critical molecule in the apoptosis cascade. The lead compound here is venetoclax which has been shown to be superior with regards to efficacy and tolerability compared to CIT in CLL. Taken together, these targeted agents either focusing on BTK or BCL-2 have transformed our treatment paradigm so that for the majority, if not all, CLL patients today in the frontline and the relapsed/refractory setting, targeted treatment with these agents is the standard of care.

How do you see zanubrutinib, BeiGene’s BTKi, positioned within the CLL treatment landscape?

Mehrdad Mobasher: At BeiGene, we are committed to bringing innovative therapies to cancer patients globally. One of the areas our scientists have especially in focus in hematology is finding new treatments for patients with B-cell malignancies, including CLL.

Our scientists specifically designed the mode of action of the BTKi zanubrutinib to succeed where others have not. Our clinical data shows zanubrutinib is the only BTKi that has demonstrated superiority in clinical trials in both frontline CLL compared to bendamustine-rituximab, a common CIT, and in relapsed/refractory CLL compared to ibrutinib. These results included the high-risk population in both settings.

As an example, zanubrutinib was studied in the ALPINE trial, head-to-head versus ibrutinib, the first-generation BTKi. Zanubrutinib is the only BTKi that has shown superiority in efficacy in all comers relapsed/refractory CLL patients, including the hard-to-treat patient population of those with 17p and/or TP53 mutations. Zanubrutinib has a safety and tolerability profile that provides a distinct advantage over other BTKis, such as low rates of cardiac and other adverse events and safety issues including those leading to treatment discontinuation (as recently presented at EHA). The most common AEs of any grade with zanubrutinib and ibrutinib were COVID-19, diarrhea, and upper respiratory tract infection, and the most commonly reported grade ≥3 AEs were neutropenia and hypertension.

We have worked to make zanubrutinib available to patients with a range of B-cell malignancies, resulting in it having the broadest label in this class both in the EU and the US. It is EMA approved for use in adult patients in four disease areas:  Chronic lymphocytic leukemia, Waldenström’s macroglobulinemia (after one prior therapy or first line in patients unsuitable for CIT), marginal zone lymphoma (after at least one prior anti-CD20-based therapy), and R/R follicular lymphoma (in combination with obinutuzumab and after at least two prior systemic therapies), for which it is the only approved BTKi. The US FDA has approved it for five disease areas (relapsed/refractory mantle cell lymphoma as well as the four above), highlighting its important role in treating B-cell lymphomas.

Could you discuss recent data BeiGene published at the ASCO and EHA congresses? How could this information help physicians make more informed decisions in such a complex landscape?

Mehrdad Mobasher: The zanubrutinib data that we presented at ASCO (May 31–June 4, IL, USA) and at EHA (13–16 June, Madrid, Spain) further emphasizes the differentiated clinical profile of zanubrutinib. BeiGene is committed to adding data to the growing body of evidence leading to zanubrutinib’s increasingly recognized role in this complex treatment paradigm in CLL. We have several ways to do that. We continue to generate data from our ongoing studies, and we do post-hoc analyses of previous studies to address specific and important clinical questions.

Now that zanubrutinib has been available for the treatment of CLL, we have the leverage to look at real-world databases and with the totality of what we can do, we continue to generate more data to help physicians make the best decision for their patients. A few examples of zanubrutinib data that we showed at these conferences are below.

The SEQUOIA trial, a study in the frontline setting of CLL, comprises a randomized comparison of zanubrutinib (Arm A) versus CIT (Arm B) and demonstrated the superiority of zanubrutinib that led to its approval in many countries across the world. Arm C of this trial has, to date, the largest pool of high-risk CLL patients with TP53 mutation and/or 17p deletion. The efficacy of zanubrutinib in this arm was comparable to its efficacy in Arm A, with a favourable safety profile in both arms. The most common grade 3 or higher treatment-related adverse event was neutropenia (11% of patients in Arm A, 51% in Arm B, and 15% in Arm C). Data from these 3 arms have been presented before.

Data from arm D of the SEQUOIA trial were presented at EHA, addressing the use of a combination treatment for the subset of high-risk CLL patients with TP53 mutation and/or 17p deletion. This arm shows how the BCL-2 inhibitor venetoclax can complement zanubrutinib in this setting. Zanubrutinib is the backbone and BCL-2 inhibitors may be added to deepen the responses for these high-risk patients as shown in this dataset. At 31 months follow-up, this combination showed a favourable safety and tolerability profile, with infections, diarrhea, hypertension and second primary malignancies being the most common grade ≥3 non-hematologic treatment-related adverse events. The most common all grade and grade ≥3 hematologic toxicity was neutropenia. We will continue to follow this arm and report results.

Also at EHA, Dr Talha Munir (Leeds Teaching Hospitals NHS Trust, UK) presented an analysis looking at the economic impact and quality of life based on an independent meta-analysis appraising the adverse event profile of patients who received zanubrutinib or acalabrutinib. His analysis concluded that zanubrutinib had both cost-saving and quality of life benefits compared to acalabrutinib.

Another tool that we have shared results on is a network meta-analysis looking at three clinical trials that have used BTKis. This analysis suggests that zanubrutinib may be the most efficacious BTKi for high-risk CLL patients, offering significantly delayed disease progression and favorable response compared to other BTKis included in the analysis. This type of analysis is not based on head-to-head data and should be viewed in context with certain limitations when comparing treatment options (disclosed in the publication), with the recognition that we can’t run randomized trials to answer every clinical question that may arise.

What does this rapid innovation in CLL treatment mean for you in the clinic?

Stephan Stilgenbauer: We do have diversity in CLL related to disease biology and patient characteristics.  Regarding disease biology, we know that genetic characteristics of the leukemia cells are very important for prognosis. With CIT, 17p deletion/TP53 mutation has important prognostic significance. In addition, the mutational status of the immunoglobulin genes holds prognostic impact, with unmutated IGHV showing inferior outcomes.

For genetic high-risk subgroups, the targeted treatment options we have available have dramatically improved outcomes compared to more low-risk populations. On the other hand, we have patient characteristics that are of relevance. CLL patients are usually elderly, with the median age at diagnosis of ~72 years and these patients have comorbidities including hypertension, cardiac disease, liver disease and renal disease. Therefore, the tolerability of these new agents is important.

We have a particular spectrum of adverse events. With BTKis, these include cardiac arrhythmias and hypertension. For BTKis, second-generation BTKis, such as zanubrutinib and acalabrutinib, are better tolerated because they reduce this adverse effect profile. BCL-2 inhibitors such as venetoclax can induce a very brisk rapid-onset tumor cell reduction, which may lead to tumor lysis syndrome, in particular when renal function is impaired.

Taken together, we now have a range of great choices in our therapeutic armamentarium that, based on genetic disease characteristics and comorbidities, we can choose from wisely. We know that for patients with a 17p deletion or TP53 mutation, continuous BTKi therapy has proven superior to venetoclax or BCL-2 inhibitor-based therapy, possibly due to the continuous treatment applied in this scenario. On the other hand, we know that patients with unmutated IGHV genes may relapse earlier, so this subgroup needs further development.

Increasing tolerability, with new combinations and drugs, is of importance in particular for CLL individuals who may be fragile with regard to their co-existing conditions and co-medications. For instance, when patients are on anticoagulants, BTKis can increase the risk of bleeding so management of these patients and patient education becomes a key issue. Overall, we have choices for our patients and recent developments have dramatically improved outcomes for our patients.

Mehrdad Mobasher: At BeiGene, it has been so important to be in close communication with experts in the field to do the trials right to address the questions and the challenges. That’s why, in the SEQUOIA study, we had several cohorts. The randomized cohort of zanubrutinib versus CIT excluded del 17p and/or TP53 mutated patients to make sure we were not exposing those patients to CIT since it is known to yield inferior outcomes in these patients, and we only study those patients in a large single arm cohort using zanubrutinib monotherapy.

In the randomized cohort the outcomes of patients on zanubrutinib monotherapy were the same in patients with mutated and unmutated IGVH status. Similarly, in the relapsed/refractory study, the ALPINE trial enrolled all-comer patients, and pre-specified a subgroup of patients with TP53 mutation and/or del17p. In this subgroup we saw a hazard ratio for PFS of 0.52.

What impact has the evolution of treatment from chemotherapy-based regimens toward more targeted therapies had on patients and the physicians who treat them?

Stephan Stilgenbauer: With the increased and improved range of treatment options, we have many more choices today that have been shown to improve outcomes for patients. On the other hand, in contrast to CIT, we have new, although rare and usually mild, adverse events. We have new drug interactions and risks, such as bleeding, hypertension, cardiac events, and renal failure with these novel agents. Patients and healthcare providers need to adapt to these new scenarios.

We need to remind patients that mild but bothersome adverse events such as arthralgias can be managed and overcome. Patient education is important to make the most out of these great options and not risk throwing away valuable treatment options prematurely.

At the recent EHA meeting in Madrid, you hosted a panel discussion of global CLL experts. What were their insights from clinical experience in treating CLL?

Mehrdad Mobasher: One insight we heard was that one of the most important challenges remains access and that’s a global issue wherever the patients and physicians are.

That’s why, at BeiGene, we are committed to making our treatments accessible to patients no matter where they live. We work with healthcare systems and foundations such as the Max Foundation to ensure zanubrutinib is broadly available to CLL patients.

Another significant area of interest was how BTKis differ and how the toxicities differ, and at EHA we talked a lot about how to manage toxicities. Second generation BTKi acalabrutinib was designed to be more specific against the target to mitigate some of the toxicities associated with ibrutinib and has demonstrated an improved safety profile but similar efficacy in the head-to-head clinical trial ELEVATE-RR vs ibrutinib (non-inferiority study, PFS, HR=1.0). Next-generation zanubrutinib was designed to be more specific and more potent than first and second generation BTKis, with the ALPINE trial results, which included high-risk patients, showing a superior efficacy (PFS, HR=0.65 in all-comers; HR=0.52 in patients with del(17p)/TP53 mutation) and a favorable safety profile, including cardiac safety vs ibrutinib. We are committed to sharing more of our data to answer the questions of physicians and support treatment decision-making.

Can you share any patient case studies?

Mehrdad Mobasher: At EHA, one of the clinicians shared a fascinating case about a 75-year-old patient diagnosed in 2016, who had high-risk features: del 17p and unmutated IGHV.

Similar to many patients with CLL, she went through a period of active monitoring, and then it became obvious she needed treatment. She started on ibrutinib and began suffering from side effects. Within two months, she was so unwell that she was hospitalized with atrial fibrillation and pneumonia that led to pulmonary effusion. The physician decided to stop this treatment given the adverse profile and switched to venetoclax plus rituximab with a fixed-duration therapy.

The patient did well, both in terms of safety and efficacy despite high-risk features and went to complete remission with eradication of minimal residual disease. Unfortunately, within a year, she progressed and the physician was debating how best to treat this patient given the adverse effect profile that she had with ibrutinib. It was decided to put the patient on zanubrutinib. Within weeks, the patient was symptomatically getting better, blood counts were improving, lymphadenopathy was decreasing, she showed a clinical response and is tolerating zanubrutinib treatment very well. I found that case a good example of what we are trying to achieve: in addition to showing superiority in 1L and R/R CLL in SEQUOIA and ALPINE, providing a patient, who may be intolerant to one BTKi, with an alternative BTKi that has benefits in terms of efficacy and tolerability.

Do you have any specific patient cases that highlight the complexities of CLL treatment and strategies for decision-making?

Stephan Stilgenbauer: I will share a forward-looking case on a new treatment option, which is not licensed or available in routine clinical practice. This case that really struck me concerns a 61-year-old, a relatively young CLL patient diagnosed in 2013, who experienced the usual period of needing no treatment and at the end of 2019 required treatment according to the IWCLL criteria.

In just over four years, unfortunately, he was one of the few patients who rapidly failed all the available treatment options, possibly because he had unmutated IGHV genes and a 17p deletion and TP53 mutation, which is genetically the most challenging-to-treat subgroup.

At the end of 2019, in relatively rapid sequence, this patient failed ibrutinib, venetoclax, idelalisib (a PI3K inhibitor) and then went on to an experimental treatment with a non-covalent BTKi. Then, the dramatic phenomenon of Richter’s transformation occurred. This is the transformation of the indolent type of CLL disease into an aggressive lymphoma, which is a very dismal condition with very few therapeutic options.

We treated this patient with R-CHOP standard chemoimmunotherapy for aggressive lymphoma. He was refractory to three cycles, he was then treated off-label with a venetoclax-based regimen combined with an antibody, again without a response, and then we were in the fortunate situation to have a trial open with another class of drug, namely a BTK degrader. This was an experimental compound developed by BeiGene. BTK degraders, in contrast to BTKis, don’t just block the enzymatic activity of BTK, but lead to the degradation of that molecule. It is not only inhibited – it’s erased in the cells. It was really striking to see, that the patient went onto this treatment, a single agent, oral drug, very well-tolerated, and within three months of that treatment, achieved a complete metabolic response documented by PET-CT. Due to the high-risk nature of the disease, he went on to allogeneic bone marrow transplantation as a consolidation strategy. This patient would have never made it to this procedure as he was totally refractory prior to the treatment.

This is a very instructive example of how further development focusing on a well-established drug target, namely BTK, with another class of a totally different treatment principle can be successful, despite the patient failing prior covalent and non-covalent BTKis, among other drugs. This is truly an early indication – we have to say with all caveats from early-phase clinical trial data – of promising developments in the field. Mehrdad, what is your take on the novel agents here?

Mehrdad Mobasher: I absolutely agree. To sum up what BeiGene is doing, we have taken the approach to tackle the unmet need of patients with CLL. Zanubrutinib is approved in over 70 countries around the world in various disease areas.  We continue to investigate it in a relatively broad clinical program to truly unlock its full potential in new therapeutic areas.

In our portfolio, for example, we have a novel investigational BCL-2 inhibitor, sonrotoclax. This second generation BCL-2 inhibitor has unique properties and is in a Phase III trial in combination with zanubrutinib. We want to address the increased need from physicians and patients to have fixed-duration therapy that is safe and efficacious. This year at EHA, we shared data on the same combination in relapsed/refractory patients. We are encouraged by the results we saw and hopeful this will address a population of patients for which fixed-duration treatment is desired.

In addition, we have a BTK degrader that we’re studying in a range of B-cell malignancies, including Richter’s transformation and CLL. CLL patients, even the ones who are not transformed, unfortunately, are still not cured, and may face progression down the line. At EHA, we shared data on a cohort of relapsed/refractory CLL patients where there was robust antitumor activity in these heavily pretreated patients. For example, we showed in the cohort treated with 200 milligrams an overall response rate of 88% at data cutoff. The presenter guided that one patient had responded after that cutoff, which would mean an overall response of 94% in patients with five median prior lines of therapy. These are the kind of patients that entered this trial, and we were very impressed with the overall response, including two complete remissions (13% in 200mg dose cohort).

The treatment also had a generally tolerable safety profile, with the most common adverse events being contusion, fatigue, diarrhea and neutropenia. We didn’t see atrial fibrillation or high-grade hypertension that some patients experience with BTKis. This is an early phase trial, but we are in expansion in Phase II. In future, we can present more data, and hopefully, address another area of unmet need.

Stephan Stilgenbauer: As the medical director of our comprehensive cancer center, I’m responsible for overseeing all cancer activities and ensuring that this dramatic progress observed in CLL also happens in other tumor entities where there’s possibly even more need for improving outcomes.

I think it is very important that we learn from CLL approaches such as specific targeting of critical molecules in disease biology with technologies such as degraders. Developments are underway targeting relevant tumor biology aspects such as EGFR or RAS pathways to make the progress that we’ve seen in CLL and other lymphoid malignancies available in other deadly diseases such as lung cancer, pancreatic cancer, colorectal cancer and gynecologic malignancies among others. I look forward to the future treatment landscape of these tumor types hopefully being transformed in the same way we’ve seen for CLL.

Mehrdad Mobasher: BeiGene and our academic collaborators have this same passion and mission. We talked a lot about CLL and all the great progress that we have made, but CLL is not the only B-cell malignancy that we’re focused on. With our BCL-2 inhibitor, we have studies in acute myeloid leukemia and multiple myeloma. We are also looking at areas of unmet need for patients such as Richter’s transformation and in diffuse large B cell lymphomas. We are also expanding our hematology development to new disease areas including AML/MDS and Multiple Myeloma. Outside hematology, we have a large pipeline in solid tumors. We hope that one day we can really enact change optimizing how we approach targets with these novel modalities across different diseases.

We’ve touched on the future and unmet needs. Could you both share your hopes for the future of CLL treatment?

Stephan Stilgenbauer: We have made great strides for the majority of patients. Still, we experience from time to time these few unfortunate cases, such as the patient I described in which, unfortunately, available options fail. As a scientist, I see the obligation to better characterize disease biology and patient characteristics, to identify those individuals early, and direct them to better treatment approaches. Additionally, I believe the tools and agents we have at hand can still be refined.

Novel combinations can be developed and new treatment principles such as the degradation of the target protein should be taken forward. We have made great progress for the benefit of our patients but need to continue pushing hard to make them available truly for everybody with a long-term goal of curing this disease and other cancers in, if possible, all of our patients.

Mehrdad Mobasher: From the BeiGene perspective, since CLL is one of our core diseases now, we are passionate about understanding the disease biology and which patient should get which treatment.

We are looking into treatment approaches and ways of combining medicines. For example, fixed-duration therapy is desired, however, it might not be for everyone. We want to be able to better understand and predict which patients will respond. One of the tools that we have in research, is minimal residual disease status at the end of fixed duration therapy. We are very interested in using that as a tool to improve the way patients are treated.

Sometimes despite all the advances we’ve discussed, there are still patients who have several progressions, and we want to develop medicines that can address those unmet needs, understand how best we can sequence these treatments and how best we can combine medicines.

Thank you both. It has been inspiring to hear about the truly patient-centric approach being taken and aspects of access to these emerging therapies.

 

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The opinions expressed in this article are those of the author and do not necessarily reflect the views of Oncology Central or Taylor & Francis Group.