Commentary

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Battiwalla Talks Bispecific Antibodies, BTK Inhibitors, and Emerging Therapies in Hematologic Malignancies

Minoo Battiwalla, MD, discusses the role of bispecific antibodies as an alternative to CAR T-cell therapies in NHL, treatment strategies for aggressive follicular lymphomas, and more.

Minoo Battiwalla, MD, MS

Minoo Battiwalla, MD, MS

In an interview with OncLive® regarding his colleagues’ presentations in a recent State of the Science Summit™ on hematologic oncology, Minoo Battiwalla, MD, highlighted the current treatment armamentarium, emerging targeted therapies, and ongoing challenges in non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), and acute myeloid leukemia (AML).

This included the increasing role of bispecific antibodies as a lower-toxicity alternative to CAR T-cell therapies in NHL; the expanding array of BTK inhibitors in CLL/SLL; treatment strategies for aggressive follicular lymphomas (FL); and the advantages of targeted therapies, particularly menin inhibitors, in the management of AML. He also emphasized the importance of continued research to refine these therapies, optimize treatment sequences, and address unmet needs in high-risk and refractory patient populations; Battiwalla expanded on quadruplet therapy and early-line CAR T-cell therapy in multiple myeloma in an additional interview.

Battiwalla serves as director of blood cancer outcomes research at Sarah Cannon Research Institute in Nashville, Tennessee.

OncLive: What are key considerations when selecting between bispecific antibodies for the treatment of NHLs such as diffuse large B-cell lymphoma (DLBCL)?

Battiwalla: Bispecific antibodies in NHL have taken off and offer an alternative to CAR T-cell therapies, which are generally considered to have far higher potency but with a higher risk of toxicity. The advantage of bispecific antibodies is that we might be able to use them in patients with a reduced performance status or, encouragingly, after stem cell transplant or the administration of prior CAR T-cell therapy. There are a number of molecules which are already approved for various indications, and this is going to be a very crowded field soon.

Mosunetuzumab-axgb [Lunsumio] is approved for patients with FL who have [progressed on] 2 or more lines of prior therapy, and epcoritamab-bysp [Epkinly] and glofitamab-gxbm [Columvi] have been approved for patients with DLBCL who [progressed on] 2 or more prior lines of therapy. Odronextamab [formerly REGN1979] is the next one [coming down the pike]; it has received FDA priority review acceptance for patients with relapsed/refractory DLBCL and FL after 2 prior lines of therapy and it is highly expected to receive imminent approval. In terms of consideration and selection amongst these options, most centers are going to go with what they are familiar with because all of these have slight differences.

However, there are some theoretical differences. For example, we expect to see a marginally higher rate of neurotoxicity with odronextamab compared with some of the other bispecific antibodies. Epcoritamab is interesting because it has the advantage of subcutaneous administration. All of these [agents] ultimately have maintenance dosing strategies—which are every either every 2, 3, or 4 weeks—so I don’t believe there is much advantage in terms of the dosing frequency with these alternatives. It’s going to be interesting to see how we incorporate all the bispecific antibodies into the armamentarium for treating these aggressive lymphomas.

What is the optimal role for pirtobrutinib in the BTK inhibitor treatment sequence for patients with CLL and SLL, particularly those with high-risk features?

We are spoiled for choices with BTK inhibitors in the treatment of CLL and SLL. On the one hand, you have the first-generation covalent inhibitors such as ibrutinib [Imbruvica], acalabrutinib [Calquence], and zanubrutinib [Brukinsa]. Now we have pirtobrutinib [Jaypirca], the noncovalent BTK inhibitor that binds to the target reversibly and allows for overcoming previous BTK inhibitor resistance. The interesting [thing about] pirtobrutinib is that it produces overall response rates of approximately 80% regardless of prior BTK inhibitor exposure, with a median progression-free survival of close to 2 years in BTK inhibitor-naive patients and approximately 15 months in BTK inhibitor-exposed patients. [Patients with] high-risk features such as the TP53 mutation, deletion 11q, or unmutated IgVH still respond well to pirtobrutinib.

Given all of these [data], it’s wise to start treatment with a covalent BTK inhibitor of choice typically based upon safety profile where zanubrutinib may have an advantage over acalabrutinib and ibrutinib. Then you keep pirtobrutinib as an active agent. Not to mention, CAR T-cell therapies have just been FDA approved in this space for patients who are venetoclax [Venclexa]- and BTK inhibitor-refractory. Most physicians will [probably] want to make sure that [the patient is] not just refractory to the covalent BTK inhibitors but also pirtobrutinib before they proceed to CAR T-cell therapies. We have many agents that are effective in CLL, and this is very encouraging news for the field.

How do emerging therapies such as bispecific T-cell engagers (BiTEs), EZH2 inhibitors, and BTK inhibitor combinations contribute to the management of aggressive variants of FL?

FL is typically considered to be indolent, but there are aggressive variants that are usually defined [by] progression of disease at 24 months. Such aggressive FLs usually deserve added attention and [patients with them] are likely to cycle through numerous therapies. In this space, we have only seen the establishment of anti-CD19 CAR T-cell therapies for refractory cases. These include both axicabtagene ciloleucel [Yescarta; axi-cel] and tisagenlecleucel [Kymriah; tisa-cel]. However, we now have BiTEs such as mosunetuzumab. There’s also the EZH2 inhibitor tazemetostat [Tazverik], which works both on EZH2-mutated and wild-type FL and is now deriving possibly even more potency [when administered] in combination with lenalidomide [Revlimid] and rituximab [Rituxan]. Finally, there is a definite role for BTK inhibition with zanubrutinib and the possibility of synergy with anti-CD20 [targeted agents], which could provide another combination with non-overlapping toxicity.

We have a fair number of ways to target CD19 through CAR T-cell therapies as well as bispecific antibodies, EZH2—which is a novel validated target—, and then BTK inhibitors. There are new novel targets for FL, and the whole goal of [treatment] in FL is to prolong survival. None of these patients are going to be cured in the advanced stages, and in order to [prolong survival], you have to select combinations which also minimize toxicity.

What are the primary barriers to accessing CAR T-cell therapy in hematologic malignancies, and how can these challenges be addressed?

CAR T-cell therapies have proven to be very effective in several indications, both for NHL and broadly for myeloma. The big issue with CAR T-cell therapy is managing access which is limited for several reasons. One reason is the enormous cost [of therapy], which requires a fair amount of comprehensive evaluation before the treatment can be given. Another aspect that is important is the high risk of toxicity. As CAR T-cell therapy expands broadly outside of specialized transplant centers, there are always patients who almost idiosyncratically have extremely high levels of toxicity requiring very prompt management, which is concerning for nonspecialized centers. We are talking about high-grade cytokine release syndrome and neurotoxicity. As of now, none of the commercially available CAR T-cell therapies are ready to be moved out into the community setting.

Finally, there is a prolonged period before patients who are initially referred can ultimately receive their CAR T-cell therapy. Although this duration has been shrinking with more efficient intake, this does remain a barrier for patients with more aggressive variants, particularly of large B-cell lymphoma, who cannot wait. In this context, careful selection of bridging and continuation therapies to get those patients to CAR T-cell therapy has proven to be crucial. This has required a lot of effort and coordination between referring community oncologists and the transplant centers. To summarize, access barriers for these very efficient therapies are a huge issue for the field.

How has the integration of FLT3-ITD inhibitors into frontline AML management changed the landscape of targeted therapy for this disease?

AML has traditionally been treated either with aggressive induction approaches, typically combination chemotherapy [or] venetoclax-based treatment for those who require less intensive management. AML has defined molecular mutations which are amenable to targeting. The first successful example of that was the use of the FLT3-ITD inhibitors; FLT3 inhibition has been incorporated into frontline AML management, as well as in a maintenance space, and has served as a template for development of targeted inhibitors in AML. We now have multiple other targets such as the IDH1/2 genes, which can be efficiently targeted.

What data have been seen with menin inhibitors in AML and what potential do the agents have in the treatment paradigm?

The most interesting [advancement in AML] has been the development of menin inhibitors. Menin inhibitors are applicable to patients with AML who either have an NPM1 mutation or those who have 11q23 gene rearrangements resulting in translocations of the MLL gene, also known as KMT2A. In early trials of menin inhibitors, including oral menin inhibitors, we are seeing stupendous results with high overall response rates. This probably implies that there is going to be a forthcoming indication for menin inhibitors in various lines of therapy for a large proportion of patients with AML. Although this [drug class] is not yet FDA approved, it is on the verge [of approval] and is going to dramatically change the therapeutic landscape.

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