BTK Inhibitor–Associated AEs Can Influence Treatment Selection in MCL

William B. Pearse, MD

Although the covalent BTK inhibitors acalabrutinib (Calquence) and zanubrutinib (Brukinsa) have widened the scope of treatment options for patients with relapsed/refractory mantle cell lymphoma (MCL), the toxicities associated with these agents must be managed appropriately, according to William B. Pearse, MD. He added that questions remain regarding the optimal balance between efficacy and adverse effects (AEs) with BTK inhibitor–based combination regimens.

“BTK inhibitors have a wide range of clinical activity, both in the up-front and the relapsed/refractory settings,” Pearse said in an interview with OncLive®.

In the interview, Pearse, an assistant professor of medicine at the University of California, San Diego School of Medicine, discussed the current roles of acalabrutinib and zanubrutinib in MCL management, how the AE profiles of each agent influence treatment decisions, and ongoing research efforts that aim to determine the feasibility of leveraging BTK inhibitors in combination regimens for specific patient subsets.

In particular, Pearse noted the potential clinical impact of combination regimens for patients with TP53-mutated MCL. For instance, in a phase 1/2 trial (NCT04855695), 2 of the 9 response-evaluable patients had TP53-mutated, relapsed/refractory MCL, both of whom achieved a complete response (CR) with the combination of acalabrutinib plus venetoclax (Venclexta) and obinutuzumab (Gazyva).¹ Furthermore, he highlighted the ongoing phase 2 BOVen trial (NCT03824483), which is evaluating zanubrutinib plus venetoclax and obinutuzumab in the frontline, TP53-mutant MCL setting. Early data demonstrated that the combination was generally well tolerated in a cohort of 25 patients and induced a best overall response rate (ORR) of 96%, which included an 88% CR rate.²

OncLive: Where do BTK inhibitors currently fit into the MCL treatment armamentarium?

Pearse: Acalabrutinib and zanubrutinib are the 2 FDA-approved agents in the relapsed/refractory [MCL] setting. [In 2023], Janssen and AbbVie withdrew the accelerated FDA approval for [ibrutinib (Imbruvica)] use in the relapsed/refractory setting, so typically, acalabrutinib and zanubrutinib are the drugs that are used in the relapsed/refractory setting for patients [with MCL].

However, compelling data on incorporating BTK inhibition into the frontline setting have emerged over the past few years. [For example,] the [phase 3] TRIANGLE study [(NCT02858258), findings from which were] presented [at the 2022 ASH Annual Meeting], incorporated the use of [ibrutinib] with a conventional cytarabine-containing induction regimen, with or without stem cell transplantation. Some of those data are still maturing. However, the use of BTK inhibition in the frontline setting is becoming more commonplace with objective data showing its utility, efficacy, and safety in that setting.

Combination regimens using BTK inhibitors [and agents] such as venetoclax, improve ORRs, CR rates, and progression-free survival rates, but with more toxicity relative to BTK inhibitor monotherapy in the relapsed/refractory setting. However, compelling [studies have demonstrated] response rates [with BTK inhibitors–based combinations] for particularly [difficult-to-treat] patient populations, such as [those with] TP53-mutated MCL who typically have poorer prognoses when conventional chemoimmunotherapy strategies are used in the induction setting and when stem cell transplantation is used in the up-front setting. Combination BTK regimens with other targeted agents can be attractive but are not typically used in common practice for all-comers and can sometimes be considered on a case-by-case basis, at least in the relapsed/refractory setting. Resistance patterns are common in patients who were previously exposed to BTK inhibitors, particularly those who harbor mutations at the C481 locus of the BTK protein. However, the novel noncovalent BTK inhibitor pirtobrutinib can restore BTK sensitivity in these patients with meaningful long-term disease control outcomes.

What patient characteristics and disease factors do you consider when deciding between acalabrutinib and zanubrutinib in the relapsed/refractory setting?

A lot of times, patient comorbidities may influence one decision or the other when using acalabrutinib or zanubrutinib in the relapsed/refractory setting. [In] an MCL diagnosis, all patients have their own medical history, so it’s important to think about the complete perspective to [determine] which BTK inhibitor may be best for that patient. Some AEs that are particular to acalabrutinib vs zanubrutinib may sway our decisions one way or the other.

It’s important to note that acalabrutinib is associated with a high incidence of gastrointestinal toxicity, [such as] diarrhea. Headaches can be common with acalabrutinib, as well. Fatigue can be perhaps anecdotally more profound with zanubrutinib. I’m not aware of any clinical data that prospectively study one treatment option vs the other in MCL. [This guidance] is based mainly on AE profiles and anecdotes rather than data.

However, when considering using [acalabrutinib or zanubrutinib], the AE profiles are important. With zanubrutinib, we commonly see hematologic toxicities. Neutropenia, low platelet counts, and thrombocytopenia are common. Anemias can also be common. We also see a seemingly increased risk in the incidence of upper respiratory infections, [such as] pneumonias. [We might want to choose] pulmonary pathology for patients with pre-existing lung disease. Often, patients’ medical comorbidities may influence our [treatment] decisions.

[Based on] the phase 2 data we have investigating acalabrutinib or zanubrutinib in the relapsed/refractory setting, both [agents] have impressive ORRs in the 80% range. CR rates vary from trial to trial, some of these numbers are quite small, and MCL is a bit of a rare disease. However, the CR rates are also reasonably comparable between acalabrutinib and zanubrutinib, [and there are] perhaps numerical improvements with zanubrutinib vs acalabrutinib, but the AE profile is perhaps the more important arbiter of determining 1 drug over the other.

What other ongoing research could continue to shift the roles of the available BTK inhibitors and potentially address some unmet needs throughout the MCL treatment paradigm?

When considering clinical trials that encourage clinicians [to refer patients], we want to think about where the unmet need is. Admittedly, MCL is a rarer lymphoma; it’s not the most common disease we come across, so it can be challenging to accrue specific patient populations to specific trials. Often, our numbers are low.

However, with that in mind, a significant area of clinical need is for patients with MCL who are carriers of the TP53 mutation. These patients have poorer outcomes with conventional induction therapies. Even with cytarabine-based induction regimens, patients do not respond as well or have as good longitudinal outcomes when they have the TP53 mutation present.

A clinical trial that is currently ongoing, the BOVen trial, aims to incorporate zanubrutinib, venetoclax, and obinutuzumab as a frontline regimen for patients with MCL. This [trial] has a real opportunity for determining how the combination of BTK inhibition with other targeted agents can help us identify chemotherapy-sparing regimens that may have meaningful activity for this subset of patients. The BOVen trial will give us some useful information, particularly about zanubrutinib in combination with other targeted agents.

References

1. Kim AI, Armand P, Redd RA, et al. Phase I safety and preliminary efficacy of acalabrutinib, venetoclax, and obinutuzumab (AVO) in patients with relapsed/refractory mantle cell lymphoma. Blood, 2023;142(suppl 1):3031. doi:10.1182/blood-2023-173103
2. Kumar A, Soumerai J, Abramson JS, et al. A multicenter phase 2 trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in patients with treatment-naïve, TP53-mutant mantle cell lymphoma. Blood. 2023;142(suppl 1):738. doi:10.1182/blood-2023-180069