BTK Inhibitor–Based Combinations Represent the Future of MCL Management

Research has shown that BTK inhibitor–based combination regimens are associated with improved efficacy compared with single-agent BTK inhibitors in patients with mantle cell lymphoma (MCL), although the efficacy of these agents when combined with chemotherapy has yet to be fully parsed out, according to Peter Martin, MD.

“We need to investigate even more complicated strategies to improve [outcomes for] patients who have the most unmet needs,” Martin said in an interview with OncLive® during the 42nd Annual Chemotherapy Foundation Symposium.

In the interview, Martin discussed the current uses for BTK inhibitors in patients with MCL, the efficacy of combination regimens in this disease, and the need for future research to help solidify the role of these agents in the MCL treatment paradigm.

Martin is a professor of medicine and chief of the Lymphoma Program at Weill Cornell Medicine in New York, New York.

OncLive: What questions remain regarding the role of BTK inhibitors in MCL?

Martin: A lot of questions have been answered over the past decade, but [we’ve been] left with even more questions. [BTK inhibitors] work well as single agents in the second-line setting but we can do better, and combination strategies are likely to be that way forward. The issue is, whenever we add new drugs to other new drugs, [those regimens are associated with] increased adverse effects [AEs]. The question is always one of balance and which patients benefit from those new drugs.

For example, in a patient with low-risk MCL, [we may use] a BTK inhibitor plus other drugs that will make it work better but also potentially reduce their quality of life [QOL] over long periods of time. Patients with very high–risk MCL, like blastoid MCL or TP53-mutated MCL, need better options than just BTK inhibitors as single agents. However, when we add drugs like venetoclax [Venclexta], lenalidomide [Revlimid], or rituximab [(Rituxan) to these patients’ treatment strategies], the incremental benefit is there, but it’s not as great as in lower-risk patients.

The role of BTK inhibitors in the frontline setting is also unknown at this point. A few trials have [evaluated these agents] in transplant-ineligible older patients. I am not convinced by the [findings from the phase 3] SHINE [NCT01776840] and ECHO [NCT01776840] trials that investigated the role of BTK inhibitors in addition to bendamustine plus rituximab [BR]. Whether that’s an issue with bendamustine itself, or, for some reason, [an issue with drug-drug] interactions [in that combination] is unclear to me. At this point, I am choosing to add BTK inhibitors to BR but in the future, we may see data that indicate that we can potentially leave the chemotherapy behind and move forward just with BTK inhibitors.

In younger patients, though, we have data showing that adding a BTK inhibitor to a pre-transplant induction regimen like R-CHOP [Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] or R-DHAP [rituximab, cisplatin, cytarabine, and dexamethasone] improves outcomes significantly, including potentially overall survival [OS]. The question we’ll see is: Do [these patients] need chemotherapy at all? It’ll take a longer time to get to that answer but right now, [adding a BTK inhibitor] is appropriate in a young patient receiving an intensive [chemotherapy] regimen.

How do you decide between available BTK inhibitors for patients with MCL?

Currently, 3 BTK inhibitors are approved for [use in] MCL. The 2 covalent BTK inhibitors, acalabrutinib [Calquence] and zanubrutinib [Brukinsa], are more or less interchangeable, at least based on the data we have. Maybe that will change at some point, but currently, they [are both] appropriate for any patients in whom you would consider a BTK inhibitor. We also have pirtobrutinib [Jaypirca], which is a noncovalent BTK inhibitor approved for patients who have received a prior covalent BTK inhibitor. [Overall, for BTK inhibitors], not much selection [is needed] other than the decision between acalabrutinib and zanubrutinib, and in the absence of strong data, I would choose either one.

What were the benefits of adding venetoclax to ibrutinib (Imbruvica) vs using ibrutinib alone in patients with previously treated MCL in the phase 3 SYMPATICO trial (NCT03112174)?

In the SYMPATICO trial, which was a randomized phase 3 trial, [initial findings from which were] presented [in 2023] and from which subsequent interesting follow-up data in patients with TP53 mutations [were presented in June 2024], adding venetoclax to ibrutinib improved progression-free survival [PFS] outcomes compared with ibrutinib alone. [In the primary analysis], venetoclax plus ibrutinib improved PFS outcomes by 9.8 months, [eliciting a median PFS of] 31.9 months compared with 22.1 months [with ibrutinib alone].¹ That benefit seems meaningful, given data indicating that patients who progress on a single-agent BTK inhibitor and subsequently receive venetoclax will respond to venetoclax for approximately 3 to 4 months. That indicates a benefit with the combination as opposed to the sequential approach. That said, in the SYMPATICO trial, there was no OS difference [between the 2 arms], which challenges the assertion that there’s a difference between concurrent and sequential therapy [with ibrutinib and venetoclax].

Additionally, although there wasn’t a big difference in the incidence of grade 3/4 AEs [between the arms], there was a difference in the incidence of grade 1/2 AEs that would negatively impact a patient’s QOL. I don’t have an answer to the question of whether we should add venetoclax for all patients who receive a single-agent BTK inhibitor in the second-line setting [because] it increases some of the QOL-affecting AEs. However, it also improves PFS, without clearly improving OS. At this point, [the decision to add venetoclax to ibrutinib is] a matter of patient selection. [We should] discuss with patients [the outcomes] we might expect, both good and bad, and try to have shared decision-making.

SYMPATICO does show us that that combination is more effective than a BTK inhibitor by itself. In scenarios where we’re trying to find ways to make BTK inhibitors work better, adding venetoclax is one of the strategies that’s going to do that. That’s why we see a lot of triplet regimens currently being evaluated in MCL, specifically BTK inhibitors plus an anti-CD20 agent plus venetoclax or another BCL-2 inhibitor. That’s a good strategy to try to make improvements upon BTK inhibitors.

However, any time we add drugs [to a regimen], we’re going to see potentially an improvement in outcomes but also an increase in AEs. We’ll have to be careful when we’re calculating the [risk/benefit profile]. There’s going to be a role for shared decision-making in the absence of an OS benefit [with the addition of venetoclax to ibrutinib].

What evidence currently informs whether BTK inhibitors and chemotherapy have a synergistic effect in patients with MCL?

The answer to the question of whether BTK inhibitors act synergistically with chemotherapy can be potentially inferred from 3 frontline clinical trials: the SHINE trial, the ECHO trial, and the phase 3 TRIANGLE trial [NCT02858258]. In both SHINE and ECHO, there was a small PFS benefit without a significant OS benefit [with a BTK inhibitor plus BR vs chemotherapy alone].^2,3 The PFS benefit, from my perspective, is not necessarily outsized relative to what I might expect from sequential therapy [with] frontline BR followed by a BTK inhibitor. We don’t have those data but at this point, I’m not convinced that the combination of BR plus a BTK inhibitor shows synergy, whereas it increases infection risk, especially COVID-19 infection risk. Whether [the lack of synergy is] a BTK inhibitor issue or a bendamustine issue, I don’t know, but I wouldn’t be surprised if it’s a bendamustine issue [rather than an issue with the BTK inhibitor] because we’ve seen that before with bendamustine-based combinations. In the phase 2 E1411 trial [NCT01415752] of bortezomib plus BR induction vs lenalidomide plus rituximab maintenance, we didn’t see benefits [with the BR regimen vs the doublet in patients with treatment-naive], even though those drugs are active in MCL.⁴

In the TRIANGLE trial in younger, transplant-eligible patients [with previously untreated MCL] who received R-CHOP alternating with R-DHAP plus or minus autologous stem cell transplant [ASCT], there was a benefit in failure-free survival [with ibrutinib plus immunotherapy and ASCT vs immunotherapy plus ASCT alone] but also an indication of an improvement in OS.⁵ Time will tell. We’re still waiting for those data to become mature, but if there is an OS benefit [with the addition of ibrutinib], that may indicate synergy [between BTK inhibitors and chemotherapy]. As we move away from chemotherapy toward non-chemotherapy regimens, one of the questions that will come up is: Are we leaving chemotherapy behind too soon? 

References

1. Wang M, Jurczak W, Trněný M, et al. Ibrutinib combined with venetoclax in patients with relapsed/refractory mantle cell lymphoma: primary analysis results from the randomized phase 3 Sympatico study. Blood. 2023;142(suppl 2):LBA-2. doi:10.1182/blood-2023-191921
2. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med. 2022;386(26):2482-2494. doi:10.1056/NEJMoa2201817
3. Calquence plus chemoimmunotherapy reduced the risk of disease progression or death by 27% vs. standard of care in patients with untreated mantle cell lymphoma in ECHO phase III trial. News release. AstraZeneca. June 16, 2024. Accessed November 27, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/calquence-plus-chemoimmunotherapy-reduced-the-risk-of-disease-progression-or-death-by-27-percent.html
4. Smith MR, Jegede OA, Martin P, et al. Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL. Blood. 2024;144(10):1083-1092. doi:10.1182/blood.2024023962
5. Dreyling M, Doorduijn J, Giné E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306. doi:10.1016/S0140-6736(24)00184-3