Ibrutinib Plus Chemo Induction Followed by Ibrutinib Maintenance Could Be New Standard in MCL

Martin Dreyling, MD

The addition of ibrutinib (Imbruvica) to induction chemotherapy with autologous stem cell transplant (ASCT; A+I) or without transplant (I) plus subsequent ibrutinib maintenance provided superior outcomes than that achieved with chemotherapy followed by ASCT and observation (A) in patients with mantle cell lymphoma (MCL). These findings may call the role of ASCT into question, according to Martin Dreyling, MD.

Findings from the phase 3 TRIANGLE study (NCT02858258) presented at the 2022 ASH Annual Meeting demonstrated that A+I resulted in a failure-free survival (FFS) rate of 88% at 3 years vs 72% with A alone (HR, 0.52; P = .0008), which confirmed the superiority of A+I over A alone. Additionally, the superiority of A vs ibrutinib plus induction chemotherapy followed by 2 years of ibrutinib and subsequent observation (I) was rejected; the 3-year FFS rates in the A arm was 72% vs 86% in the I arm (HR, 1.77; P = .9979). The comparison of A+I vs I are ongoing, and no FFS superiority decision has been determined yet.

Although no decision has been made regarding whether ASCT adds to ibrutinib, toxicity data favor the use of ibrutinib only, said Dreyling, who is the lead study author and an associate professor of medicine at the University of Munich, München, Germany.

“In my opinion, the old standard of ASCT is the past. Both ibrutinib-containing arms were superior,” he added. “We are still waiting for [more data to clearly show] the difference [between the] 2 experimental arms, but at [this point in time,] the toxicity [data] favor the ibrutinib[-containing] arm[s] and that [marks] a major shift in standard of care [SOC] for us.”

In an interview with OncLive^®, Dreyling, who is also the head of the Lymphoma Program in the Department of Internal Medicine III, LMU University Hospital, Munich, Germany, discussed the safety and efficacy data from the TRIANGLE study done in patients with previously untreated MCL who are younger than 66 years, and the impact of these results on the use of ASCT in this population.

OncLive^®: What was the rationale for conducting the TRIANGLE trial?

Dreyling: About 20 years ago, we established SOC [for MCL], which was dose intensification [of chemotherapy followed by ASCT. This [approach] is more efficient than conventional high-dose chemotherapy, but it is also [more] toxic.

[To] improve on [this approach], we [conducted the TRIANGLE trial, which investigated a] BTK inhibitor, and they are the most potent salvage treatment at least [for those with] early relapses. It became a huge study, with almost 900 patients in the 3 study arms.

Please expand on the trial design and patient population of the TRIANGLE study.

The standard arm in the TRIANGLE trial was [R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone)/R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin)] induction [therapy] followed by ASCT [and no] maintenance. We compared [this standard arm with] 2 experimental arms: an add-on arm [of] ASCT [after] ibrutinib [plus R-CHOP/R-DHAP], and a third [arm evaluating] ibrutinib [with induction R-CHOP/R-DHAP] but [no] ASCT. Importantly, we added ibrutinib [to the experimental arms as] part of the R-CHOP induction cycles, and as fixed-duration maintenance [treatment]. All patients [in the experimental arms] stopped ibrutinib maintenance after 2 years.

[The study population consisted of] patients who qualified for ASCT. Usually, these are patients younger [than] 70 years [and who are] rather fit and have confirmed previously untreated MCL. All other inclusion criteria were standard, [including] reasonable performance status and no major organ failures, as that would disqualify these patients [from participating on the trial].

What key efficacy data were reported during the meeting?

When [we] compared the standard arm with the add-on arm, we could see a huge [FFS benefit]; that correlates to an additional 15% after 3 years and a hazard ratio [HR] of [about] 0.5. As such, this was a major achievement.

[In] the head-to-head comparison, we [originally] postulated that we [would] only keep ASCT as the standard [treatment] if it improves [patient] outcomes [compared with] ibrutinib. Interestingly, we observed that ibrutinib was the superior [regimen]. Again, the differences [in outcomes] were clinically meaningful, with [an approximate] 15% [increase] after 3 years. To summarize, both experimental arms [showed] significantly better [FFS] and clinically meaningful benefits [vs the standard arm] and [suggest] an overall survival [OS] benefit.

What should be taken away regarding safety?

Safety [data] became critical [when distinguishing] between the 2 experimental arms. The third [study] comparison flipped the [original] question, and [evaluated the addition or removal] of ASCT [to] ibrutinib. [Survival] curves [in both experimental arms] overlapped, so safety became important to look at.

[We found] that ASCT plus ibrutinib significantly increased hematological toxicity, [and the risk of] infection. On the other hand, [adverse effects seen with] ibrutinib alone were comparable to ASCT, but [the regimen did not show] the acute toxicity [associated with] ASCT.

Is there anything that you would like to add?

It’s quite striking that the ibrutinib arms already [indicate numerically] superior OS. [It is almost impossible to] catch up [to this result] with salvage [therapy]. It’s also important [to note] that [about] 80% of patients in the control arm did receive ibrutinib salvage [therapy], according to clinical standard. [These data] mean [that] the old standard is definitely out.

What factors are necessary to consider when selecting which patients could benefit from an ibrutinib-containing regimen?

When [determining] which patients [will] benefit most from this [kind of regimen, it is important to] consider p53[mutation status] because it plays an enormous role in MCL. Dose-intensified approaches [often] do not work in p53-mutated cases. If we look at the ibrutinib-containing arms, there is a huge benefit [experienced by] this patient population. [Therefore,] these patients [would] mostly benefit from the new approach; it allows them to skip toxicity [and experience] a significantly improved outcome.

What is the impact of this trial on international collaborative cancer research? 

Forget about ASCT. Move on to ibrutinib. I [believe that] this approach will soon be included in US guidelines. This [trial] is proof of the benefit of independent academic trials. We are asking clinically relevant questions, and this is good because [they] prompt us to consider how we can improve in the interests of our patients.

I am a strong believer in the [collaborative effort made for this research]. No single European country would have been able to achieve [these results.] It really shows that if we work together, we can achieve more [than what we can] as clever individuals.

Reference

Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized Triangle trial by the European MCL Network. Blood. 2022;140(suppl 1):1-3. doi:10.1182/blood-2022-163018