Ibrutinib-Containing Regimens Remain of Interest Despite Agent’s Withdrawal in MCL and MZL

Insufficient phase 3 evidence has led to the voluntary withdrawal of ibrutinib (Imbruvica) for the treatment of patients with mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), according to Thomas M. Habermann, MD.¹ 

However, Habermann emphasized that upcoming research on the use of ibrutinib-containing regimens and other BTK inhibitors could still revolutionize the treatment landscape in these disease spaces. Formal publication of positive results from the phase 3 TRIANGLE trial (NCT02858258) of ibrutinib plus induction chemotherapy with or without autologous stem cell transplant (ASCT) could be particularly practice-changing for younger patients with MCL, he explained.²

In 2013 and 2017, the FDA granted accelerated approval to ibrutinib in MCL and MZL, respectively. The approvals were based on overall response rate (ORR) data from an open-label, multicenter, single-arm phase 2 study (NCT01236391), and the phase 2 PCYC-1121 study (NCT01980628), respectively.3,4 However, confirmation of clinical benefit in the phase 3 SHINE (NCT01776840) and SELENE (NCT01974440) trials was required for full approval of ibrutinib in these spaces.¹

Results from the SHINE trial demonstrated that patients with previously untreated MCL experienced improved progression-free survival (PFS) with ibrutinib plus bendamustine and rituximab (Rituxan) vs bendamustine and rituximab alone but did not experience an overall survival (OS) advantage. Moreover, the combination of ibrutinib and chemoimmunotherapy produced greater toxicities vs the control regimen. Data from SELENE revealed that the addition of ibrutinib to bendamustine plus rituximab or rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) did not reach its primary end point of PFS in patients with relapsed/refractory MZL or follicular lymphoma.¹

“There’s been so much happening in MCL and MZL in the past decade,” said Habermann, a professor of medicine at the Mayo Clinic College of Medicine, and a hematologist and internist in the Division of Hematology, Department of Internal Medicine, at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, as well as a member of the Lymphoma Research Foundation’s Scientific Advisory Board. “It’s a very competitive market, with [several] BTK inhibitors that are more selective, less toxic, and [have] ongoing randomized clinical trials nationally and internationally.”

In an interview with OncLive®, Habermann expanded on previous data that supported the initial accelerated approval of ibrutinib in MZL and MCL, phase 3 data leading to the agent’s voluntary withdrawal, and investigations of ibrutinib and other BTK inhibitors that could significantly change the treatment landscape in MCL and MZL. 

OncLive: What has previously been seen with the use of ibrutinib in patients with MCL and MZL, and could you expand on the research that led to the FDA accelerated approval of ibrutinib in these spaces?

Habermann: On April 6, 2023, the FDA announced its intent to withdraw an accelerated approval [for ibrutinib]. This pathway [was] based on overall response rates from 2 [phase 2] studies. In MCL, patients were eligible [for treatment with ibrutinib] if they received at least 1 prior line of therapy. For MZL, [patients were eligible] if they required systemic therapy and had previously been treated with at least one anti-CD20 antibody treatment.

The initial [study] targeting BTK with ibrutinib in relapsed MCL was published in the New England Journal of Medicine on August 8, 2013. [In this trial], patients were treated with a daily dose of 560 mg, and 111 patients were treated. Grade 3 or higher hematologic toxicities included neutropenia (16%), thrombocytopenia (11%), and anemia (10%), which were acceptable.

What was unique about this study was that the ORR was 68%, [which is] essentially twice the [ORRs] seen [with] bortezomib [Velcade], and lenalidomide [Revlimid] in previous phase 2 trials. [Ibrutinib had] a complete remission [CR] rate of 21%, which was also high, and the partial remission [PR] rate was 47%. Prior treatment with bortezomib had no effect [on responses]. The study and other data resulted in the accelerated approval of ibrutinib based on response rates.

[Regarding the phase 2 trial] in MZL, Ariela Noy, MD, of Memorial Sloan Kettering Cancer Center [MSK], reported an ORR of 48% and a CR rate of 3% in 63 patients treated with a median of 2 lines of prior therapy. Longer follow-up resulted in an ORR of 58%. This led to the approval [of ibrutinib] in MZL.

The voluntary withdrawal [of ibrutinib in MCL occurred because] no improvement in OS [was observed], although this was a secondary end point. There were also more toxicities in the ibrutinib [arm].

Could you expand on the trial design and patient population of the confirmatory phase 3 SHINE and SELENE trials?

The SHINE and SELENE trials were both phase 3 trials. The SHINE trial is published in the New England Journal of Medicine. [However], we have no abstract or paper data [from] the SELENE trial to date, so it’s difficult to discuss.

The histology in SHINE was MCL. In the SELENE trial, 347 patients with follicular lymphoma and 56 patients with MZL [were enrolled]. That trial was not powered to look at differences in outcomes in MZL.

The treatment [in] the SHINE trial was ibrutinib with bendamustine and rituximab vs bendamustine and rituximab alone with maintenance [rituximab] in both arms. In SELENE, patients could either have bendamustine plus rituximab or R-CHOP in combination with ibrutinib.

[The SELENE trial] was [conducted] in previously treated patients, which was different from the untreated patient [population] in the SHINE trial. Both trials were placebo-controlled and had PFS as the primary end point. We’re awaiting the results of the SELENE trial, but with the withdrawal, I think we might be able to anticipate that there weren’t significant differences [between treatment arms].

What primary outcomes were reported in the confirmatory phase 3 SHINE trial of patients with previously untreated MCL, and how did these results contribute to the voluntary withdrawal of ibrutinib for this population?

The study designed for the [full] FDA approval of ibrutinib [in MCL] was not [conducted] in the relapsed/refractory disease setting but [rather] was [designed] in the frontline setting. [In the confirmatory SHINE study], patients [with] untreated MCL [were] treated with ibrutinib with bendamustine and rituximab vs bendamustine and rituximab [alone]. [In the study], 261 patients were randomized to ibrutinib plus bendamustine and rituximab and maintenance rituximab, and 262 were randomized to bendamustine plus rituximab and maintenance rituximab. The median PFS in the ibrutinib arm was statistically significant at 6.7 years vs 4.4 years with a P value of 0.01 in the control arm. That was the primary end point.

However, the OS was not statistically significantly different [between arms], with a hazard ratio of 1.07. The OS [rate] at 7 years was 55% in the ibrutinib group and 56.8% in the placebo group. Death due to disease progression occurred in 11.5% or 30 patients [in the ibrutinib group] and 20.6% or 54 patients in the control group. Death due to progression or adverse effects [AEs] occurred in 58% [of patients] in the ibrutinib arm and 26.7% [of those] in the control arm. Second-line therapy was administered in 52 [19.9%] and 106 [40.5%] patients, respectively. Some patients crossed over and [were] retreated with ibrutinib. There was no benefit [for patients with] high-risk simplified Mantle Cell Lymphoma International Prognostic Index [MIPI] score, or TP53mutations. TP53 was mutated in 10% and 9.2% of patients, respectively. During the post-treatment follow-up, 46 patients [17.6%] in the ibrutinib group and 37 patients [14.1%] in the placebo group died.

The issue [with ibrutinib] was toxicities. Atrial fibrillation occurred in 13.9% of patients in the ibrutinib group and 6.5% of those in the placebo group. Four patients in the ibrutinib arm [experienced aspergillosis infections vs] 1 in the control arm. AEs during treatment were the primary cause of death in 28 patients [10.7%] in the ibrutinib arm and 16 patients [6.1%] in the placebo arm. The incidence of infections, particularly pneumonia, was similar in the 2 groups [during] the first 6 months but was higher in the ibrutinib group than in the placebo group during the maintenance period.

With this withdrawal, what unmet needs remain in this population?

Patients with TP53 mutations and blastic variants do not have improved outcomes with ibrutinib, or this class of drugs, to date. This population remains an unmet need. Therapeutic approaches that result in complete remissions, and potentially cure lymphoma are what we really need.

What advances are you hoping to see from future research within this disease space?

Results [from] other BTK inhibitor trials are pending. [A trial of] zanubrutinib [Brukinsa] and rituximab vs bendamustine and rituximab is ongoing and not [yet] reported. Results [from] a randomized trial of acalabrutinib [Calquence], with or without bendamustine and rituximab are also pending. Broad international efforts [are occurring] now. The hope is that we take broad and different approaches in international studies. We await the formal publication of the [phase 3] TRIANGLE trial, which is potentially practice changing.

Ibrutinib [could] replace peripheral blood ASCT [as the new standard of care, but] we’re awaiting that result and further interpretation. Another example is a trial I’m involved in with Dr Noy at MSK. [This] is a multicenter, randomized, double-blind placebo-controlled phase 3 trial [NCT04212013] of ibrutinib in combination with rituximab in patients [with] treatment naïve MZL. The status of that trial is not determined at this point in time.

How would you summarize how the treatment landscape has evolved in MCL and MZL?

The two major toxicities [associated with BTK inhibitors] are atrial fibrillation and bleeding. The toxicities are different with the different BTK inhibitors. The trials with acalabrutinib, zanubrutinib and pirtobrutinib will be interesting to follow. CAR T-cell therapy has [also] now come into [the armamentarium for] patients with multiple relapses.

The European MCL Network’s TRIANGLE trial, which looked at the efficacy and safety of ibrutinib [plus] standard first-line treatment as a substitute for ASCT in younger patients with MCL, is fascinating. This abstract came out at the [2022 ASH Annual Meeting] in December, and the paper is about to be submitted. The authors concluded that the current standard high-dose regimen is not superior to a new ibrutinib-containing regimen. That’s going to be of significant interest [in the field]. The other fascinating thing is that patients [with] TP53 aberrations appear to be doing well. [Ultimately], it’s going to be essential to see the actual publication.

References

1. Update on Imbruvica (ibrutinib) US accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. April 6, 2023. Accessed May 2, 2023. https://www.jnj.com/update-on-imbruvica
2. 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
3. Imbruvica (ibrutinib) capsules now approved in the US for mantle cell lymphoma patients who have received at least one prior therapy. News release. Janssen Biotech, Inc. November 13, 2013. Accessed April 7, 2023. https://www.jnj.com/media-center/press-releases/US FDA approves Imbruvica (ibrutinib) as first treatment specifically indicated for relapsed/refractory marginal zone lymphoma (MZL) – a rare type of non-Hodgkin’s lymphoma. News release. AbbVie. January 19, 2017. Accessed April 7, 2023. https://news.abbvie.com/news/