Ibrutinib Maintenance Appears Safe in MCL Following Induction Therapy

June 25, 2019
Brandon Scalea

Ibrutinib as a maintenance therapy for patients with mantle cell lymphoma who respond to frontline induction therapy with or without autologous stem cell transplant appeared safe and feasible, according to the results of a recent study presented at the 2019 ASCO Annual Meeting.

Reem Karmali, MD, MS

Ibrutinib (Imbruvica) as a maintenance therapy for patients with mantle cell lymphoma (MCL) who respond to frontline induction therapy with or without autologous stem cell transplant (ASCT) appeared safe and feasible, according to the results of a recent study presented at the 2019 ASCO Annual Meeting.

Thirty-six patients with advanced stage (n = 28) and extranodal disease (n = 9), were included in this study; 50% of these patients had low-risk MIPI score (n = 18), while 19% (n = 7) and 31% (n = 11) had intermediate- and high-risk MIPI scores, respectively.

For induction, 47% of patients received bendamustine plus rituximab (Rituxan), 50% received a cytarabine-based regimen, and 3% received R-CHOP. Half of the patients underwent ASCT during their first complete remission (CR) prior to study enrollment.

Results from the initial safety report showed that 92% (n = 33) of patients achieved a CR, while 8% (n = 3) of patients had a partial response (PR) with induction therapy, with 1 PR to CR conversion observed with maintenance ibrutinib. At a median follow-up of 19 months, 67% (n = 24) of patients remain on ibrutinib maintenance therapy for a median 16.5 cycles (range, 1-49 cycles).

Treatment-related adverse events (TRAEs) led to dose reductions or interruptions in 69% (n = 25) of patients, with 25% (n = 9) needing to permanently discontinue therapy. One patient developed progressive disease on ibrutinib maintenance, and 1 patient died during therapy, noted Reem Karmali, MD, MS, who is lead study author and an assistant professor of medicine of Hematology and Oncology at Northwestern University Feinberg School of Medicine.

In an interview withTargeted Oncologyduring the 2019 ASCO Annual Meeting, Karmali shared early data with ibrutinib maintenance therapy and highlighted recent advances and challenges in the treatment of patients with MCL.

TARGETED ONCOLOGY: How would you describe the current MCL treatment paradigm?

Karmali:MCL is a disease that remains incurable despite our best efforts, but several recent advances have been made. BTK inhibitors such as ibrutinib and acalabrutinib (Calquence) have shown profound activity in MCL. This isn't surprising since BTK is a very important part of B-cell receptor signaling, which we know is crucial to MCL differentiation, proliferation, and survival. BTK inhibitors are very active in relapsed/refractory MCL, with response rates in the 70% to 80% range. The question is, “Can these agents can be moved into the frontline setting and improve outcomes in these patients?”

This patient population as a whole is a significant unmet need because [the disease] is incurable. For the patients we treat, response rates are high, but relapse is very common. With subsequent lines of therapy, response rates tend to get shorter and shorter.

TARGETED ONCOLOGY: Could you expand on some of the challenges that are still faced in this space?

Karmali:We do get really high response rates with chemoimmunotherapy, but a big challenge is how to best treat patients in the frontline setting. There is no clear standard of care. Our treatments are variable, and they depend on several different patient factors. When we do see a patient with a relatively aggressive disease course who is symptomatic, treatments can range from rituximab monotherapy to chemoimmunotherapy with or without ASCT. It is unclear whether patients need to be consolidated with an ASCT and whether rituximab maintenance is appropriate, depending on what type of induction therapy the patient is started on. Certainly, there is an important ongoing US Cooperative Group study, in which investigators are looking to address this question of whether an ASCT is needed across the board in MCL.

Aside from picking the right therapy for patients, one of the biggest challenges is the fact that despite all of the effective therapies we have, patients still relapse. When they relapse, their outcomes tend to be quite poor.

TARGETED ONCOLOGY: What is the role of ibrutinib in MCL?

Karmali:Ibrutinib has significant activity in relapsed/refractory MCL, and that's on the basis of it being a BTK inhibitor, which we know targets an important protein in the disease. Ibrutinib is now being evaluated in the frontline setting, and the SHINE trial is looking at bendamustine plus rituximab with or without ibrutinib, and potentially ibrutinib maintenance following induction therapy. Other trials are looking at frontline ibrutinib as well.

TARGETED ONCOLOGY: What was the rationale to use ibrutinib as a maintenance therapy?

Karmali:With MCL, response rates are quite high with frontline therapy. The issue is that patients do relapse; that is to be expected. The question is whether we can improve upon frontline approaches. One way to do that is with maintenance therapy, and the optimal use of maintenance therapy [has not been] identified. We do know that rituximab improves progression-free survival (PFS) and overall survival (OS), but we want to know if we can do better than that. With ibrutinib having the level of activity that it does, it makes sense to consider it in the frontline setting. That's what we were hoping to do with our multicenter phase II study.

TARGETED ONCOLOGY: Could you discuss this phase II trial and the initial findings presented at the 2019 ASCO Annual Meeting?

Karmali:We looked at ibrutinib maintenance in treatment-naïve patients and required intensive induction therapy to begin with. Patients could be treated with chemoimmunotherapy with or without an ASCT, and for those who achieved a CR or PR, they could be enrolled on the trial and receive ibrutinib maintenance at a dose of 560 mg daily for up to 4 years or until disease progression. We accrued a total of 36 patients. In these 36 patients, it is important to note that these patients had some high-risk features. Over 75% of our patients had advanced-stage disease, and 50% had either an intermediate- or high-risk histology. Approximately 25% of our patients had extranodal disease. When we look at the treatment patterns here, 47% of our patients were treated with bendamustine plus rituximab upfront, 25% were treated with R-hyperCVAD [rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone] and the remaining were treated with R-CHOP with or without cytarabine-containing cycles.

With induction alone, 33 out of 36 patients actually achieved a CR. Therefore, that supports the idea that we can get high response rates with chemoimmunotherapy induction alone. It is important to note that 50% of our patients did get ASCT, so that plays into the high response rates. There were 3 patients who had a PR. With our 36 patients who went onto ibrutinib maintenance, there was 1 conversion of a PR to a CR. Of the remaining 2 patients in PR, 1 stayed there, and 1 developed progressive disease. We were able to feasibly give ibrutinib maintenance for prolonged periods of time.

Thus far, we have 19 months of follow-up, and with that, 24 out of the 36 patients continued to be on ibrutinib maintenance, which speaks to the feasibility. Of those patients, there is 1 patient with progressive disease, and 1 patient who has died.

TARGETED ONCOLOGY: What does the toxicity profile look like for this regimen?

Karmali:For the most part, we found that the toxicities were in line with what one would expect from ibrutinib's safety profile. With treatment exposures, patients tolerated the drug quite well for the most part. With our follow-up of 19 months, the median number of cycles delivered were 16.5. In fact, one-quarter of patients have already completed 2 or more years of ibrutinib maintenance. With these patients, 2 of them have even completed the full 4 years with our data at this point. In terms of the toxicities, about two-thirds of patients had TRAEs that required dose modification. About 20% of patients required a permanent dose modification or reduction, and 25% of our patients actually needed permanent discontinuation of drug.

The main reason for discontinuation seemed to be atrial fibrillation, which we saw in 9 patients. For the most part, however, ibrutinib was well tolerated and in line with what one would expect with ibrutinib.

TARGETED ONCOLOGY: What are the next steps for this research?

Karmali:The study shows that ibrutinib maintenance is feasible and the toxicities are manageable. The key is going to be longer-term follow-up, as well as looking at minimal residual disease (MRD) status in our patients. Our primary objective was to look at efficacy, and this is defined by 3-year PFS rates.

However, one of our exploratory analyses was to look at MRD status and an IgH polymerase chain reaction¬—based methodology. We expect that MRD will give us a better idea if we can deepen response with ibrutinib maintenance, and we hope to show there is benefit by correlating MRD status with PFS and OS. If we can show this, it will make the argument that ibrutinib maintenance ought to be explored further.

TARGETED ONCOLOGY: Beyond this work, were there any other studies presented at the meeting that you were particularly excited about?

Karmali:In MCL, it was very exciting to see data on CAR T-cell therapy. There was a subset analysis of the TRANSCEND study, which looked at lisocabtagene maraleucel (liso-cel; JCAR017) a CD19 construct. The trial itself included [patients with] aggressive B-cell lymphomas, but [there was a] subgroup of [patients with] MCL.

What they found was that responses were quite high, despite the fact that this was a high-risk population. Patients had a high Ki-67 and all patients had been previously treated with ibrutinib. There were even patients with blastoid variant disease, and we know these patients have poor outcomes. Therefore, we saw that liso-cel was able to achieve high responses in these patients with durable responses in a few of them. This is an important area of research that needs continued exploration.

Reference:

Karmali R, Abramson JS, Stephens DM, et al. Ibrutinib maintenance following induction for untreated mantle cell lymphoma (MCL): initial safety report.J Clin Oncol. 2019;37(suppl 15; abstr 7542). doi: 10.1200/JCO.2019.37.15_suppl.7542.