Ibrutinib Continues to Showcase Efficacy as MCL Therapy

Brad S. Kahl, MD

Ibrutinib (Imbruvica) continues to be the standard of care for the treatment of relapsed/refractory patients with mantle cell lymphoma (MCL) since its FDA approval in 2013, and long-term follow-up data of the Bruton's tyrosine kinase (BTK) inhibitor continue to demonstrate its clinical activity.

Following the pooled analysis of these data, one-quarter of this patient population remained progression free and more than half were alive when treated with ibrutinib. Clinical outcomes were best for patients who achieved a complete remission (CR) and those who were treated with ibrutinib at first relapse or progression.

This analyzed pooled data from 111 patients from the PCYC-1104 study, 120 from SPARK, and 139 from RAY. The median duration of follow-up was 41.1 months (95% CI, 37.3-42.5) and the median treatment exposure was 11.1 months.

With 41 months of follow-up, 26.5% of patients achieved a CR. At 2 and 3 years, 36% (95% CI, 31%-42%) and 26% (95% CI, 20%-32%) of patients were progression free, respectively. The median progression-free survival (PFS) was 13 months, whereas the median PFS for patients with 1 prior line of therapy was 33.6 months and, in patients achieving a CR, the median PFS was 46.2 months. Overall, 53% (95% CI, 47%-58%), 45% (39%-50%), and 37% (25%-49%) of patients were alive at 2, 3, and 5 years, respectively. The median overall survival was 26.7 months (Table).

“The data for ibrutinib are better than anything else in the second-line setting. That is the reason why it is becoming a commonly utilized second-line therapy in MCL,” said Brad S. Kahl, MD.

In an interview withTargeted Oncology, Kahl, a professor in the Department of Medicine, Washington University School of Medicine in St. Louis, Siteman Cancer Center, shed more light on the impact of BTK inhibition on the treatment landscape for patients with MCL.

TARGETED ONCOLOGY:Can you share insight on how treatment for MCL is evolving to include more targeted approaches, such as BTK inhibition?

Kahl:Historically, there were not great options for relapsed/refractory MCL. We had conventional chemotherapy, which worked unsatisfactorily. We had bortezomib (Velcade), which had a relatively low overall response rate and short duration of response. We have had lenalidomide (Revlimid), which has a low response rate but can have durable responses for patients with relapsed MCL. When we were nally introduced to BTK inhibition, first with ibrutinib, we were happy to see higher response rates in the 60% to 70% range, along with better durability with responses lasting on average of 18 months.

There were long-term follow-up data presented at the 2017 ASH Annual Meeting this year for ibrutinib from 3 studies that were pooled. It showed that for patients who have a CR on ibrutinib, the median duration of response is over 4 years. That is much better than anything we have seen historically. That was a nice advance for recurrent MCL.

We were very happy to see acalabrutinib (Calquence) added into the mix a few months ago. The acalabrutinib data look similar and comparable to the ibrutinib data. They have not been compared in a head-to-head trial so we do not know for sure whether acalabrutinib offers signi cant advantages over ibrutinib. However, for those of us who treat these patients, we are happy to have acalabrutinib as an option. I suspect many physicians will be using that agent to get more experience with it.

TARGETED ONCOLOGY:Is the MCL treatment paradigm moving away from chemotherapy, or will that still have a role?

Kahl:Chemotherapy is still the mainstay for frontline treatment. None of the targeted therapies have moved their way rmly into frontline treatment. There are some important trials that should read out in the next year looking at adding BTK inhibition to chemotherapy. It is not like the chemotherapy was jettisoned; they are just looking at adding BTK inhibition to chemotherapy. For the foreseeable future, chemotherapy is going to be the mainstay of frontline therapy. There will be trials developed in the next few years that will challenge that paradigm but those will not read out for a while. I see chemotherapy as the mainstay.

Targeted agents are having an impact in the management of relapsed/refractory disease. I believe they will see most of the use in that setting for the next couple of years.

TARGETED ONCOLOGY:What factors do you consider when determining optimal sequence of therapies for patients?

Kahl:There are a lot of factors that go into that decision. How old is the patient? What are their prior lines of therapy? How well have those prior lines of therapy worked for that patient? What are the options to consider at this time? It is an individualized approach that is going to vary from patient to patient.

TARGETED ONCOLOGY:Do you foresee any combinations with ibrutinib now that we know its single-agent eficacy?

Kahl:There is a big international trial called SHINE. That trial is a fully enrolled randomized clinical trial for older patients with MCL investigating bendamustine and rituximab (Rituxan; BR) versus BR plus ibrutinib. That trial could change the standard of care for older patients if the BR-plus-ibrutinib arm is better for PFS. Younger patients are typically treated with more intensive therapy approaches, which are usually high-dose cytarabine-containing regimens and stem cell transplantation. There is an important trial in Europe occurring right now called the TRIANGLE study. That trial is investigating whether ibrutinib adds [anything] to traditional intensive chemotherapy. It also has an arm that subtracts the stem cell transplant to see if ibrutinib could make the role of stem cell transplantation obsolete. That is an important trial, but it will not read out for many years— making it too soon to say whether it will have an impact.

TARGETED ONCOLOGY:Aside from BTK inhibition, what other advancements are moving through the pipeline?

Kahl:There is a drug called venetoclax (Venclexta), which is a small molecule BCL-2 inhibitor that has good single-agent activity in relapsed MCL. Because of its mechanism, there is a lot of interest in combining that agent with standard cytotoxic chemotherapy. For example, in one of the research groups that I work with, we are about to initiate a trial that will be testing BR plus venetoclax as initial therapy for older patients with MCL. We think that is a rational combination.

The other area to keep an eye on is chimeric antigen receptor (CAR) T-cell therapy. There are not a lot of data for CAR T cells in MCL yet, but the data in acute lymphoblastic leukemia and diffuse large B-cell lymphoma is promising and has us hopeful that CAR T-cell therapy will be effective in the management of MCL. There are some ongoing trials, but very little data to report yet.

References:

1. Rule S, Dreyling M, Goy A, et al. Median 3.5-year follow-up of ibrutinib treatment in patients with relapsed/refractory mantle cell lymphoma: a pooled analysis. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 151.