Relapsed/Refractory MCL Landscape Continues to Evolve

Michael Wang, MD

Mantle cell lymphoma (MCL) remains an incurable disease, but according to Michael Wang, MD, it is becoming one of the most dynamic fields in oncology. In a presentation during the 2018 SOHO Annual Meeting, Wang recapped some of the biggest advancements in relapsed/refractory MCL, as well as the promise for novel therapies in this setting.

“We are in a new era to treat this disease,” said Wang. “That is why I am saying that the relapsed MCL setting is very exciting. Every few years we have new drugs coming up to affect patients and their quality of life.”

Wang began by highlighting the phase I first-in-human study of venetoclax (Venclexta) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL). In this study, patients with MCL had the highest overall response rate (ORR), complete response (CR) rate, and second-highest partial response (PR) rate of all 6 subgroups of lymphoma on the study. Of 106 patients, 28 had MCL, and the ORR for these patients treated with venetoclax was 75%, with a CR of 21% and PR of 54%. Stable disease was observed in 5 patients.¹

Findings from the phase II AIM study of ibrutinib (Imbruvica) in combination with venetoclax in previously untreated or relapsed/refractory patients with MCL showed a 16-week CR rate of 42% per CT imaging.²Investigators reported that the CR was 9% at 16 weeks in a historical cohort of patients who received ibrutinib monotherapy (P <.001). At week 16, CR rate as measured by PET imaging was 62%. ORR was 71% (95% CI, 49-87) with the inclusion of PET assessments, comprising a CR rate of 62% and partial response rate of 8%. After a 15.9-month median follow-up, median progression-free survival (PFS) had not been reached.

One of the most exciting advancements in the treatment of MCL has been the introduction of BTK inhibitors, according to Wang. Both ibrutinib and acalabrutinib (Calquence) have been evaluated in the relapsed/refractory setting.

Data for acalabrutinib monotherapy in patients with relapsed/refractory MCL were presented at the 2017 ASH Annual Meeting.³Findings the phase II ACE-LY-004 trial, in which patients were administered oral acalabrutinib at 100 mg twice daily until disease progression, ORR was 81% with a CR rate of 40%. At 12 months, PFS was 67% (95% CI, 58%-75%) and the 12-month overall survival (OS) rate was 87% (95% CI, 79%-92%). At the time of analysis, the median PFS and OS had not yet been reached. Additionally, the median duration of response (DoR) had not been reached, with 72% of patients still responding at 12 months (95% CI, 62%-80%).

Wang said that moving beyond chemotherapy is important for some patients for whom the toxicities are too great. Since MCL is incurable, quality of life is an important factor to consider when choosing treatment. The tolerability and activity of the chemotherapy-free triplet of umbralisib, ublituximab, and ibrutinib has been evaluated in patients with advanced chronic lymphocytic leukemia (CLL) and NHL.

Findings for this triplet have shown an ORR of 100% in patients with CLL, MCL, and marginal zone lymphoma.⁴Additionally, there was an 88% ORR with a 50% CR rate in patients with relapsed/refractory indolent NHL. These findings served as a rationale for the UNITY-NHL trial (NCT02793583). This trial is assessing the safety and efficacy of ublituximab plus TGR-1202 with or without bendamustine and TGR-1202 alone in patients with previously treated NHL.

Wang also shed light on the NCI-MATCH trial (NCT02465060), which is a basket study of patients with advanced or refractory solid tumors, lymphoma, or multiple myeloma. This trial uses genetic testing to guide targeted therapy for patients enrolled. The primary objective of this study is to evaluate the objective response when using targeted study agents in patients with advanced or refractory solid tumors, lymphoma, or myeloma. Wang says that patients with MCL who are in advanced stage or are refractory may be eligible for this trial.

Lastly, Wang said that one of the most promising and most exciting therapies to enter the MCL landscape is chimeric antigen receptor (CAR) T-cell therapy. ZUMA-2 (NCT02601313) is currently evaluating the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (Yescarta) in patients with MCL who no longer respond to treatment. Eligibility criteria for this study include pathologically confirmed relapsed/refractory MCL, an ECOG performance score &le;1, and the patient cannot have received more than 5 prior therapies. The primary endpoint of ZUMA-2 is ORR, with secondary endpoints of DoR, OS, PFS, and safety. Data from this trial are expected to be released soon.

&ldquo;In my opinion, lymphoma is one of the most exciting areas of clinical research in the field of oncology, and MCL is one of the most important and exciting areas in the field of lymphoma.&rdquo; said Wang. &ldquo;There is no bigger challenge than the treatment of patients with relapsed/refractory MCL.&rdquo;

References:

1. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma.J Clin Oncol.2017;35(8):826-833. doi: 10.1200/JCO.2016.70.4320.
2. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma.N Engl J Med.2018; 378:1211-23. doi: 10.1056/NEJMoa1715519.
3. Wang M, Rule S, Zinzani PL, et al. Efficacy and safety of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma in the phase 2 ACE-LY-004 study. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract 155.
4. Nastoupil L, Lunning MA, Vose JM, et al. Chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib is well tolerated and highly active in patients with advanced CLL and NHL. Abstract presented at: 22nd Congress of European Hematology Association; June 22-25, 2017; Madrid, Spain. Abstract S772.