Targeted Agents Continue to Advance in MCL, With CAR T on the Horizon

Andrew D. Zelenetz, MD, PhD

Several drugs have been developed in the lymphoid space in recent years, including BTK inhibitors and BCL-2 inhibitors, which have shown significant activity in mantle cell lymphoma (MCL), said Andrew D. Zelenetz, MD, PhD.

BTK has emerged as an important target in MCL, for which there are now 2 FDA-approved agents. In 2013, the FDA granted the first-in-class BTK inhibitor ibrutinib (Imbruvica) an accelerated approval for use in patients who have received ≥1 prior therapy. In 2017, the FDA granted an accelerated approval to the second-generation BTK inhibitor acalabrutinib (Calquence) for the same indication.

More recently, the FDA granted a priority review designation to a new drug application (NDA) for the second-generation BTK inhibitor zanubrutinib (BGB-3111) for patients with MCL who have received ≥1 prior therapy. The application was partially based on data from a phase II (NCT03206970) trial conducted in China, which showed an ORR of 84.7% and a CR rate of 76.5% with zanubrutinib.¹

Now that BTK inhibitors have demonstrated impressive activity as monotherapy, the next step is to examine their efficacy in earlier settings, explained Zelenetz. Although data have yet to read out in that regard, researchers are anticipating combinations of ibrutinib and R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) as well as with bendamustine and rituximab (BR).

“There are many interesting ongoing studies in MCL that are leading to improved outcomes for patients,” said Zelenetz.

The phase III PCYC-1143 trial is one such study, in which patients with relapsed/refractory disease were randomized to receive either ibrutinib alone or in combination with the BCL-2 inhibitor venetoclax (Venclexta). Results showed that the combination led to an approximately 5-fold improvement in the CR rate versus ibrutinib alone at week 16.²

Data from the phase II ZUMA-2 trial are also pending, and could help establish the role of CAR T-cell therapy in the space, he added.

In an interview with OncLive during the 2019 Annual SOHO Meeting, Zelenetz, medical director of Quality Informatics at Memorial Sloan Kettering Cancer Center, discussed the use of emerging targeted therapies in MCL.

OncLive: Could you highlight the progress that has been made in MCL over the years?

Zelenetz: MCL is a relatively rare disease. An oncologist who treats lymphoma in the United States will see a new diagnosis of MCL every 1 to 2 years; it’s is a pretty uncommon disease with only about 4000 cases a year in the United States. As a result, it's the lymphoma [treatment] that has lagged a little bit behind.

However, important drugs have been approved in this space. Several years ago, bortezomib (Velcade) was approved for the treatment of patients with relapsed/refractory MCL. The agent certainly has activity, but because of the treatment-emergent neuropathy, it is not used widely. Lenalidomide (Revlimid) is also approved [for use in these patients], and when used in combination with rituximab, it is a highly active regimen.

BTK has been shown to be a good target in MCL. BTK sits downstream of several signaling pathways that are critical in the disease. BTK inhibition results in substantial clinical activity. Ibrutinib and acalabrutinib are both approved for the treatment of patients with relapsed/refractory MCL. We're waiting for clinical trial data regarding their use in the frontline setting to mature in order to see whether we can add these drugs to conventional R-CHOP or BR to improve outcomes. One of the big trials we're waiting for is the SHINE trial, which is comparing BR with BR plus ibrutinib.

Another important class of drugs is the BCL-2 inhibitors. Venetoclax has activity in several diseases, but especially in MCL. There are ongoing studies dedicated to determining the optimal use of all of these agents in MCL. One of the more exciting studies that has just completed is a randomized study of ibrutinib alone versus the combination of ibrutinib and venetoclax. Early data suggest that the combination is highly active. That trial accrued ahead of schedule, so we're waiting for the [full] results.

What are the data with CAR T-cell therapy in MCL?

We are waiting for the formal presentation of the ZUMA-2 data. We know that the 3 anti-CD19 CAR T-cell products, axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (Kymriah), and now, lisocabtagene maraleucel (liso-cel; JCAR017), have activity in MCL. We're waiting on the data to see which patients were selected and what the durability is. [We're not sure whether] we are going to see the same long-term remissions in MCL that we're seeing in large cell lymphoma. It's an exciting possibility, but we really need to see more data before we say that CAR T cells are right for patients with MCL.

In August 2019, the FDA granted a priority review designation to an NDA for zanubrutinib for patients with relapsed/refractory disease. Could you discuss the activity of this agent?

Zanubrutinib is a BTK inhibitor that has a much more restricted kinome compared with ibrutinib. The agent is quite similar to acalabrutinib; it is an oral bioavailable drug that has excellent activity in chronic lymphocytic leukemia (CLL) and MCL. There was evidence of activity in MCL in the phase I study, so the company went ahead and did a phase II study. [The study] was done entirely in China and showed excellent ORRs and CR rates; they were a little bit higher than we would've expected for a single-agent BTK inhibitor. However, the study was reviewed by an independent response committee that confirmed these responses. Ibrutinib and acalabrutinib have provisional approvals pending randomized data. I'm a little bit surprised that the FDA took a study without any patients from the United States for consideration of accelerated approval. We'll see what the FDA does; the [action] date is in February 2020.

References

1. Song Y, Zhou K, Zou D et al. Zanubrutinib in patients with relapsed/refractory mantle cell lymphoma. Presented at: 15th International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland.
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(13):1211-1223. doi: 10.1056/NEJMoa1715519.