Expert Highlights Advances in MCL and DLBCL

Charalambos (Babis) Andreadis, MD, MSCE

Recent data from the phase III ZUMA-2 trial demonstrated an unprecedented 93% objective response rate in patients with relapsed/refractory mantle cell lymphoma (MCL) who received a single infusion of the investigational CAR T-cell therapy KTE-X19, said Charalambos (Babis) Andreadis, MD, MSCE.

The data, which were presented at the 2019 ASH Annual Meeting, also showed a complete response (CR) rate of 67% with the anti-CD19 CAR T infusion.

As such, a biologics license application for KTE-X19 as a potential therapy for adult patients with relapsed/refractory MCL was submitted to the FDA in December 2019.

“New therapies are certainly needed [in MCL],” said Andreadis. “CAR T-cell therapy has shown significant benefits in this patient population. In patients with relapsed/refractory MCL, both lisocabtagene maraleucel (liso-cel; JCAR017) and axicabtagene ciloleucel (Yescarta; axi-cel) have shown 70% to 90% response rates, and 50% to 60% CR rates. That is going to be the future of this field.”

The treatment paradigms of other non-Hodgkin lymphomas (NHL), such as diffuse large B-cell lymphoma (DLBCL), are also seeing immune-based therapies emerge. Antibody-drug conjugates (ADCs) and bispecific T-cell engagers (BiTEs) are among potential candidates to “[signal] the next wave of approvals in [NHL],” particularly for patients who fail CAR T-cell therapy, according to Andreadis.

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Andreadis, an associate professor of clinical medicine in the Department of Medicine at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed immunotherapeutic advances in MCL and DLBCL based on data from the 2019 ASH Annual Meeting.

OncLive: How has immune-based therapies evolved in NHL?

Andreadis: Regarding immunotherapy in NHL, CAR T-cell therapy has been around for a few years. We have clinical trial and real-world data suggesting tremendous activity in patients with large-cell lymphoma and other aggressive B-cell neoplasms.

At the 2019 ASH Annual Meeting, we finally saw the large presentation of the [ZUMA-2] trial with KTE-X19 for patients with relapsed/refractory MCL after many lines of therapy.

Right now, we are asking, "In what patient population can we use CAR T-cell therapy in?" Can we give it to patients with central nervous system disease? What about other lymphomas like follicular lymphoma? Can we give it in the clinic? We are getting the data that may increase the applicability of CAR T-cell therapy in those areas.

Also, we are looking for [what to do] after if a patient fails CAR T? Why does it stop working? What other therapies are available in that setting to help patients? For example, we have started to see data with BiTEs and other immunotherapies.

How have BTK inhibitors impact the MCL treatment landscape?

BTK inhibitors have revolutionized the field [of MCL]. They have shown significant response rates that led to the approvals of ibrutinib (Imbruvica), acalabrutinib (Calquence), and now zanubrutinib (Brukinsa) [for patients with MCL who received at least 1 prior line of therapy]. Unfortunately, patients will relapse following BTK inhibitor therapy. The median duration of response is about 1 to 1.5 years.

What is current standard of care for relapsed MCL?

A standard of care doesn't really exist. MCL is a disease that responds well to initial therapy, so we try to throw [everything we have] at it [early]. We do a lot of intensive upfront therapy, including autologous stem cell transplant.

When a patient relapses, ibrutinib or a BTK-like agent is the drug of choice.

Proteasome inhibitors like bortezomib (Velcade) and carfilzomib (Kyprolis) have shown activity in ongoing studies, but there is not an optimal approach. We try to get patients [who respond to proteasome inhibitors] to an allogeneic stem cell transplant, but that [procedure] is more difficult to perform and associated with higher toxicities. We need a drug in this setting.

What data have demonstrated what to do after a patient fails CAR T-cell therapy?

At the 2019 ASH Annual Meeting, there were 3 presentations of CD20-targeted bispecific antibodies. Of course, CD20 is a target we all love in B-cell lymphomas because it is stably expressed in B cells.

We saw stable CD20 expression after [CD19-directed CAR T cell] failure, in data presented at ASH. Therefore, it is not that the B cells shed all their unique antigens and CD20 is a valid target in that patient population.

We also saw response rates of 50% to 70% in patients treated with bispecific antibodies, some whom failed CAR T prior.

Beyond CAR T-cell therapy and bispecific antibodies, what other immune-based approaches are we seeing?

ADCs are emerging in DLBCL. We have them in T-cell lymphoma and Hodgkin lymphoma with CD30, but there has not been a lot of development in DLBCL.

Now we have polatuzumab vedotin (Polivy) which has shown activity in patients with relapsed/refractory DLBCL. Other targets such as CD74 are also being explored.

Could you expand on the data we’ve seen with polatuzumab vedotin?

The data so far on polatuzumab vedotin are [from when it was used] in combination with bendamustine and rituximab (Rituxan) for patients with relapsed/refractory DLBCL. Currently, those patients—who are historically considered transplant candidates—do not have a lot of treatment options.

Preliminary data showed significant activity with the combination compared to historical controls. It remains to be seen what the activity of single-agent polatuzumab vedotin and what the optimal combinations with the agent are. It is currently being studied in the frontline setting and other lines of therapy as well; however, it is likely the agent will need to be combined to show significant activity.

What does the future of CAR T-cell therapy look like in the population of patients with relapsed/refractory DLBCL?

CAR T-cell therapy works well, but the average patient still has a hard time getting it because of referral patterns, how complicated the treatment is, or issues with reimbursement.

It is hard to show a big breakthrough for the majority of patients. Going forward, we need to get CAR T more affordable and accessible. We also need to work to simplifying the procedure, perhaps by using allogeneic CAR T cells as the university CAR T cell. Lastly, we should [continue to] work with bispecific antibodies that may provide an off-the-shelf option that does the same thing.

Wang ML, Munoz J, Goy A, et al. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in Patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL): results of the phase 2 ZUMA-2 study. Blood. 2019;134(suppl 1):754. doi: 10.1182/blood-2019-126064.