Expert Sorts Through Treatment Strategies in Follicular Lymphoma

Chaitra S. Ujjani, MD

Chaitra S. Ujjani, MD

PI3K inhibitors, BTK inhibitors, and EZH2 inhibitors have taken greater precedence in the field of follicular lymphoma in recent years, explained Chaitra S. Ujjani, MD.

Among the PI3K inhibitors, idelalisib (Zydelig), duvelisib (Copiktra), and copanlisib (Aliqopa) are FDA approved for use in patients with relapsed disease. Moreover, umbralisib, which is a newer-generation PI3K inhibitor that received a breakthrough therapy designation in January 2019 in marginal zone lymphoma (MZL), is under ongoing evaluation in follicular lymphoma.

Moreover, BTK inhibitors, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (BGB-311), are showing moderate responses in phase II trials.

Additionally, checkpoint inhibitors, such as pembrolizumab (Keytruda), and CAR T-cell therapies, such as axicabtagene ciloleucel (axi-cel; Yescarta), are being investigated in treatment-naïve patients and relapsed settings.

“Time will help us understand where the real value of these drugs lies,” said Ujjani, a medical oncologist, Seattle Cancer Alliance, and a clinical associate professor, Division of Medical Oncology, at the University of Washington School of Medicine.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Ujjani discussed the various therapeutic classes and agents that are showing the most promise in the field of follicular lymphoma.

OncLive: How do the available PI3K inhibitors compare against each other in follicular lymphoma?

Ujjani: It's an interesting class of drugs because they target a pathway downstream of the B-cell receptor, and we know the B-cell receptor is atomically active in follicular lymphoma. The first PI3K inhibitor to be approved by the FDA was idelalisib; it's an inhibitor of the delta isoform of PI3K. That approval was based on a study that was published about 5 years ago, which showed a response rate of about 50% in patients with previously treated follicular lymphoma. These patients were heavily pretreated, had to have received prior rituximab (Rituxan), and an alkylating agent. However, idelalisib is associated with some adverse events (AEs), such as colitis, pneumonitis, as well as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations. [The agent] has a boxed warning for infections as well, so it's nice to have options in terms of PI3K inhibitors.

The second-generation inhibitors differ a little bit in their structure and their inhibition of PI3K. We have duvelisib, which is a delta-gamma inhibitor, and copanlisib, which is an alpha and delta inhibitor. Duvelisib is [an oral agent] that was recently FDA approved based on the phase II DYNAMO study, showing a response rate of about 42% and a median progression-free survival (PFS) of a little more than 8 months. Copanlisib was approved based on the phase II CHRONOS-1 study. In this particular study, the response rate was a little bit higher at 59%. However, we can't compare these trials directly. This was a similar population—patients who were previously treated with rituximab and chemotherapy. In this study, patients had a slightly longer median PFS of a little more than 11 months.

The newer-generation PI3K inhibitor umbralisib is an interesting agent; it's an oral agent dosed once daily and it doesn't seem to induce as much colitis, pneumonitis, and AST and ALT elevations as idelalisib. Data on a PI3K inhibitor from MEI Pharma were presented at the 2019 ASCO Annual Meeting and showed some pretty striking activity, with response rates close to 80%; this is impressive with this class of drugs.

How do you see the BTK inhibitors fitting into the paradigm?

Ibrutinib has shown response rates ranging from about 20% to 40% in the phase II setting. Acalabrutinib is a second-generation BTK inhibitor, but there have been more data with zanubrutinib. Zanubrutinib differs a little bit from ibrutinib in the sense that it's thought to be a little more selective for BTK with hopefully less AEs; it's dosed twice daily. There has been some interesting data with that [agent] in combination with CD20-directed monoclonal antibodies. It will be interesting to see where this doublet goes.

Venetoclax (Venclexta) has shown impressive responses across the spectrum of hematologic malignancies. Could it have a similar impact in follicular lymphoma?

The 2 diseases in which venetoclax really has marked activity is chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. Those are the 2 diseases where we see really impressive response rates. We see good but not quite as impressive response rates in follicular lymphoma, nearing 40%. There has been some activity in diffuse large B-cell lymphoma (DLBCL) as well.

The exciting thing about venetoclax is we can give it for a shortened duration of therapy. In CLL, it can be given for as short as 1 year, which is really exciting. The downside to most of these novel therapies is that they've been studied for indefinite dosing, and that's just not feasible. Patients don't want to take drugs for that long. AEs can be cumulative over time; even some low-grade fatigue can be really mind-numbing after 3 years.

Where does tazemetostat fit in?

The real value of tazemetostat is in patients who have the activating mutation EZH2. The response rates [with this agent] are quite impressive at over 80%. Hopefully, patients will be screened for this mutation in the future. Then, we can create a more personalized regimen for them. For the folks who don't have the mutation, we know that the activity is relatively modest and it's not worth offering that drug to them.

Is there a use for checkpoint inhibitors in this space?

In terms of immunotherapy, pembrolizumab has shown pretty impressive activity with rituximab. We have a similar study at our own institution looking at the doublet, not only in relapsed follicular lymphoma, but in transformed follicular lymphoma and DLBCL. Immunotherapy is attractive for not just the relapsed population, but for previously untreated patients, as well. There are going to be some data coming out looking at pembrolizumab in combination with standard R-CHOP for DLBCL. There have also been data looking at atezolizumab (Tecentriq) in combination with R-CHOP for patients with previously untreated large cell lymphoma and follicular lymphoma. I do believe there is a role for immunotherapy in this disease.

Where do we stand with CAR T-cell therapy?

CAR T-cell therapy is fascinating. Right now, the current FDA-approved agents are anti-CD19 CAR T-cell therapies. [These products are] approved for use in patients with relapsed large cell lymphoma and transformed follicular lymphoma. The ZUMA-5 study is looking at axi-cel in patients with relapsed follicular lymphoma and MZL. That study is currently accruing, and we're excited to see what that data will look like.