Tazemetostat Plus Lenalidomide and Rituximab Under Investigation in R/R Follicular Lymphoma

The EZH2 inhibitor tazemetostat (Tazverik) in combination with lenalidomide (Revlimid) and rituximab (Rituxan) has shown early signals of efficacy in patients with follicular lymphoma (FL) who are refractory to rituximab or who relapsed within 24 months from their first line of therapy, according to Jennifer Effie Amengual, MD.

The ongoing 3-stage SYMPHONY-1 trial (NCT04224493) is investigating tazemetostat plus lenalidomide and rituximab in patients with relapsed/refractory FL. Stage 1 was a phase 1b safety run-in portion where all patients received tazemetostat plus lenalidomide and rituximab. The primary end point of stage 1 was the recommended phase 3 dose (RP3D) of tazemetostat, which was determined to be 800 mg twice daily. Stage 2 is a double-blinded phase 3 portion that will randomly assign patients to receive either tazemetostat or placebo plus lenalidomide and rituximab. The primary end point of stage 2 is progression-free survival (PFS). Patients participating in the optional third stage will receive oral tazemetostat at the RP3D plus lenalidomide and rituximab in 28-day cycles.¹

“It’s easy to treat patients in this clinical trial,” Amengual said.

In 2020, the FDA approved tazemetostat monotherapy in patients with relapsed/refractory EZH2-positive FL who have received at least 2 prior systemic therapies or who have relapsed/refractory disease with no other available satisfactory treatment options.²

In an interview with OncLive®, Amengual discussed unmet needs in FL that SYMPHONY-1 aims to address; the potential benefits of tazemetostat plus lenalidomide and rituximab in patients who are refractory to rituximab or who relapse within 24 months of their initial therapy; and where this regimen may fit into the relapsed/refractory FL treatment paradigm alongside investigative CAR T-cell therapies.

Amengual is the Herbert Irving Assistant Professor of Medicine in the Division of Hematology and Oncology in the Center for Lymphoid Malignancies and Herbert Irving Comprehensive Cancer Center at the Columbia University Irving Medical Center in New York, New York.

OncLive: What is the rationale for the SYMPHONY-1 trial?

Amengual: The SYMPHONY-1 trial is designed for patients with relapsed FL. There’s still a need [in this patient population]. Patients with FL are not cured of their disease. Even some of the more [recently approved drugs], such as bispecific antibodies, can be intensive.

SYMPHONY-1 combines tazemetostat, an oral agent [targeting] EZH2, with lenalidomide plus rituximab, for relapsed or refractory FL. This trial targets the biology that drives FL. There are mutations in EZH2 in approximately 20% to 40% of [patients with] FL. Even in patients who do not have mutations in this enzyme, it tends to be upregulated. We recognize that this is a mechanism-driving disease, so this is a biologically targeted regimen that’s mostly oral and [is a] well tolerated, low-intensity therapy.

What are the class effects of EZH2 inhibitors?

EZH2 inhibitors are well tolerated. Some of the associated adverse effects [AEs] are mild decreased appetite and headache. [Patients] can have mild cytopenias, [but] that’s mostly related to prior therapies. In patients who haven’t seen many therapies previously, tazemetostat doesn’t generally trigger many dose-limiting toxicities.

What patient population is this trial evaluating?

The [phase 1b part of the] trial [was] open to patients who had received 1 line of prior therapy or more. They must have been treated with rituximab or a prior anti-CD20 therapy.

What recommendations do you have for community oncologists looking to refer patients to this trial, given that it is a second-line trial?

The SYMPHONY-1 trial is open in the second line. [Tazemetostat is] a great option [for patients to whom] we don’t want to [immediately give] more intensive therapies. [This regimen is] easy to give as an outpatient [treatment]. Tazemetostat is an oral drug, and lenalidomide is as well, which we all have practice using. Rituximab is only given for the first 5 cycles, so patients only need to come in for infusions for a few months, and after that, they are maintained on 2 oral medications.

So far, in our experience, the response rates have been excellent. Across the board, what’s been reported in some of the abstracts that have been presented are that [most] patients who are refractory to rituximab in their last line of therapy, which is about one-third of patients, responded to the treatment. Even patients who had relapsed within 24 months from their initial line of therapy, [which we classify as] POD24 patients, had outstanding responses. All the patients who were POD24 responded to the regimen. That makes up about one-third of the phase 1 patient population. It is significant and compelling [that with] this simple, non-toxic regimen, we can overcome some treatment barriers that we see both in rituximab-resistant or -refractory patients and patients with POD24.

Do you anticipate any enrollment barriers or challenges?

We have not seen any barriers to enrollment. One issue that comes up occasionally is getting lenalidomide. It’s always approved by insurance, but sometimes, patients have a high copay. Uniformly, though, we get that worked out. That’s been our only barrier.

Right now, there’s much excitement regarding some of the bispecific antibodies. However, we’re not jumping right to those for many patients, because of the potential toxicities and requirements for admission to the hospital, and [because of] the potential for cytokine release syndrome, which is a significant potential toxicity.

One of the end points of the phase 3 portion of the trial is PFS. If that end point is positive, how might this finding influence the relapsed/refractory FL treatment landscape?

If the PFS is favorable, this is an easy combination that I can see going forward to clinical practice. It’s building on a regimen that we’ve been using for many years that has a track record of success. It does not lead to any more toxicities than we’re already familiar with [regarding lenalidomide plus rituximab]. If it can improve upon PFS, and perhaps even limit the number of cycles of rituximab given so that [later in] treatment, [patients can] focus on 2 oral drugs, that’s attractive both to patients and to clinicians.

What might be the role of the SYMPHONY-1 regimen in the context of CAR T-cell therapy?

When we consider the SYMPHONY-1 trial in relation to CAR T-cell therapy, we’re looking at 2 different modalities. If a patient is young and fit, and we are seriously considering CAR T-cell therapy, I don’t believe we would consider the SYMPHONY-1 trial.

I have referred few patients [with FL to] CAR T-cell [therapy]. [CAR T-cell therapy is associated with AEs] that can be lasting. Cytopenias can persist following CAR T-cell therapy. I’m only considering [CAR T-cell therapy] in a select patient population.

[The SYMPHONY-1] regimen may do great in the post–CAR T-cell therapy setting. Because it’s chemotherapy free and bendamustine can lead to impaired T-cell function, it [may be] appropriate in the pre–CAR T-cell therapy setting as well. This regimen could improve performance status and disease control, allowing a patient to go to CAR T-cell therapy, ultimately. However, I don’t see these 2 strategies overlapping in many ways.

What other ongoing research avenues in FL may complement the SYMPHONY-1 trial?

In some younger, fit patients, combining this strategy with a bispecific [antibody] could be interesting. EZH2 inhibition can modulate immune response and perhaps upregulate CD20. Perhaps we can find ways to use this epigenetic modulation to further improve immunotherapies. That might be [a research direction] we see in the future.

References

1. Study of tazemetostat versus placebo when given in combination with lenalidomide and rituximab in participants with relapsed/refractory follicular lymphoma (SYMPHONY-1). ClinicalTrials.gov. Updated August 14, 2023. Accessed August 16, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04224493
2. FDA granted accelerated approval to tazemetostat for follicular lymphoma. News release. FDA. June 18, 2020. Accessed August 16, 2023. https://www.fda.gov/drugs/fda-granted-accelerated-approval-tazemetostat-follicular-lymphoma