Tazemetostat/Lenalidomide/Rituximab Regimen Enters Phase 3 Research in R/R Follicular Lymphoma

Steven I. Park, MD

The addition of tazemetostat (Tazverik) to standard lenalidomide (Revlimid) plus rituximab (Rituxan) has elicited early signals of efficacy in patients with relapsed/refractory follicular lymphoma (FL) in the safety run-in portion of the phase 1b/3 SYMPHONY-1 trial (NCT04224493), prompting the continuation of this research in the phase 3 portion of the study, according to Steven I. Park, MD. 

The phase 1b portion of the trial investigated the safety of the regimen and determined the recommended phase 3 dose (RP3D) of tazemetostat to be 800 mg twice daily. Preliminary efficacy findings showed that of 41 evaluable patients, 51.2% achieved a complete response, 46.3% achieved a partial response, and 2.4% had stable disease.¹ The phase 3 portion of SYMPHONY-1 is ongoing to evaluate the triplet vs placebo plus lenalidomide and rituximab in patients with relapsed/refractory FL.²

“It’s exciting that we now have more treatment options available for patients with relapsed FL, but the options are still limited for second-line therapy,” Park said.

In an interview with OncLive^®, Park discussed the unique design of the SYMPHONY-1 trial, the importance of enrolling patients to the phase 3 portion of the study, and why tazemetostat in combination with lenalidomide and rituximab could represent an effective and tolerable therapeutic option for frail or older patients with relapsed/refractory FL.

Park is vice chair for research in the Department of Hematologic Oncology and Blood Disorders of Atrium Health Levine Cancer Institute in Concord, North Carolina.

OncLive: What is the rationale for the SYMPHONY-1 trial? What unmet needs does it aim to address?

Park: SYMPHONY-1 is a phase 1b/3 study of tazemetostat in combination with rituximab and lenalidomide in [patients with] relapsed FL. Tazemetostat is a first-in-class EZH2 inhibitor, and it’s an oral agent approved by the FDA for patients with FL who have received at least 2 prior lines of therapy. EZH2 is part of the PI3K complex, which leads to gene suppression, including tumor suppressor genes. It’s been shown that the overexpression of EZH2 can lead to cancer progression and worse clinical outcomes. Knowing that approximately 20% to 30% of patients with FL harbor EZH2 mutations, it is a good target for treatment of [patients with] FL.

As a single agent, tazemetostat has shown good clinical activity in relapsed FL, and it is considered a good option, especially for patients who cannot tolerate a more intense regimen. Now, the question is whether we can improve clinical outcomes even more by combining tazemetostat with lenalidomide and rituximab, which is 1 of the most commonly used regimens for [patients with] relapsed FL in the second-line setting. The idea is to bring more effective regimens as earlier lines of therapy in FL.

Why was SYMPHONY-1 designed as a phase 1b/3 trial?

There are 2 phases in the study design. [The first] was a phase 1b safety run-in [portion]. We know the safety of tazemetostat, and we know the safety of lenalidomide plus rituximab, so we have a good idea of the safety [profiles of these treatment regimens]. However, before we embarked on a larger phase 3 portion, we wanted to make sure we had the correct dose [of tazemetostat] in combination with lenalidomide and rituximab. In the phase 1b portion, [there was] a brief safety run-in to determine the safety of this combination and the RP3D. It was not exactly a true phase 1 portion; it was a brief stage before we proceeded with the larger phase 3 study.

What stood out from the findings of the phase 1b portion?

The phase 1b portion of the study were presented at the 2022 ASH Annual Meeting and the [2022] ASCO Annual Meeting. [Results showed that] 800 mg twice-daily dosing [of tazemetostat] was safe when combined with lenalidomide plus rituximab. In terms of the efficacy in the phase 1b cohort, the tazemetostat plus lenalidomide and rituximab combination showed an overall response rate of 97.6%, regardless of the patient’s EZH2 mutational status, which was promising.

The phase 1b portion was not designed to evaluate efficacy or survival outcomes, but the signal is promising. We saw good responses, even in patients with EZH2 wild-type [disease], and several patients have had durable responses with this combination. Thus far, the results have looked promising.

What are your referral recommendations for the phase 3 portion of the study, which is currently enrolling?

If you’re considering lenalidomide plus rituximab for your patients with FL as a second-line therapy or beyond, this study should be a great option, since the patients will receive the standard lenalidomide plus rituximab or lenalidomide plus rituximab in combination with tazemetostat.

What specific exclusion or inclusion criteria of the trial should be highlighted?

The eligibility criteria are typical. This [regimen] is for the second line and beyond. Patients need to have previous exposure to rituximab or other anti-CD20 antibodies.

Otherwise, [the study is enrolling patients with] typical relapsed FL, including patients who have relapsed within 24 months of their initial therapy [POD24], who tend to have a worse prognosis. It’s been shown that patients with POD24 do much worse. In the preliminary assessment [of SYMPHOMY-1], they seem to respond well to this combination. Certainly, those patients could enroll in this study.

What benefits might patients with POD24 receive from enrolling in SYMPHONY-1 vs pursuing another treatment options, such as CAR T-cell therapy?

It’s debatable whether patients with POD24 have a worse prognosis. It has turned out that a lot of those patients truly have transformed lymphoma, not typical FL. [The decision between SYMPHONY-1 and other treatment options] depends on the patient. If the patient has FL with aggressive behavior but is young and has good baseline functional status, CAR T-cell therapy certainly could be considered. However, not many patients can undergo CAR T-cell therapies, especially older patients who are frail. Those patients should be considered for this study.

If the primary end point of the phase 3 portion of the trial is positive, what would be the potential implications of these findings?

If the trial shows that the addition of tazemetostat [to lenalidomide plus rituximab] improves progression-free survival compared with the standard lenalidomide plus rituximab, it could change the standard for relapsed FL in the second-line setting and beyond. If this new combination leads to a deeper and more sustained remissions with minimal added toxicity, it will be an attractive option, especially for patients who cannot tolerate more intense therapy.

What ongoing research efforts in FL could complement this study?

It’s an exciting time to treat FL, with multiple novel therapeutic options available. CAR T-cell therapy and bispecific antibodies have received the most attention, since they have led to excellent clinical activity in relapsed FL. The idea of combining a small molecule inhibitor with cellular immunotherapy is still new. However, it will be interesting to see whether there will be any added or even synergistic effects if we combine tazemetostat with immunotherapy or a bispecific antibody.

References

1. Batlevi CL, Salles G, Park SI, et al. Tazemetostat in combination with lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma: phase 1b results of Symphony-1. Blood. 2022;140(suppl 1):2296-2298. doi:10.1182/blood-2022-166991
2. 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 September 28, 2023. Accessed October 24, 2023. https://www.clinicaltrials.gov/study/NCT04224493