Tazemetostat Addition Aims to Bolster Efficacy of Lenalidomide Plus Rituximab in R/R Follicular Lymphoma

Steven Park, MD

Although relapsed/refractory follicular lymphoma (FL) remains a difficult- to-treat disease, the emergence of anti-CD20 monoclonal antibodies in recent years has signaled progress, including the 2019 FDA approval of rituximab (Rituxan) plus lenalidomide (Revlimid).¹ Investigators are hoping to build on the efficacy displayed by this regimen in the phase 1b/3 SYMPHONY-1 trial (NCT04224493), which is evaluating the addition of tazemetostat (Tazverik) to lenalidomide and rituximab, and are hoping that positive findings from the trial will eventually lead to the addition of another safe and effective option to the treatment arsenal for relapsed/refractory FL.

Tazemetostat is a first-in-class EZH2 inhibitor. EZH2 plays a role in controlling the biology of germinal B cells, and overexpression or mutation of the epigenetic regulator has been linked with malignant transformation in B-cell malignancies. Preclinical data have demonstrated that the combination of EZH2 inhibitors with lenalidomide and/or rituximab has potential synergistic anti-tumor activity.²

In June 2020, the FDA granted accelerated approval to tazemetostat monotherapy in adult patients with relapsed/refractory EZH2-mutated FL who have received at least 2 prior systemic therapies or who have relapsed/refractory disease with no other available satisfactory treatment options.³

“It’s been shown that the overexpression of EZH2 can lead to cancer progression and worse clinical outcomes,” Steven Park, MD, vice chair for research in the Department of Hematologic Oncology and Blood Disorders at the Atrium Health Levine Cancer Institute in Concord, North Carolina, said in an interview with OncologyLive. “So knowing that approximately 20% to 30% of patients with FL harbor mutations in EZH2, it’s a good target for treatment. As a single agent, tazemetostat has shown good clinical activity in relapsed/refractory FL. It is considered a good option, especially for patients who cannot tolerate a more intense regimen. The next question is whether we can improve the clinical outcomes even more by combining tazemetostat with lenalidomide and rituximab, which is one of the most commonly used regimens for relapsed/refractory FL in the second-line setting. The idea is to bring more effective regimens into earlier lines of therapy."

Tazemetostat Triplet Regimen Displays Early-Phase Efficacy, Tolerability

Stage 1 of SYMPHONY-1 consisted of a phase 1b safety run-in, which included adult patients with stage I to IIIA disease who had previously received at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy.4 Patients could not have previously received lena- lidomide, tazemetostat, or another EZH2 inhibitor.

This phase of the research utilized a 3+3 dose-escalation design in which patients received oral tazemetostat at 400 mg, 600 mg, or 800 mg twice daily in 28-day cycles. All patients were treated with oral lenalidomide at a daily dose of 20 mg (creatinine clearance, ≥ 60 mL/min) or 10 mg (creatine clearance, < 60 mL/min) on days 1 to 21 for 12 cycles and intravenous rituximab atadoseof375mg/m2 ondays1,8,15,and22of cycle 1, then on day 1 of cycles 2 to 5. Coprimary end points of phase 1b were determining the recommended phase 3 dose (RP3D) of tazemetostat as well as evaluating safety and tolerability.

The median age in the overall population (n = 44) was 67 years (range, 39-83). Most patients were male (59.1%), had an ECOG performance status of 0 (75.0%), and had received prior treatment with an anti-CD20 monoclonal antibody in combination with chemotherapy (75.0%).

The median time from last treatment was 15.7 months (range, 0.6-193.6). The median number of prior lines of systemic therapy was 1 (range, 1-4), with patients receiving either 1 (68.2%), 2 (15.9%), 3 (4.5%), or 4 (11.4%) previous therapies.

At the data cutoff date of June 14, 2022, findings from stage 1 of SYMPHONY-1 demonstrated that the overall response rate (ORR) among all efficacy-evaluable patients (n = 41) was 97.6%, which included a complete response (CR) rate of 51.2%. Similar efficacy was seen across subgroups; patients with EZH2 wild-type disease (n = 33) and EZH2-mutated disease (n = 7) experienced ORRs of 97.0% and 100%, respectively, including respective CR rates of 45.5% and 71.4%. Moreover, patients who were rituximab refractory (n = 14) and sensitive (n = 26) experienced ORRs of 100% and 96.2%, respectively, and those with disease that progressed within 24 months (POD24; n = 11) and those with non-POD24 (n = 30) disease achieved ORRs of 100% and 96.7%, respectively.

“The response rates have been excellent,” Jennifer Effie Amengual, MD, 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, said in an interview with OncologyLive. “[Most] patients who are refractory to rituximab in their last line of therapy, which is approximately one-third of patients, responded to the treatment. Even patients who had relapsed
within 24 months from their initial line of therapy, [who we classify as] POD24 patients, had outstanding responses. All the patients who were POD24 responded to the regimen; that makes up approximately one-third of the phase 1 patient population. It is significant and compelling [that with] this simple, nontoxic regimen, we can overcome some treatment barriers that we see both in rituximab-resistant or -refractory patients and [those] with POD24.”

Additionally, at a median follow-up of 11.2 months, the median progression-free survival (PFS) was not yet reached in the overall population nor in any subgroup. However, the estimated 12-month PFS rate in the overall population was 84.8%; the estimated 12-month PFS rates among those with EZH2 wild-type, EZH2-mutated, rituximab-refractory, rituximab-sensitive, POD24, and non-POD24 disease were 84.8%, 83.3%, 81.8%, 85.8%, 77.8%, and 86.4%, respectively.

Safety findings from the phase 1b portion showed that the combination had a consistent and manageable safety profile; 70.5% of patients in the overall population experienced at least 1 treatment-emergent adverse effect (TEAE).

The most common grade 1 or 2 TEAEs included fatigue (43%), nausea (41%), pain (39%), and diar- rhea (32%). Common grade 3 or 4 TEAEs consisted of neutropenia (34%), thrombocytopenia (11%), and pain (5%). Serious TEAEs occurred in 36.4% of patients, with no event being reported at a frequency of at least 20%.

At least 1 dose modification of any study drug was required in 70.5% of patients. Tazemetostat therapy necessitated dose interruption, reduction, and discontinuation in 61.4%, 4.5%, and 13.6% of patients, respectively.

Treatment was ongoing in 25 patients overall at data cutoff, with 3 patients experiencing progressive disease. No dose-limiting toxicities were identified. Study authors selected 800 mg twice daily as the RP3D of tazemetostat.

SYMPHONY-1 Phase 3 Underway

Following the positive phase 1b findings from SYMPHONY-1, investigators have initiated the double-blinded phase 3 portion of the trial, which comprises 2 stages. Stage 2 will compare the safety and efficacy of tazemetostat in combi- nation with lenalidomide and rituximab with that of placebo plus lenalidomide and rituximab in patients with relapsed/refractory FL. The optional stage 3 part will then examine tazemetostat plus lenalidomide and rituximab in patients with EZH2-mutated FL if findings from stage 2 futility analyses reveal that the efficacy of the combination fails in the overall population but is promising among patients with EZH2-mutated disease⁵.

“It’s very exciting that we now have more and more treatment options available for relapsed/ refractory FL, but the options are still limited for second-line therapy,” Park said. “If you’re considering rituximab for [patients with] FL as a second-line therapy or beyond, this study is a great option because patients will receive standard rituximab or rituximab in combination with tazemetostat.”

The phase 3 portion of SYMPHONY-1 aims to enroll a total of approximately 540 adult patients with relapsed/refractory grade I to IIIA FL who were previously treated with at least 1 prior chemotherapy, immunotherapy, or chemoimmunotherapy. Patients also need to have a minimum life expectancy of 3 months; an ECOG performance status of 2 or less; and adequate renal, bone marrow, and liver function to be eligible for enrollment. Those with prior exposure to taze- metostat or another EZH2 inhibitor, with prior exposure to lenalidomide, or who undergo major surgery within 4 weeks preceding the first dose of study treatment will be excluded.

In both stage 2 and stage 3, patients in the investigational arm will receive oral tazemetostat 800 mg twice daily in continuous 28-day cycles for 12 cycles plus oral lenalidomide 20 mg daily (creatinine clearance, ≥ 60 mL/ min) or 10 mg (creatine clearance, < 60 mL/ min) on days 1 to 21 for 12 cycles and intrave- nous rituximab 375 mg/m² on days 1, 8, 15, and 22 of cycle 1, then on day 1 of cycles 2 to 5. After patients complete 12 months of combination treat- ment, tazemetostat monotherapy will be given at 800 mg twice daily for up to 2 years.

In the control arm, patients will receive placebo in place of tazemetostat and lenalidomide and rituximab at the same dosing schedule as in the investigational arm. Placebo will also be given twice daily for up to 2 years following the initial 12 months of treatment with the combination.

The primary end point in phase 3 is PFS. Secondary end points include ORR, overall survival, duration of response, health-related quality of life, and safety and tolerability.

“If the PFS is favorable, this is an easy combi- nation that I can see going forward to clinical practice,” Amengual said. “It’s building on a regi- men 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.”

The phase 3 portion of SYMPHONY-1 is recruiting patients, and the estimated primary completion date is June 2028.