Tazemetostat Plus Lenalidomide and Rituximab for Relapsed/Refractory FL: Promising Data From SYMPHONY-1 Trial

Connie Batlevi, MD, PhD, shares updated safety and efficacy data from the SYMPHONY-1 trial of tazemetostat, a first-class oral selective EZH2 inhibitor, for patients with FL.

Transcript:

My name is Dr. Connie Lee Batlevi. I am one of the lymphoma attendings at Memorial Sloan Kettering Cancer Center. We are here to discuss the SYMPHONY-1 trial, which is the phase 1B/3 study evaluating tazemetostat plus lenalidomide and rituximab in patients with relapse or refractory (R/R) follicular lymphoma (FL). So patients with FL represent a wide spectrum in terms of disease, status, disease pace, as well as chronological age.

Tazemetostat was a first-in-class EZH2 inhibitor that showed a heightened response in patients with EZH2 mutations, but a fairly reasonable response. And also patients with wild-type EZH2. The treatment is also exceedingly well tolerated, and we also knew that epigenetic dysregulation is an essential hallmark of FL. This led us to be interested in combining the agent with existing second line regimens for FL.

One of these non-chemotherapy regimens for R/R FL is rituximab and lenalidomide, which in existing studies showed an overall response rate (ORR) of approximately 73 to 70%, as well as a medium progression-free survival (PFS) of 36 to 39 months. It was our hope that based on in vitro synergistic activity that tazemetostat in combination with lenalidomide that we could improve on these results. So for that reason, the SYMPHONY-1 trial was developed to essentially study the triplet combination tazemetostat, rituximab, and lenalidomide in patients with R/R FL after one prior line of therapy.

In terms of the study, this is an international multi-center randomized double blind trial. The phase 1B portion is completed and we're still finalizing the results. But the phase 3 study is going to start in a short time. The study goes for second-line or more patients. Tazemetostat is given orally twice a day for 12 months, followed by maintenance tazemetostat for two years. The lenalidomide is given daily 21 out of 20-day cycles for 12 months. And then the rituximab is given in the initial five months of treatment.

So far, we have the initial ORR from the phase 1B study, and that is promising, but too early. The ORR thus far is approximately 91%. However, the long-term duration of response (DOR) and PFS is too early to tell for this phase 1B cohort. However, in the safety component of the phase 1B, we are finding that the combination is generally well tolerated, which is expected. There are some neutropenias which occurred, and that is expected for lenalidomide-based treatment. Thrombocytopenias were also observed, and that is also consistent with the toxicity profile of lenalidomide as well.

I think the randomized trial between rituximab lenalidomide versus rituximab, lenalidomide, and tazemetostat that will certainly be very interesting. I think that if we continue to demonstrate that there really is good safety and efficacy profile, this will be one of the first or series of agents in FL, where we're moving further and further away from chemotherapy-based regimens. It all also speaks to the migration of treating FL as generally with DNA toxic agents or chemotherapy in general. These are essentially target therapies that are focusing on very specific parts of FL. For example, immunomodulation through lenalidomide and also epigenetic regulation through tazemetostat.

The next phase after the phase 1B is to continue the study. It's already written as a phase 3 study. So that's stage two of this, and that's where we'll enter the randomization arm, where some patients will get rituximab and lenalidomide and other patients will get rituximab, lenalidomide and tazemetostat.