Leonard Shares Significance of the Tazemetostat Approval in Follicular Lymphoma

John P. Leonard, MD

Tazemetostat (Tazverik) induces meaningful responses in patients with relapsed/refractory follicular lymphoma whose tumors are EZH2 positive, according to John P. Leonard, MD, and with its recent regulatory approval, it offers an option to patients who don’t have many options available.

On June 18, 2020, the FDA approved the EZH2 inhibitor for use in patients with relapsed/refractory follicular lymphoma who also have tumors that harbor EZH2 mutations, as detected by an FDA-approved test, and who have received a minimum of 2 prior systemic therapies or have no other satisfactory treatment options available to them.

The regulatory decision was based on data from an ongoing, multicenter phase 2 trial (NCT01897571), which involved 2 open-label, single-arm cohorts. Cohort 4 consisted of patients with EZH2-mutated follicular lymphoma and cohort 5 was comprised of patients with EZH2 wild-type follicular lymphoma. Patients received 800 mg of tazemetostat orally twice daily or until disease progression or unacceptable toxicity.

Results showed an overall response rate (ORR) in cohort 4 was 69%, with 12% complete responses (CRs) and 57% partial responses (PRs). The median duration of response (DOR) reported with the agent was 10.9 months. The ORR in cohort 5 was 34%, with 4% CRs and 30% PRs. The median DOR in this cohort was 13 months.

With regard to safety, the most common adverse effects (AEs) included fatigue, upper respiratory tract infection, musculoskeletal pain, nausea and abdominal pain. Serious adverse reactions occurred in 30% of patient and a majority of these cases were a result of infection.

“Well, in follicular lymphoma, we've been focusing on developing new options for patients that are not [eligible for] chemotherapy or who want an alternative that has a more favorable safety profile,” said Leonard. “This agent can also be effective in patients who have already undergone chemotherapy or in patients who have limited therapy options. Tazemetostat is another option for this subset of follicular lymphoma and there’s no question that patients can benefit from this treatment.”

In an interview with OncLive, a professor of medicine and the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College and an attending physician at NewYork-Presbyterian Hospital, further discussed the FDA approval of tazemetostat in patients with follicular lymphoma.

OncLive: What does the approval of tazemetostat bring to patients with relapsed/refractory EZH2-positive disease and those who have no other suitable treatment options?

Leonard: Follicular lymphoma is typically an incurable disease, so these patients need many treatments over the course of their lifetime. Having new options is important, particularly when patients have already been through chemotherapy and some of the other therapies that are available. In EZH2-mutant disease, the effectiveness of this drug is pretty substantial, with an overall response rate in these patients of about 70%, give or take. This is a very meaningful response rate for patients with EZH2-mutant follicular lymphoma. In the wild-type group of patients, the response rates are lower, at approximately 35%. However, that is still a meaningful response rate for a subset of patients who, in some cases, don't have other options.

Could you provide some background on tazametostat and its mechanism of action?

Tazemetostat is an oral inhibitor of EZH2. EZH2 is involved in germinal center formation and plays a role in epigenetics. In some ways, this is an epigenetic-targeted drug. The bottom line is that [the agent] seems to have activity, particularly in germinal center-derived lymphomas, within the lymphoma subgroup. Follicular lymphoma is one of [those lymphomas]. [This agent] might also be operative in subsets of patients with diffuse large-B cell lymphoma, although the approval is not yet in that setting.

Do you see the approval impacting the use of next-generation sequencing at all?

As part of the approval, there is a test that's available now to look for EZH2 mutations. The cobas EZH2 Mutation Test was approved as a companion diagnostic [for tazemetostat] and will be available for clinicians to order. People are also, in some cases, doing mutation panels on their patients with lymphoma. EZH2 mutations are a marker that is often available as part of those panels. A minority of patients have EZH2 mutations in follicular lymphoma, somewhere around 20%. With that said, while efficacy is lower in the wild-type group of patients, it's still potentially meaningful for a subset of patients depending on what other options they have.

Could you expand on the data from the phase 2 trial that led to the approval?

The data, as summarized by the FDA approval, shows that the ORR in about 42 patients with EZH2-mutant follicular lymphoma was 69%; 57% of those cases were partial responses. The DOR was 10.9 months with the agent, and, in some cases, those responses were longer. In the wild-type group of patients, there was a 34% ORR with 30% being PRs. The majority of patients had PRs with a DOR of 13 months.

What does the safety profile of the agent look like?

This is an oral agent that is taken twice daily, which is great for patients because they can take it from home. I would say that the safety profile is reasonably favorable compared with some of the other options, such as chemotherapy, that these patients might otherwise be getting. The main AEs include fatigue, nausea, and occasional high-grade AEs, such as infection.

Is there a confirmatory phase 3 trial planned?

Yes, there is a confirmatory phase 3 trial that is adding tazemetostat to lenalidomide (Revlimid) plus rituximab (Rituxan) in patients with follicular lymphoma. In this randomized trial, we'll see if the addition of tazemetostat adds to the efficacy of lenalidomide plus rituximab [and we’ll also understand more about] the safety profile.

Reference:

1. FDA granted accelerated approval to tazemetostat for follicular lymphoma. News release. FDA. June 18, 2020. Accessed June 23, 2020. bit.ly/310qcSe.