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US Oncology Hematology Research Program
Rocky Mountain Cancer Centers
John M. Burke, MD, has disclosed that he received consulting fees from AbbVie, Adaptive Biotechnologies, AstraZeneca, Epizyme, Kura, MorphoSys, Roche/Genentech, and Verastem and fees for non-CME/CE services from Seattle Genetics.
On June 18, 2020, the FDA approved tazemetostat, a novel EZH2 inhibitor, for the treatment of adult patients with relapsed/refractory follicular lymphoma (FL). Tazemetostat joins the treatment arsenal against relapsed/refractory disease, which includes chemoimmunotherapy regimens (ie, R-CHOP, R-CVP, and bendamustine plus obinutuzumab), lenalidomide plus rituximab, PI3K inhibitors (ie, idelalisib, duvelisib, and copanlisib), and autologous stem cell transplant.
A Unique Mechanism of Action
Tazemetostat is an inhibitor of EZH2, a methyltransferase that is an epigenetic regulator of gene expression and is required for normal B-cell biology and formation of germinal centers. Gain of function mutations in EZH2 suppress the exit of B-lymphocytes from the germinal state and increase the risk of B-cell cancer. Such gain of function mutations are present in approximately 20% of FL cases. Even when EZH2 mutations are not present, FL cells depend on EZH2 to maintain their growth and survival. Tazemetostat inhibits both mutated EZH2 and wild-type (unmutated) EZH2, although it inhibits mutated EZH2 more potently.
Phase II Clinical Evidence
A phase II clinical trial of tazemetostat in relapsed/refractory FL enrolled patients in 2 cohorts: one with mutated EZH2 (n = 45) and another with wild-type EZH2 (n = 54). Tazemetostat was dosed at 800 mg by mouth twice daily. The median age of the 99 patients was 61-62 years and the median number of previous therapies was 2 in the mutated EZH2 cohort and 3 in the wild-type EZH2 cohort. Approximately one half of the patients were refractory to their last regimen.
In the cohort of patients with EZH2 mutations, the primary endpoint of ORR was 69%, with 12% achieving CR. The median duration of response was 10.9 months but these data are not yet mature and may change with additional follow up. In the cohort of patients with wild-type EZH2, the ORR was lower at 34%, with 4% achieving CR; the median duration of response was 13.0 months. Of note, patients in the wild-type EZH2 cohort were more heavily pretreated than the EZH2-mutant cohort (median of 3 vs 2 previous therapies, respectively), which may be explained by a bias to enroll patients with EZH2-mutant disease on the trial sooner. This difference between the cohorts in median number of previous therapies may have contributed to the improved efficacy of tazemetostat observed in the mutated EZH2 cohort.
In both cohorts, response rates for patients refractory to rituximab or to previous therapy as well as for those who had progression of disease within 24 months of their preceding therapy (POD24) were comparable to the overall ORR, meaning that tazemetostat can work even in high-risk patients. Furthermore, the median time to response was almost 4 months in both cohorts, so physicians should be aware that it may take longer to see a response with tazemetostat as compared with the timing of responses they are used to seeing with chemoimmunotherapy.
Tazemetostat was a very well-tolerated treatment. Only 8% of patients permanently discontinued therapy due to adverse events, and 9% of patients required dose reductions. Grade 3/4 adverse events were rare and included asthenia, fatigue, anemia, and thrombocytopenia. The most common, any-grade adverse events were fatigue, respiratory tract infections, musculoskeletal pains, nausea, and abdominal pain.
Approval of Tazemetostat for R/R FL
Based on the response benefit with tazemetostat observed in the phase II trial, the FDA granted accelerated approval of tazemetostat for 2 indications in FL: adult patients with relapsed/refractory FL whose tumors are positive for an EZH2 mutation and who have received ≥ 2 previous lines of therapy, and for adult patients with relapsed/refractory FL when no satisfactory alternative treatment options are available. A companion diagnostic to detect EZH2 mutations was also approved.
Tazemetostat does carry a warning for increased risk of secondary malignancy. One pediatric patient on a different trial developed a T-cell lymphoblastic lymphoma, which resulted in a thorough review of all patients who had received tazemetostat to clarify this risk. This review did reveal a low incidence of myelodysplastic syndromes and acute myeloid leukemia (0.7%). Of course, patients with FL on the phase II trial and in clinical practice have been previously treated with alkylating agents, which are known to cause myelodysplastic syndromes and acute myeloid leukemia.
Regarding drug–drug interactions, moderate or strong CYP3A inhibitors like diltiazem may increase tazemetostat concentrations and therefore tazemetostat toxicities. Coadministration of tazemetostat with such CYP3A inhibitors should be avoided if possible; if not possible, tazemetostat dose reductions are suggested in the prescribing information. In contrast, moderate or strong CYP3A inducers like hormonal contraceptives can decrease plasma concentrations and reduce efficacy of tazemetostat and should be avoided if possible.
Tazemetostat in Clinical Practice
I think tazemetostat is an attractive new option for relapsed/refractory FL, for both oncologists and patients, with a good response rate and a very favorable toxicity profile as compared with other available treatment options in this setting.
One example of a good candidate for tazemetostat is a patient whose disease has progressed after 2 previous lines of therapy and has an EZH2 mutation. For example, if a patient has received 2 lines of chemoimmunotherapy, or perhaps chemoimmunotherapy followed by lenalidomide plus rituximab, the physician may want to consider testing for an EZH2 mutation; if positive, the patient would be an ideal candidate for tazemetostat.
Another example of a candidate for tazemetostat is a patient that has received 3 previous lines of therapy, such as chemoimmunotherapy, lenalidomide plus rituximab, and a PI3K inhibitor. If such a patient is thought not to be a good candidate for additional chemoimmunotherapy or other treatments, testing for an EZH2 mutation is not even necessary, and the patient could be treated with tazemetostat.
A third example of a patient ideal for tazemetostat might be someone who has received prior therapy—even if only 1 line of therapy—but is frail or has comorbidities that preclude use of alternatives such as additional chemoimmunotherapy, lenalidomide plus rituximab, or PI3K inhibitors. Again, such a patient need not be tested for an EZH2 mutation and could be treated with tazemetostat.
Patient Monitoring and Education
There are no specific monitoring requirements provided in the prescribing information for tazemetostat. Because tazemetostat causes some cytopenias, I plan to monitor blood counts monthly at the beginning of treatment with this drug. After a few months of therapy, if cytopenias and other toxicities have not occurred, I plan to extend the monitoring interval to every 2-3 months.
Regarding the risk of secondary malignancies, wording in the prescribing information states that tazemetostat increases the risk of developing secondary malignancies, so certainly clinicians need to advise patients of that small possibility.
Molecular Testing for EZH2 Mutations
One question to consider is when to test patients for EZH2 mutations. As I mentioned, the test is not required, but the results of the test could be informative for treatment decisions. For example, it could help you and your patient who has received 2 lines of therapy (eg, chemoimmunotherapy and lenalidomide plus rituximab) decide between using tazemetostat or a PI3K inhibitor. The benefit of testing in this scenario is to inform patients of their likelihood of response to tazemetostat. However, if the physician feels that a PI3K inhibitor might be too risky for a particular patient—for example, a patient with underlying pulmonary disease in whom pneumonitis could be devastating—tazemetostat could be used without testing for an EZH2 mutation.
Integrating Tazemetostat Into the Treatment Paradigm for Relapsed/Refractory FL
A common question that arises when making treatment decisions for relapsed/refractory FL is: How do we optimally sequence the available options? The short answer is that these are individual doctor/patient decisions to make, and the answer may be different for different patients. In my practice when presented with multiple treatment options, I discuss with my patients the advantages and disadvantages of each option to help them make an informed decision.
Specifically considering where to fit tazemetostat into the treatment paradigm for relapsed/refractory FL, let’s return to our example patient who has received 2 lines of therapy (eg, chemoimmunotherapy and lenalidomide plus rituximab) and is deciding between using tazemetostat or a PI3K inhibitor as third-line therapy. In my discussion with the patient, I would consider the following information, with the caveat that we need to be careful when making comparisons across studies. In patients with EZH2 mutations, the ORR with tazemetostat was approximately 70%, albeit in a small group of patients, which compares favorably with response rates of approximately 40% to 60% with PI3K inhibitors. With response rates being similar, I would then consider the toxicity profiles of both class of agents. As discussed, tazemetostat is a well-tolerated drug whereas PI3K inhibitors can occasionally cause some serious toxicities like pneumonitis, diarrhea, and liver enzyme abnormalities. Thus, for a patient with an EZH2 mutation in the third-line setting, I would consider using tazemetostat before a PI3K inhibitor. By contrast, for patients without an EZH2 mutation, the response rate to tazemetostat was lower, at 34%, so you may get a better response starting with a PI3K inhibitor. However, you still need to factor in the respective toxicity profiles: It is a difficult decision, where the trade-off is a somewhat lower response rate but lower toxicity with tazemetostat as compared with a higher response rate but increased toxicity with a PI3K inhibitor.
What questions do you have about the use of tazemetostat in your patients with relapsed/refractory FL? I encourage you to answer the polling question and post your thoughts and questions in the discussion box below