Efficacy of tazemetostat in patients with EZH2m and EZH2wt R/R FL

EP: 1.Case Presentation: Relapsed/Refractory Follicular Lymphoma

EP: 2.R/R FL Patient Case Review and Impressions

EP: 3.First-line Therapy Options in ND Follicular Lymphoma

EP: 4.Considerations for Therapy in R/R FL

EP: 5.Second-line Treatment Options for R/R FL Patients

EP: 6.Treatment Challenges Beyond the Second-line in R/R FL

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EP: 7.Efficacy of tazemetostat in patients with EZH2m and EZH2wt R/R FL

EP: 8.Managing Side Effects of Tazemetostat in R/R FL

EP: 9.Future Directions and Unmet Needs in the Treatment of R/R FL

Loretta Nastoupil, MD: Tazemetostat is our first therapy that targets a specific mutation, EZH2, which occurs in about 20% to 30% of patients with follicular lymphoma. In a single-arm phase 2 study, tazemetostat was explored as 800 mg twice daily, again, an oral therapy, among patients with both wild-type and mutated EZH2. We observed in this study that the response rate among EZH2-mutated patients was significantly higher than in patients who had the EZH2 wild-type status. That meant an overall response rate approaching 70% vs around the mid-30% range.

What was striking to me was that despite the dramatic difference in overall response rate, the progression-free survival [PFS] was quite similar among both the wild-type and mutated populations: approximately 11 months vs 13 months. That compares favorably to other agents that have been approved in the third-line or later space with a median PFS from 10 to 11 months. The duration of response was quite favorable, particularly between the EZH2 mutated and wild type.

As a result of the efficacy being comparable in terms of the durability of response or progression-free survival, it has an interesting label. It’s approved for patients who’ve had 2 prior lines of therapy and an EZH2 mutation, but it’s also approved for patients with EZH2 wild-type or unknown status in the relapsed setting if they do not have an acceptable alternative standard of care. That’s because the safety profile of tazemetostat is quite favorable. There are very low rates of grade 3 or higher toxicities. The vast majority of adverse events were grade 1. There were very low rates of treatment discontinuation and few instances of dose modification as a result of adverse events, which is quite notable given that this was chronic therapy. That compares very favorably to other agents in the third-line or later space, including PI3 kinase inhibitors, lenalidomide-based approaches, and most certainly in comparison to CAR [chimeric antigen receptor] T-cell therapy. That’s why the label allows for some flexibility, particularly for older, frailer patients for whom more intensive therapy options may not be as appealing. 

Because the safety profile is viewed to be very favorable, there are studies underway looking at tazemetostat combinations in earlier lines of therapy, which makes rational sense. Because the EZH2 mutation can be an early event in lymphomagenesis, there is even consideration for moving it into frontline combination strategies. It would make sense that it would have efficacy in patients with EZH2 mutations because it inhibits EZH2.

The questions arise as to why we see comparable efficacy among the wild-type patients. Though it’s complex, we may not fully understand the mechanism of action. We know that EZH2 plays a critical role in the development of normal B cells and the maturation process where they go from an immature B cell in the germinal center to a plasma cell that’s capable of making an antibody or a memory B cell. An EZH2 mutation can lead to arrest in that normal B-cell development, trapping these malignant B cells in the genotoxic germinal center where they’re exposed to multiple rounds of somatic hypermutation and acquire additional genetic alterations over time. There’s also likely a role of EZH2 in the microenvironment in terms of impact on protumor immune cell subsets. That will favor the survival of follicular lymphoma cells, which also suggests that’s why it may even have a role in EZH2 wild-type follicular lymphoma and its impact on that microenvironment.

This transcript has been edited for clarity.

Case: A 75-Year-Old Woman With Relapsed/Refractory Follicular Lymphoma

Initial presentation

• A 75-year-old woman complains of a 3-month history of fatigue, occasional fevers, decreased appetite, fatigue, and a 12-lb weight loss
• PMH: Medically-controlled hypertension, osteoporosis, hypercholesterolemia managed with diet and exercise
• PE: palpable bilateral axillary and left cervical lymph nodes, ~ 3 cm in both axillae and 2 cm in the cervical nodes; spleen palpable 4 cm below left costal margin

Clinical workup

• Labs: ANC 1.6 x 109/L, WBC 11.4 x 109/L, 43% lymphocytes, Hb 9.8 g/dL, plt 98 x 109/L, LDH 325 U/L, B2M 3.7 µg/mL; HBV negative
• Excisional biopsy of the axillary lymph node on IHC showed CD 20+, CD 3+, CD5+, CD 10+, BCL2+; follicular lymphoma grade 2
• Bone marrow biopsy showed paratrabecular lymphoid aggregates, 42% involvement
• Cytogenetics: t(14;18) (q32;q21)
• Molecular testing: EZH2m+
• PET/CT showed bilateral axillary, left cervical, and mediastinal lymphadenopathy (3.3 cm, 3.1, cm and 4.6 cm respectively)
• Ann Arbor Stage IV; ECOG 1
   

Treatment

• She was treated with bendamustine and rituximab for 6 cycles, achieved partial response and continued rituximab maintenance
• 24 months later she complained of ULQ discomfort, loss of appetite, fevers new onset itching; she was currently taking antibiotics for her 2nd bacterial infection in the past 6 months
  • Repeat PET/CT revealed progression of disease
  • She was started on R-CHOP for 6 cycles and continued on rituximab maintenance
  • Repeat lymph node biopsy grade 2 follicular lymphoma
• 12 months later she complained of continued weight loss, increased itching and worsening fatigue; recurrent infections continued
  • She was started on tazemetostat 800 mg BID