Phase II study update of tazemetostat in patients with relapsed/refractory follicular lymphoma

Patients with relapsed/refractory (R/R) follicular lymphoma (FL) represent a difficult-to-treat population, with limited treatment options. About 20% of FL patients have mutations in EZH2,¹ an epigenetic regulator of gene expression and cell fate decision that is required for normal B cell biology.² EZH2 biology is relevant in both mutant (MT) and wild-type (WT) EZH2 FL. Tazemetostat is a first-in-class, selective, oral EZH2 inhibitor, that has demonstrated antitumor activity in MT or WT EZH2 R/R FL patients, in a multicenter, open-label (NCT01897571) phase I/II study.³

The Lymphoma Hub has previously published an interim update from the phase II part of the study. At the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition, Franck Morschhauser, CHRU Lille, Lille, FR, reported efficacy and safety data from the FL cohorts of the phase II study.⁴

Study design and patient characteristics⁴

• Patients with FL (N= 99), aged ≥ 18 years, who had received ≥ 2 prior treatments (including at least one anti-CD20-based regimen), with a performance status of 0–2, and measurable disease, were prospectively assigned to cohorts according to EZH2 mutational status:
  • EZH2 MT cohort (n= 45)
  • EZH2 WT cohort (n= 54)
• The median age was 62 (38─80) for MTEZH2 and 60.5 (36─87) for WT EZH2; the median number of prior therapies was two (1─11) for MT EZH2 and three (1─8) for WT EZH2
• More patients who experienced disease progression within 24 months of diagnosis (POD24) were in the WTEZH2 cohort (59.3%) than in the MT EZH2 cohort (42.2%)
• Tazemetostat was administered orally twice daily at a dose of 800 mg until progressive disease or withdrawal
• The primary endpoint was objective response rate (ORR)
• Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety

Results⁴

• Data cuts: efficacy 9^th August 2019 and safety 24^th May 2019
• The most frequent treatment-emergent adverse events (TEAEs) of grade ≥ 3 are represented by anemia (5%), thrombocytopenia (5%), asthenia (3%), fatigue (2%), abdominal pain (1%), and vomiting (1%)
• Treatment-related TEAEs of grade ≥ 3 had a low rate, the most frequent included thrombocytopenia (3%), anemia (2%), asthenia (1%), and fatigue (1%)
• Due to TEAEs:
  • Patients that discontinued treatment: 8%
  • Patients that had a dose reduction: 9%
  • Patients that had a dose interruption: 27% 
• No treatment-related deaths were reported
• Efficacy data, assessed by both independent radiology committee (IRC) and the investigator, are shown in Table 1
• Evidence of tumor reduction (IRC assessed) was seen in 44/45 (98%) patients in the MTEZH2 cohort and 35/49 (71%) patients in the WT EZH2 cohort
• The median overall survival (OS) was not reached in either cohort with a median follow-up of 22 months in the MT cohort and 35.9 months in the WT cohort
• The ORR in high-risk subgroups:
  • Refractory to rituximab subgroup: 59% and 31% in MT and WTEZH2, respectively
  • POD24 subgroup: 63% and 25% in MT and WTEZH2, respectively
  • Refractory to prior treatment subgroup: 64% and 29% in MT and WTEZH2, respectively
• There were eight patients (18%) in the MT EZH2 cohort and nine patients (17%) in the WT EZH2 cohort who continued on treatment after disease progression

Table 1. Study outcomes

CI, confidence interval; CR, complete response; DOR, duration of response; MT, mutant; NE, non-evaluable; NR, not reached; ORR, objective response rate; PR, partial response; PFS, progression-free survival; WT, wild-type.
^aMedian DOR is still maturing for the MT EZH2 cohort

 

Parameter

MT EZH2 (n= 45)

WT EZH2 (n= 45)

Investigator

IRC

Investigator

IRC

ORR, n (%)

(95% CI)

CR, n (%)

PR, n (%)

Stable disease, n (%)

Progressive disease, n (%)

35 (78)

(62.9─88.8)

4 (9)

31 (69)

10 (22)

0

31 (69)

(53.4─81.8)

6 (13)

25 (56)

13 (29)

1 (2)

18 (33)

(21.1─47.5)

3 (6)

15 (28)

16 (30)

16 (30)

19 (35)

(22.7─49.4)

2 (4)

17 (31)

18 (33)

12 (22)

Median time to first response, months

(range)

3.8

(1.6─11)

3.7

(1.6─10.9)

3.5

(1.6─16.3)

3.7

(1.6─16.3)

Median DOR^a, months

(95% CI)

8.3

(5.5─13.8)

10.9

(7.2─NE)

14.7

(7.6─NR)

13

(5.6─NR)

Patients ongoing, n (%)

13 (29)

0

Median follow-up, months (range)

22 (2.8─43.5)

35.9 (0.3─48.8)

Median PFS, months

(95% CI)

13.8

(8.4─16.4)

13.8

(10.7─22)

5.6

(3.3─11.1)

11.1

(3.7─14.6)

Conclusions⁴

• Tazemetostat was generally well tolerated, with a low incidence of treatment-related TEAEs of grade ≥ 3 
• Tazemetostat demonstrated clinically durable, single-agent activity in patients with R/R FL, including high-risk subgroups, and pronounced responses in patients with EZH2 mutations
• Based on this data, a new drug application has been submitted to the US Food & Drug Administration (FDA) for accelerated approval of tazemetostat for the treatment of patients with R/R FL