January 2021 Volume 19, Issue 1, Supplement 2

A SPECIAL MEETING REVIEW EDITION

Highlights in Relapsed/Refractory Follicular From the 62nd American Society of Annual Meeting and Exposition A Review of Selected Presentations From the All-Virtual 62nd ASH Meeting and ​ Exposition • December 5-8, 2020

Special Reporting on: • Analyzing Efficacy Outcomes From the Phase 2 Study of Single-Agent as Third-Line Therapy in Patients With Relapsed or Refractory to Identify Predictors of Response • , the Once-Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε Demonstrates Clinical Activity in Patients With Relapsed or Refractory Indolent Non-: Results From the Phase 2 Global UNITY-NHL Trial • Primary Analysis of ZUMA-5: A Phase 2 Study of in Patients With Relapsed/ Refractory Indolent Non-Hodgkin Lymphoma • Tazemetostat Is Associated With Lower Risk for Safety Outcomes Versus the PI3-Kinases , Duvelisib, and in Patients With Relapsed/Refractory Follicular Lymphoma Who Have Received at Least 2 Prior Systemic Treatments: A Matching-Adjusted Indirect Comparison of Single-Arm Trials • Treatment and Outcome of Patients With Follicular Lymphoma Relapsed or Progressed After Frontline and • Mosunetuzumab Shows Promising Efficacy in Patients With Multiply Relapsed Follicular Lymphoma: Updated Clinical Experience From a Phase 1 Dose-Escalation Trial • Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients With Relapsed or Refractory Follicular Lymphoma (CITADEL-203) • Efficacy and Safety of in Adult Patients With Relapsed/Refractory Follicular Lymphoma: Interim Analysis of the Phase 2 ELARA Trial

PLUS Meeting Abstract Summaries With Expert Commentary by: Gilles Salles, MD, PhD Chief of the Lymphoma Service Division of Hematologic Malignancies Memorial Sloan Kettering Center New York, New York

ON THE WEB: hematologyandoncology.net

Indexed through the National Library of Medicine (PubMed/MEDLINE), PubMed Central (PMC), and EMBASE SPECIAL MEETING REVIEW EDITION

Analyzing Efficacy Outcomes From the Phase 2 Study of Single-Agent Tazemetostat as Third-Line Therapy in Patients With Relapsed or Refractory Follicular Lymphoma to Identify Predictors of Response

ollicular lymphoma is the The FDA granted accelerated The median overall survival (OS) was most common subtype of non- approval to tazemetostat after positive not reached. The ORR was 69% in Hodgkin lymphoma (NHL) results from the open-label, single-arm, patients with the EZH2 vs Fand typically follows an indolent multicenter phase 2 E7438-G000-101 35% in those with wild-type disease. course. Tazemetostat is a first-in- trial. This study included 99 heav- However, patients in the mutated and class, oral inhibitor of the histone ily pretreated patients with follicular wild-type cohorts had similar median methyltransferase EZH2, a gene that lymphoma who had wild-type or durations of response (11 months vs is mutated in up to 25% of patients mutated EZH2.3 Tazemetostat was 13 months) and PFS (14 months vs with follicular lymphoma.1,2 The US administered at a dose of 800 mg twice 11 months). The median OS was not Food and Drug Administration (FDA) daily, in continuous 28-day cycles.3 reached in either cohort. recently approved tazemetostat for the Tazemetostat was generally well tol- A post hoc exploratory analysis treatment of patients with relapsed erated and demonstrated clinically evaluated whether outcomes were or refractory follicular lymphoma. meaningful responses. In the entire affected by factors such as progression The approval includes patients whose study population, tazemetostat yielded of disease within 24 months after first- tumors are positive for an EZH2 muta- an objective response rate (ORR) of line therapy (POD24), prior lines of tion as detected by an FDA-approved 51% (95% CI, 40%-61%), a median therapy, and disease that is refractory test and who have received at least 2 duration of response of 11 months to rituximab. These factors are known prior systemic therapies, as well as (95% CI, 7-19 months), and a median to affect outcomes in patients receiv- patients who lack satisfactory alterna- progression-free survival (PFS) of ing second- or third-line treatment tive treatment options. 12 months (95% CI, 8-15 months). for follicular lymphoma.4-7 An initial

1.0 Refractory to Rituximab Regimen No Yes 0.8

0.6

0.4

0.2

Proportion of Subjects Responding + Censored 0.0 Log-rank P=.0335 0 5 10 15 20 25 Months Not refractory Number to rituximab 25 18 14 8 3 0 of Subjects at Risk Refractory to rituximab 22 12 7 2 1 0

Figure 1. Duration of response to tazemetostat in a phase 2 trial among patients with follicular lymphoma who were or were not refractory to a prior rituximab regimen. Adapted from Salles G et al. ASH abstract 2047. Blood. 2020;136(suppl 1).7

2 Clinical Advances in Hematology & Volume 19, Issue 1, Supplement 2 January 2021 HIGHLIGHTS IN RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA FROM THE 62ND ASH MEETING

1.0 Analysis Reference Range Indicator High Normal 0.8

0.6

0.4

and Progression-Free 0.2 Proportion of Subjects Alive

+ Censored 0.0 Log-rank P=.0059 0 5 10 15 20 25 30 Months

Number of High 46 28 16 8 4 1 0 Subjects at Risk Normal 49 36 23 15 11 0

Figure 2. Progression-free survival according to the level of in a phase 2 trial among patients with follicular lymphoma treated with tazemetostat. Adapted from Salles G et al. ASH abstract 2047. Blood. 2020;136(suppl 1).7 analysis evaluated data from patients Two variables showed a potential cor- References in the phase 2 study with wild-type relation with shorter ORR: increased 1. Tazverik [package insert]. Cambridge, MA; Epizyme, Inc.; 2020. or mutated EZH2. Predictive model- number of prior therapies (1 or 2 vs 2. Lue JK, Amengual JE. Emerging EZH2 inhibitors ing was used to identify variables that >2 prior therapies; odds ratio [OR], and their application in lymphoma. Curr Hematol were associated with response. The 2.81; 95% CI, 1.19-6.61; P=.02) and Malig Rep. 2018;13(5):369-382. 3. Morschhauser F, Tilly H, Chaidos A, et al. Tazemeto- modeling suggested that a decreased POD24 (OR, 2.46; 95% CI, 1.08- stat for patients with relapsed or refractory follicular ORR was associated with an increased 5.61; P=.04). Disease that was refrac- lymphoma: an open-label, single-arm, multicentre, number of prior therapies (>2) and tory to rituximab corresponded to a phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. 4. Jurinovic V, Kridel R, Staiger AM, et al. Clinicoge- POD24. Both variables showed a shorter duration of response (Figure netic risk models predict early progression of follicular potential correlation with PFS. 1; hazard ratio [HR], 0.43; P=.0335). lymphoma after first-line immunochemotherapy. An extended exploratory analysis Variables that correlated with a shorter Blood. 2016;128(8):1112-1120. 5. Li M, Dave N, Salem AH, Freise KJ. Model-based was performed to identify clinical vari- median PFS included disease that was meta-analysis of progression-free survival in non- ables that could predict ORR, dura- refractory to rituximab (HR, 0.37; Hodgkin lymphoma patients. Medicine (Baltimore). tion of response, and PFS.7 Variables P=.0006), a high level of lactate dehy- 2017;96(35):e7988. 6. Nastoupil LJ, Flowers CR, Leonard JP. Sequencing of evaluated in the exploratory analysis drogenase (HR, 2.10; P=.007; Figure therapies in relapsed follicular lymphoma. Hematology included levels of lactate dehydroge- 2), and double-refractory disease (HR, Am Soc Hematol Educ Program. 2018;2018(1):189-193. nase, presence of double-refractory 0.52; P=.03). Variables that did not 7. Salles G, Tilly H, Chaidos A, et al. Analyzing effi- cacy outcomes from the phase 2 study of single-agent disease, presence of extranodal lesions, show an effect on response outcomes tazemetostat as third-line therapy in patients with number of prior therapies, POD24 included prior stem cell transplant, relapsed or refractory follicular lymphoma to identify status, disease that was refractory to disease that was refractory to the most predictors of response [ASH abstract 2047]. Blood. the most recent prior therapy, disease recent prior therapy, and the presence 2020;136(suppl 1). that was refractory to a rituximab regi- of an extranodal target lesion. men, and prior stem cell transplant.

Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 3 SPECIAL MEETING REVIEW EDITION

Umbralisib, the Once-Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε Demonstrates Clinical Activity in Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Results From the Phase 2 Global UNITY-NHL Trial

-cell signaling plays (800 mg, twice daily) until disease received prior chemoimmunotherapy. a key role in normal B-cell progression, unacceptable toxicity, or Approximately one-third of patients development and in the devel- study withdrawal. The first assessment were refractory to their most recent Bopment of B-cell malignancies.1 A of response was conducted at the end prior therapy, and the median time recent mouse model demonstrated of cycle 3. The primary endpoint was since the last therapy was 14 months. that the phosphoinositide 3-kinase independently assessed ORR. The The median follow-up was 27.7 (PI3K)/mammalian target of rapamy- study included 117 patients with fol- months. The median time of exposure cin pathway drives the pathogenesis of licular lymphoma, 69 with marginal to study treatment was 8.4 months lymphoma.2 Umbralisib zone lymphoma, and 22 with SLL. (range, 0.2-27 months). Treatment was (TGR-1202) is a dual inhibitor of The baseline characteristics were gen- ongoing in 29% of patients. The most PI3Kδ and CK1ε, with a highly selec- erally well balanced across the 3 arms. common reasons for discontinuing tive preference for PI3Kδ compared The median age was 66 years (range, the study treatment included progres- with the α, β, and γ isoforms. The 29-88 years), and 57% of patients were sive disease (42%) and adverse events phase 2b UNITY-NHL study evalu- male. An ECOG performance status of (AEs; 15%). The most common AEs of ated umbralisib monotherapy in previ- 2 was reported in 3% of patients, and any grade included diarrhea (59.1%), ously treated NHL patients.3 The study 77% had stage III/IV disease. In the nausea (39.4%), and fatigue (30.8%). enrolled adults with histologically con- marginal zone lymphoma arm, 55% Discontinuation owing to transaminase firmed relapsed or refractory marginal of patients had the mucosa-associated elevation occurred in 2.9% of patients. zone lymphoma, follicular lymphoma, lymphoid tissue subtype. Patients had Grade 3 diarrhea led to discontinuation or small lymphocytic lymphoma (SLL) received a median of 2 prior therapies in 2.9% of patients. Among 4 patients with an Eastern Cooperative Oncology (range, 1-10), and all patients had (1.9%) with noninfectious colitis, Group (ECOG) performance status received prior anti-CD20 therapy. symptoms resolved in 3 patients, who of 0 to 2. Patients received umbralisib Ninety-one percent of patients had continued to receive umbralisib. Grade 3/4 AEs of interest included opportu- nistic (3.4%), rash (1.9%), and pneumonitis (1.0%). 60 49.3% 50.0% Among patients with follicular ORR 45.3% ORR lymphoma, the independently assessed 50 ORR 16% 5% CR ORR was 45.3%, with a complete CR 5% CR 45% response (CR) rate of 5% (Figure 3). 40 PR 40% These rates were 49.3% and 15%, PR 36% 33% 33% 34% SD respectively, in patients with marginal 30 PR SD SD zone lymphoma, and 50.0% and 5%, respectively, in SLL patients. Disease Response (%) 20 reduction was reported in 90.6% of 10 the marginal zone lymphoma patients, 83.5% of those with follicular lym- 0 phoma, and 89.5% of those with SLL. Marginal Zone Follicular Small Lymphocytic Lymphoma Lymphoma Lymphoma The median duration of response was N=69 N=117 N=22 not reached (95% CI, 10.3 months to not evaluable) in marginal zone lym- phoma patients, 11.1 months (95% Figure 3. Independently assessed response among patients treated with umbralisib monotherapy in a phase 2 trial. CR, complete response; ORR, overall response rate; PR, CI, 8.3-15.6 months) in follicular partial response; SD, stable disease. Adapted from Zinzani P et al. ASH abstract 2934. Blood. lymphoma patients, and 18.3 months 2020;136(suppl 1).3 (95% CI, 2.4 months to not evaluable)

4 Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 HIGHLIGHTS IN RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA FROM THE 62ND ASH MEETING

in SLL patients. PFS was not reached References (95% CI, 12.1 months to not evalu- 1. Niemann CU, Wiestner A. B-cell receptor signaling 3. Zinzani P, Samaniego F, Jurczak W, et al. Umbral- as a driver of lymphoma development and evolution. isib, the once daily dual inhibitor of PI3Kδ and casein able) in the marginal zone lymphoma Semin Cancer Biol. 2013;23(6):410-421. kinase-1ε demonstrates clinical activity in patients with cohort, 10.6 months (95% CI, 7.2- 2. Sindel A, McConnell I, Windle J, et al. Role of the relapsed or refractory indolent non-Hodgkin lym- 13.7 months) in those with follicular PI3K pathway in the pathogenesis of marginal zone lym- phoma: results from the phase 2 global UNITY-NHL phoma [ASH abstract 622]. Blood. 2018;132(suppl 1). lymphoma, and 20.9 months (95% CI, trial [ASH abstract 2934]. Blood. 2020;136(suppl 1). 7.4-24.1 months) in those with SLL. Primary Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

mong patients with indolent treatment included an anti-CD20 phoma. The safety analysis included NHL who have received 2 combined with 146 patients, whereas the efficacy or more lines of treatment, an alkylating agent. Patients received analysis included 104 patients. Axi- Aapproved therapies yield low rates standard conditioning treatment fol- cabtagene ciloleucel therapy was suc- of CR, and the median duration of lowed by administration of 2 × 106 cessfully manufactured for all enrolled response is approximately 13 months CAR-positive cells per kilogram. The patients. Delivery to the study site or less.1-5 The phase 2 ZUMA-5 trial primary endpoint was ORR, based on occurred at a median of 17 days after evaluated axicabtagene ciloleucel, an the Lugano criteria.7 leukapheresis. The patients’ median age autologous chimeric antigen receptor The trial enrolled 151 patients. All was 61 years (range, 34-79 years), and (CAR) T-cell therapy, in patients with patients underwent leukapheresis, and 57% of patients were male. Eighty- follicular lymphoma who had received 146 underwent conditioning chemo- six percent of patients had stage III/ at least 2 prior lines of therapy. Eligible therapy. An infusion of axicabtagene IV disease, and 49% had high tumor patients had relapsed or refractory ciloleucel was administered to 124 bulk. Patients had received a median follicular lymphoma of grade 1 to 3a patients with follicular lymphoma and of 3 prior therapies (range, 1-10), and or marginal zone lymphoma.6 Prior 22 patients with marginal zone lym- 68% had refractory disease.

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Follicular Lymphoma Marginal Zone Lymphoma All Patients 20 (n=84) (n=20) (N=104) Duration of Response (%) Duration Median follow-up, months (range) 18.5 (12.2-31.6) 12.1 (1.4-26.8) 17.5 (1.4-31.6) Median DOR, months (95% CI) NE (20.8-NE) 10.6 (8.1-NE) NE (20.8-NE) 0 12-Month DOR rate, % (95% CI) 77.0 (65.6-85.1) NE (NE-NE) 71.7 (60.7-80.1) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Months Number of Subjects at Risk Follicular lymphoma 79 75 67 62 62 59 41 33 25 9 9 8 1 0 Marginal zone lymphoma 17 12 11 11 11 5 0

All patients 96 87 78 73 73 64 41 33 25 9 9 8 1 0 Figure 4. DOR among patients with follicular lymphoma or marginal zone lymphoma treated with axicabtagene ciloleucel in a phase 2 trial. DOR, duration of response; NE, not estimable. Adapted from Jacobson CA et al. ASH abstract 700. Blood. 2020;136(suppl 1).6

Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 5 Based on an independent review Among the 104 evaluable patients, the References of the overall study population, the median PFS (Figure 5) and OS were 1. Dreyling M, Santoro A, Mollica L, et al. Phosphati- dylinositol 3-kinase inhibition by copanlisib in relapsed ORR was 92% (95% CI, 85%-97%), not reached. Twelve-month PFS was or refractory . J Clin Oncol. with a CR rate of 76% (95% CI, 67%- 73.7%, and 12-month OS was 92.9%. 2017;35(35):3898-3905. 84%). The ORR was 94% in patients AEs of grade 3 or higher occurred 2. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in with follicular lymphoma (n=84) in 86% of patients, and most com- patients with refractory indolent non-Hodgkin lym- and 85% in patients with marginal monly consisted of cytopenias (70%) phoma. J Clin Oncol. 2019;37(11):912-922. zone lymphoma (n=20). The median and infections (16%). A grade 5 AE 3. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhi- bition by idelalisib in patients with relapsed indolent time to first response was 1 month occurred in 3 patients. One death lymphoma. N Engl J Med. 2014;370(11):1008-1018. (range, 0.8-3.1 months). Among the was attributed to multisystem organ 4. Wang TP, Scott JH, Barta SK. The evolving role 25 patients with follicular lymphoma failure in a patient with of targeted biological agents in the management of indolent B-cell . Ther Adv Hematol. who had an initial partial response, release syndrome, which was related to 2017;8(12):329-344. 13 (52%) subsequently achieved a CR treatment with axicabtagene ciloleucel. 5. Morschhauser F, Tilly H, Chaidos A, et al. Tazemeto- after a median of 2.2 months (range, Overall, 7 patients (10%) experienced stat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, 1.9-11.2 months). grade 3 or higher cytokine release phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. The ORR was consistent across syndrome. The median time to onset 6. Jacobson CA, Chavez JC, Sehgal AR, et al. Primary key subgroups, including patients with of cytokine release syndrome of any analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory high tumor burden (96%), patients grade was 4 days (range, 1-15 days), (R/R) indolent non-Hodgkin lymphoma (iNHL) who had received 4 or more prior ther- and the median duration was 6 days [ASH abstract 700]. Blood. 2020;136(suppl 1). apies (93%), and those with POD24 (range, 1-27 days). Neurologic events 7. Cheson BD, Fisher RI, Barrington SF, et al. Rec- ommendations for initial evaluation, staging, and following their first anti-CD20 treat- of grade 3 or higher occurred in 28 response assessment of Hodgkin and non-Hodgkin ment (93%). After a median follow-up patients (19%). The median time to lymphoma: the Lugano classification. J Clin Oncol. of 17.5 months, the median duration onset of neurologic events of any grade 2014;32(27):3059-3068. of response was not reached for the was 7 days (range, 1-177 days), and the 104 evaluable patients (Figure 4), median duration was 14 days (range, and 64% of patients with follicular 1-452 days). Neurologic events of any lymphoma had an ongoing response. grade resolved in 93% of patients.

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Follicular Lymphoma Marginal Zone Lymphoma All Patients 20 (n=84) (n=20) (N=104)

Progression-Free Survival (%) Progression-Free Median PFS, months (95% CI) NE (23.5-NE) 11.8 (9.1-NE) NE (23.5-NE) 12-Month PFS Rate, % (95% CI) 77.5 (66.6-85.2) 45.1 (15.2-71.4) 73.7 (63.3-81.6) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Months Number of Subjects at Risk Follicular lymphoma 84 80 71 65 62 59 57 40 27 21 9 9 6 0 Marginal zone lymphoma 20 13 12 12 11 6 4 0

All patients 104 93 83 77 73 65 61 40 27 21 9 9 6 0 Figure 5. PFS among patients with follicular lymphoma or marginal zone lymphoma treated with axicabtagene ciloleucel in a phase 2 trial. NE, not estimable; PFS, progression-free survival. Adapted from Jacobson CA et al. ASH abstract 700. Blood. 2020;136(suppl 1).6

6 Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 HIGHLIGHTS IN RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA FROM THE 62ND ASH MEETING

Tazemetostat Is Associated With Lower Risk for Safety Outcomes Versus the PI3-Kinases Idelalisib, Duvelisib, and Copanlisib in Patients With Relapsed/Refractory Follicular Lymphoma Who Have Received at Least 2 Prior Systemic Treatments: A Matching-Adjusted Indirect Comparison of Single-Arm Trials

opanlisib, duvelisib, and idela­ disease stage, , number of gent AE leading to dose reduction, lisib are approved for the treat- prior lines of treatment, prior stem cell drug discontinuation, or treatment ment of patients with relapsed therapy, refractory status, and POD24. interruption. The results were signifi- Cor refractory follicular lymphoma after The study evaluated safety and efficacy cant (P<.05) for all but 2 comparisons 2 systemic treatments. However, these outcomes. (vs idelalisib for any treatment- PI3-kinase inhibitors were approved Baseline characteristics and out- emergent serious AE, P=.06; and vs based on single-arm studies, and they come data for the subpopulation with duvelisib for a treatment-emergent AE are associated with safety concerns. follicular lymphoma were reported for that led to discontinuation, P=.05). An indirect treatment comparison was matching idelalisib (n=72). Full-trial Several treatment-emergent AEs were conducted to evaluate tazemetostat vs mixed-NHL populations were avail- observed at a significantly lower inci- copanlisib, duvelisib, and idelalisib as able for duvelisib (n=129, 64% with dence with tazemetostat compared third-line or later treatment of patients follicular lymphoma) and copanlisib with the PI3K inhibitors. For example, with relapsed or refractory follicular (n=142, 73% with follicular lym- rates varied from 3% to lymphoma.1 The investigators con- phoma). Only the trial of tazemetostat 4% with tazemetostat vs 22% to 25% ducted a systematic literature review to included patients with grade 3b or with the PI3K inhibitors. identify publications of relevant clini- transformed follicular lymphoma. Comparisons of ORR showed cal trials (Table 1).2-6 All of the trials Grade 3 and higher treatment- no statistically significant differences were phase 2, open-label, single-arm emergent AEs are shown in Table 2. between tazemetostat and each of studies. Three pairwise analyses were After matching for baseline character- the comparators. However, the study conducted using a matching-adjusted istics, tazemetostat was associated with investigators identified some limita- indirect comparison methodology. The a lower risk of any-grade treatment- tions to the analysis of response. For patients were matched according to emergent AE, any treatment-emergent example, the comparator trial data were their age, ECOG performance status, serious AE, and any treatment-emer- not adjusted for the effect modifier of

Table 1. Studies Included in the Indirect Treatment Comparisons

Drug Study Name Identifier Study Title

Open-Label, Multicenter, Phase 1/2 Study of ​ Tazemetostat (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects Tazemetostat E7438-G000-1016 NCT01897571 With Adv. Solid Tumors or With B-Cell Lymphomas and Tazemetostat in Combination With Prednisolone in Subjects With DLBCL Open-Label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients Copanlisib CHRONOS-1 Part B2 NCT01660451 With Relapsed, Indolent or Aggressive Non-Hodgkin’s Lymphomas A Phase 2 Study of Duvelisib in Subjects With Duvelisib DYNAMO4 NCT01882803 Refractory Indolent Non-Hodgkin Lymphoma Efficacy and Safety Study of Idelalisib in Participants Idelalisib DELTA5 NCT01282424 With Indolent B-Cell Non-Hodgkin Lymphomas

Data from Proudman D et al. ASH abstract 2064. Blood. 2020;136(suppl 1).1

Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 7 SPECIAL MEETING REVIEW EDITION

Table 2. Safety Outcomes for Tazemetostat in a Matching-Adjusted Indirect Comparison of Single-Arm Trials

DELTA5 DYNAMO4 CHRONOS-1 Part B2 Grade ≥3 TEAE, % (95% CI) Tazemetostat Idelalisib Tazemetostat Duvelisib Tazemetostat Copanlisib

Anemia 9 (3-15) 7 (1-13) 6 (1-12) 15 (9-21) 4 (1-7) 5 (1-8) Asthenia 5 (1-8) 6 (0-11) 3 (2-4) 2 (0-5) – – Diarrhea 0 (0-0) 19 (10-29) 0 (0-0) 15 (9-21) 0 (0-0) 8 (4-13) Dyspnea 5 (2-9) 4 (0-9) – – – – Fatigue – – 0 (0-0) 5 (1-8) 2 (0-5) 2 (0-4) Hyperglycemia – – – – 1 (0-3) 40 (32-48) Hypertension – – – – 2 (0-5) 24 (17-31) Hypokalemia 5 (1-8) 7 (1-13) 3 (2-4) 3 (0-6) – – Increased ALT 0 (0-0) 13 (5-20) 0 (0-0) 5 (2-9) 1 (0-2) 1 (0-2) Increased AST 0 (0-0) 10 (3-17) 0 (0-0) 3 (0-6) 0 (0-0) 0 (0-0) Neutropenia 3 (0-8) 22 (13-32) 3 (0-7) 25 (17-32) 4 (0-8) 24 (17-31) Pneumonia 0 (0-0) 11 (4-18) 0 (0-0) 5 (2-9) 0 (0-0) 11 (6-16) Rash – – 0 (0-0) 5 (1-8) 0 (0-0) 1 (0-2) Thrombocytopenia 3 (0-8) 10 (3-17) 3 (0-7) 12 (6-17) 4 (0-8) 5 (1-8)

ALT, alanine aminotransferase; AST, aspartate transaminase; TEAE, treatment-emergent adverse event. Adapted from Proudman D et al. ASH abstract 2064. Blood. 2020;136(suppl 1).1

EZH2 mutation status. The comparator results. They concluded that tazemeto- References trials also excluded patients with grade stat was associated with a significantly 1. Proudman D, Nellesen D, Gupta D, et al. Tazemeto- stat is associated with lower risk for safety outcomes ver- 3b tumors or transformed NHL, who lower relative risk for adverse events sus the PI3-kinases idelalisib, duvelisib and copanlisib, may have had a worse prognosis. The as compared with idelalisib, duvelisib, in patients with relapsed/refractory follicular lymphoma authors noted that the efficacy data are and copanlisib, while exhibiting similar who have received at least 2 prior systemic treatments: a matching-adjusted indirect comparison of single-arm not expected to have affected the safety efficacy outcomes trials [ASH abstract 2064]. Blood. 2020;136(suppl 1). 2. Dreyling M, Santoro A, Mollica L, et al. Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lym- ABSTRACT SUMMARY Impaired SARS-CoV-2 Specific Antibody phoma: 2-year follow-up of the CHRONOS-1 study. Responses in Patients Treated With Antibodies Am J Hematol. 2019;95(4):362-371. 3. Dreyling M, Santoro A, Mollica L, et al. Phos- This study describes 7 patients with diffuse large B-cell lymphoma or follicular phatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. lymphoma who received treatment with rituximab or ocrelizumab within 3 months 2017;35(35):3898-3905. prior to the onset of COVID-19 disease (Abstract 2140). Testing for the presence 4. Flinn IW, Miller CB, Ardeshna KM, et al. of anti-spike and anti-nucleocapsid antibodies to the SARS-CoV-2 virus within DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lym- 20 days of symptom onset revealed a failure to mount an immune response to phoma. J Clin Oncol. 2019;37(11):912-922. the novel coronavirus in these patients. One patient with transformed follicular 5. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhi- lymphoma had detectable anti-spike and anti-nucleocapsid antibodies at day bition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018. +25. Two patients—1 with transformed follicular lymphoma and 1 with follicular 6. Morschhauser F, Tilly H, Chaidos A, et al. Tazemeto- lymphoma—were still seronegative for anti-spike and anti-nucleocapsid antibodies stat for patients with relapsed or refractory follicular at days +133 and +74, respectively, after symptom onset. The results suggest that lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. treatment with an anti-CD20 antibody may adversely affect the immune response to in patients with NHL.

8 Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 HIGHLIGHTS IN RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA FROM THE 62ND ASH MEETING

Treatment and Outcome of Patients With Follicular Lymphoma Relapsed or Progressed After Frontline Lenalidomide and Rituximab

retrospective analysis evaluated observed in 22% of patients, and 9% (99 vs 25 months; P=.004; Figure 6). salvage treatment strategies and had grade 3a disease. were Follicular lymphoma transformation survival outcomes in patients present in 6% of patients, and 97% had occurred in 2 patients (7%), at 2 and withA grade 1 to 3a follicular lym- Ann Arbor stage III/IV disease. Thirty 20 months after initiation of second- phoma after first-line treatment with percent of patients had more than 4 line therapy. With 4 years of follow-up lenalidomide plus rituximab.1-3 The involved nodal areas, and 27% had a after failure of first-line therapy, the study included patients with follicular high FLIPI score. median OS was not reached. lymphoma who were treated between The median time to second-line August 2008 and January 2020 at a treatment was 33 months (range, single center. Responses were evaluated 1-122 months). The POD24 rate was References based on the Lugano 2014 criteria.4 8%, and no patients developed trans- 1. Morschhauser F, Fowler NH, Feugier P, et al; REL- EVANCE Trial Investigators. Rituximab plus lenalido- Survival results were calculated from the formation of follicular lymphoma at mide in advanced untreated follicular lymphoma. N time of second-line therapy. Among 156 the time of the first relapse. The median Engl J Med. 2018;379(10):934-947. patients who met the inclusion criteria, follow-up after the first relapse was 51 2. Strati P, Jain P, Johnson RJ, et al. Long term follow- up of lenalidomide and rituximab as initial treatment of 33 (21%) had relapsed or progressive months (95% CI, 27-75 months). The follicular lymphoma [published online September 15, disease. The 33 patients whose disease response rate to first salvage therapy 2020]. Blood. doi: 10.1182/blood.2020007994. had relapsed or progressed included after first-line lenalidomide plus ritux- 3. Strati P, Samaniego F, Gallardo M, et al. Treatment and outcome of patients with follicular lymphoma relapsed 21 patients (64%) who were 60 years imab was 78%, including a CR rate or progressed after frontline lenalidomide and rituximab or younger. Eighty-five percent of of 72%, and the median PFS was 38 [ASH abstract 1128]. Blood. 2020;136(suppl 1). patients had a hemoglobin level of at months (95% CI, 1-82 months). Treat- 4. Cheson BD, Fisher RI, Barrington SF, et al. Rec- ommendations for initial evaluation, staging, and least 12 g/dL, and 24% of patients had ment with chemoimmunotherapy after response assessment of Hodgkin and non-Hodgkin an elevated level of lactate dehydroge- progression yielded a superior median lymphoma: the Lugano classification. J Clin Oncol. nase. involvement was PFS compared with biologic therapy 2014;32(27):3059-3068.

100

P=.004

n Events mPFS Chemoimmunotherapy 50 16 5 NR Biologic therapy 16 12 11

Proportion Progressed/Dead Not 0 0 12 24 36 48 60 72 84 96

PFS (months)

Figure 6. PFS in a retrospective analysis of patients with follicular lymphoma who relapsed or progressed after frontline treatment with lenalidomide and rituximab. NR, not reached; mPFS, median progression-free survival. Adapted from Strati P et al. ASH abstract 1128. Blood. 2020;136(suppl 1).3

Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 9 SPECIAL MEETING REVIEW EDITION

Mosunetuzumab Shows Promising Efficacy in Patients With Multiply Relapsed Follicular Lymphoma: Updated Clinical Experience From a Phase 1 Dose-Escalation Trial

osunetuzumab is a full- risk subgroups included 61.3% with response. After a median follow-up of length, humanized, bispe- double-refractory disease and 46.8% 18.4 months (range, 2-34 months), the cific antibody that binds with POD24. Patients had received median duration of response was 20.4 Mto CD20 and CD3, thus redirecting a median of 3 prior therapies (range, months (95% CI, 9.4-22.7 months). T cells to target malignant B cells. 2-11), and all patients had received Among patients who achieved a CR, The ongoing phase 1/1b GO29781 prior anti-CD20 therapy and an alkyl- the median duration of response was trial is investigating mosunetuzumab ating agent. slightly higher, at 21.0 months (95% monotherapy in patients with relapsed Across all 62 patients, the ORR CI, 16.0-22.7 months). or refractory B-cell NHL.1 Eligible was 67.7%, including a CR rate of Treatment-related AEs of any patients had relapsed or refractory fol- 51.6% (Figure 7). High response rates grade were observed in 72.6% of licular lymphoma of grade 1 to 3a, had were observed in high-risk patients. patients. Treatment-related serious received 2 or more prior systemic ther- Among patients with refractory dis- AEs were noted in 14.5% of patients, apies, and had an ECOG performance ease or POD24, the ORR ranged from and treatment-related AEs of grade status of 0 or 1. Mosunetuzumab was 65.2% to 75.9%. Among 13 patients 3 or higher occurred in 35.5% of administered in eight 21-day cycles. whose disease was refractory to PI3K patients. Treatment-related AEs of Dose levels ranged from 0.4 mg to inhibitors, the ORR was 92.3%. grade 3/4 included hypophosphatemia 13.5 mg. Among the 62 patients, the Four patients had received prior treat- (21.0%) and neutropenia (15.1%). median age was 59 years (range, 27-85 ment with CAR T-cell therapy, and All cytokine release syndrome events years), and 64.5% were male. High- all of these patients demonstrated a were grade 1 (n=12) or 2 (n=1). These

Complete response Partial response 100% 100 92.3% 7.7 80 75.9% 71.1% 50.0 67.7% 65.2% 20.7 60 6160 .1 21.1 17.4

40 40 84.6

51.6 55.2 47.8 50.0 50.0 20 20 Proportion of Patients With a Response (%) With Proportion of Patients 0 All Follicular Refractory Double POD24 PI3Ki Prior CAR Lymphoma Patients to Last Prior Refractory Refractory T-Cell Therapy Therapy N=62 n=46 n=38 n=29 n=13 n=4

Figure 7. Response rates among patients with multiply-relapsed follicular lymphoma treated with mosunetuzumab monotherapy in a phase 1 trial. CAR, chimeric antigen receptor; PI3Ki, phosphoinositide 3-kinase inhibitor; POD24, progression of disease within 24 months after first-line therapy. Adapted from Assouline S et al. ASH abstract 702. Blood. 2020;136(suppl 1).1

10 Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 HIGHLIGHTS IN RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA FROM THE 62ND ASH MEETING

events occurred in 17.7% of patients during dose escalation in the first treat- ABSTRACT SUMMARY A Phase 1b/3 Randomized, Double-Blind, ment cycle. Serious cytokine release 3-Stage Study of Tazemetostat or Placebo Plus Lenalidomide syndrome events were observed in 4 and Rituximab in Patients With Relapsed/Refractory Follicular patients (6.5%). The median time of Lymphoma onset for cytokine release syndrome was 1 day (range, 1-24 days), and the An ongoing 3-stage phase 1b/3 study (NCT04224493) is assessing the efficacy and median duration was 2 days (range, safety of tazemetostat combined with rituximab and lenalidomide (Abstract 2052). 1-8 days). All cytokine release syn- This international, randomized, placebo-controlled study is enrolling adult patients drome events resolved without the use with follicular lymphoma who have received at least 1 prior line of systemic therapy. of tocilizumab, admission to an inten- Patients with mixed or transformed histology will be excluded from enrollment. The sive care unit, or use of vasopressors. primary endpoints are to determine the recommended phase 3 dose, based on a CR rates were similar among patients dose-limiting toxicity rate of less than 33%, and to determine investigator-assessed who developed cytokine release syn- median PFS. Other endpoints include pharmacokinetic parameters and exploratory drome (45.5%) and those who did not analyses of EZH2 , copy number, and expression of mRNA and protein. (52.9%). A phase 3 trial will investi- gate mosunetuzumab combined with lenalidomide in previously treated patients with follicular lymphoma.2 multiply relapsed follicular lymphoma: updated clinical lenalidomide, glofitamab + lenalidomide, and glofit- experience from a phase I dose-escalation trial [ASH amab + lenalidomide + in participants References abstract 702]. Blood. 2020;136(suppl 1). with relapsed or refractory follicular lymphoma. https:// 1. Assouline S, Kim WS, Sehn LH, et al. Mosunetu- 2. ClinicalTrials.gov. A study evaluating the safety, clinicaltrials.gov/ct2/show/NCT04246086. Identifier: zumab shows promising efficacy in patients with , and efficacy of mosunetuzumab + NCT04246086. Accessed December 17, 2020.

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients With Relapsed or Refractory Follicular Lymphoma (CITADEL-203)

he CITADEL-203 study eval- the diagnosis of follicular lymphoma size was observed in 90% (106/118) uated parsaclisib monotherapy was 6 years (range, 0.2-32 years). of evaluable patients across the entire in patients with relapsed or Seventy-eight percent of patients had study group, and in 91% (86/95) of Trefractory follicular lymphoma.1 The Ann Arbor stage III/IV disease, and evaluable patients treated with the study enrolled patients with grade 46% had a FLIPI risk category of 3 or daily regimen. The median duration 1, 2, or 3a follicular lymphoma who higher. Patients had received a median of response was 15.9 months (95% CI, had received 2 or more prior systemic of 2 prior therapies (range, 1-8), and 12.0 months to not evaluable) among therapies. Patients in the weekly group 18% of patients had undergone hema- 86 responders in both treatment arms, received parsaclisib at 20 mg once daily topoietic stem cell transplant. The and 14.7 months (95% CI, 12.0-17.5 for 8 weeks, followed by parsaclisib at median follow-up was 14.5 months months) among 71 responders treated 20 mg once weekly. Patients in the (range, 0.2-28.0 months), and the with the daily regimen (Figure 8). The daily group received parsaclisib at 20 median duration of parsaclisib therapy median PFS was 15.8 months (95% mg once daily for 8 weeks, followed by was 7.1 months (range, 0.2-21.0 CI, 13.2-19.3 months) among 118 parsaclisib at 2.5 mg once daily. Dur- months). The most common reasons evaluable patients from both arms, and ing the study, the daily group regimen for discontinuing parsaclisib were pro- also 15.8 months (95% CI, 13.8-19.1 was chosen as the preferred regimen. gressive disease (29%) and AEs (19%), months) among 95 patients treated The primary endpoint was ORR based followed by patient withdrawal (7%). with the daily regimen. on the 2014 Lugano criteria.2 Among 118 evaluable patients, the Across the entire study cohort of The study enrolled 125 patients: ORR was 73% (95% CI, 64%-81%), 125 patients, the most common AEs of 23 were treated with the weekly regi- with a CR rate of 14%. Among 95 eval- grade 3 or higher were diarrhea (10%) men and 102 with the daily regimen. uable patients treated in the daily group, and neutropenia (10%). The most com- Their median age was 68 years (range, the ORR was 75% (95% CI, 65%- mon serious treatment-emergent AEs 20-88 years). The median time since 83%). A reduction in the target lesion were diarrhea (7%) and colitis (6%).

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1.0

0.9 All Treated Patients Daily Group 0.8

0.7

0.6

0.5

0.4

0.3

0.2

Duration of Response Probability 0.1

0.0 Number at Risk Daily Group 71 49 36 33 17 10 5 3 1 0 All Patients 86 61 44 41 24 16 10 7 3 0

0 2 4 6 8 10 12 14 16 18 Time to Event (months)

Figure 8. Duration of response among patients with relapsed or refractory follicular lymphoma treated with parsaclisib, administered in a daily or a weekly regimen, in a phase 2 trial. Adapted from Lynch RC et al. ASH abstract 2935. Blood. 2020;136(suppl 1).1

References phoma (CITADEL-203) [ASH abstract 2935]. Blood. response assessment of Hodgkin and non-Hodgkin 1. Lynch RC, Paneesha S, Avigdor A, et al. Phase 2 2020;136(suppl 1). lymphoma: the Lugano classification. J Clin Oncol. study evaluating the efficacy and safety of parsaclisib 2. Cheson BD, Fisher RI, Barrington SF, et al. Rec- 2014;32(27):3059-3068. in patients with relapsed or refractory follicular lym- ommendations for initial evaluation, staging, and

Efficacy and Safety of Tisagenlecleucel in Adult Patients With Relapsed/Refractory Follicular Lymphoma: Interim Analysis of the Phase 2 ELARA Trial

he international phase 2 the median age was 57 years (range, Serious AEs and grade 3/4 AEs ELARA trial evaluated the 29-73 years). Most patients (83.5%) that were considered related to study CAR T-cell therapy tisagenlec­ had stage III/IV disease at baseline, treatment were observed in 26.8% and Tleucel in adults patients with relapsed and 59.8% had a FLIPI score of 3 or 38.1% of patients, respectively. There or refractory follicular lymphoma.1 The higher. Patients had received a median were no cases of grade 3/4 cytokine trial enrolled patients with histologi- of 4 (range, 2-13) prior therapies, and release syndrome or grade 3/4 tumor cally confirmed follicular lymphoma of 77.3% were refractory to their most lysis syndrome. All reported cases of grade 1 to 3a. Patients had refractory recent prior therapy. The median dose cytokine release syndrome and neuro- disease, had relapsed within 6 months was 2.06 × 108 CAR-positive T cells. logic events resolved with appropriate of second-line or later therapy, or had At the first interim analysis, the management. relapsed after autologous hemato- median follow-up was 9.9 months, and poietic stem cell transplant. Patients 52 patients were evaluable for efficacy. References received lymphodepleting chemother- The ORR was 82.7%, with a CR rate 1. Fowler NH, Dickinson M, Dreyling M, et al. Effi- cacy and safety of tisagenlecleucel in adult patients with apy followed by a single tisagenlecleu- of 65.4%. The median duration of relapsed/refractory follicular lymphoma: interim analy- 7 8 cel infusion of 6 × 10 to 6 × 10 CAR response (Figure 9), median PFS, and sis of the phase 2 ELARA trial [ASH abstract 1149]. T cells. Prior bridging therapy was per- median OS were not reached. The Blood. 2020;136(suppl 1). 2. Cheson BD, Fisher RI, Barrington SF, et al. Rec- mitted. The primary endpoint was the 6-month PFS was 73.2% (95% CI, ommendations for initial evaluation, staging, and CR rate by independent review, based 58.2%-83.5%). At the time of data response assessment of Hodgkin and non-Hodgkin on the 2014 Lugano criteria.2 cutoff, 69% of patients had an ongoing lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068. Among the 97 enrolled patients, response.

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100

80

60 Censoring times N=43 40 Number of events (n) All patients: 7 20 Kaplan-Meier medians All patients: NE; 95% CI, 8.7 months to NE 0 Probability of Event-Free (%) 0 1 2 3 4 5 6 7 8 9 10 11 12 Number of Patients Still at Risk Time (months) All patients 43 42 41 34 22 21 16 10 8 2 1 0 0

Figure 9. Duration of response among patients with relapsed/refractory follicular lymphoma treated with tisagenlecleucel in a phase 2 trial. NE, not estimable. Adapted from Fowler NH et al. ASH abstract 1149. Blood. 2020;136(suppl 1).1

Highlights in Relapsed/Refractory Follicular Lymphoma From the 62nd American Society of Hematology Annual Meeting and Exposition: Commentary Gilles Salles, MD, PhD

mong cases of lymphoma, PI3K Inhibitors approximately 7%, a lower rate than follicular lymphoma is the Among the PI3K inhibitors already that seen with other drugs from this second most frequent subtype approved for patients with follicular family. There were a few cases of grade Athroughout the United States and lymphoma in the relapsed/refractory 3/4 opportunistic infection (3.4%), Europe.1 The disease is characterized setting are idelalisib, duvelisib, and rash (1.9%), and pneumonitis (1.0%). by an indolent course. When follicular copanlisib. At the ASH meeting, Dr Discontinuations owing to AEs were lymphoma first manifests, patients Pier Luigi Zinzani presented data limited. Approximately 3% of patients usually have few symptoms. Although for the PI3K inhibitor umbralisib.3 discontinued treatment after develop- there are effective first-line treatments, Unlike other agents, umbralisib spe- ing transaminase elevations, and 3% many patients will relapse.2 New treat- cifically targets the PI3Kδ isoform, discontinued owing to diarrhea. ment interventions are needed for dis- as well as the casein kinase 1ε.4 The Among patients with follicular ease control, remission, and improved study enrolled more than 200 patients lymphoma, the overall response rate survival. with indolent disease, including 117 was 45.3%, with 5% achieving a com- Studies presented at the 62nd patients with relapsed/refractory fol- plete response.3 These outcomes are American Society of Hematology licular lymphoma. Most of the patients similar to the other PI3K inhibitors.5-7 (ASH) meeting provided interest- had advanced disease. The median The median time to response was ing data regarding several types of number of prior therapies was 3, and 4.6 months. The median duration of treatments for these patients. These approximately one-third of patients response was 11.1 months. Subgroup treatments included a new generation were refractory to their previous line analysis showed that response was not of phosphoinositide 3-kinase (PI3K) of therapy. impacted by clinical characteristics inhibitors; ; anti- The dose of umbralisib was 800 such as the number of prior lines of body-drug conjugates; and a newer mg/day, and the median duration of therapy, chemoresistance, or resis- intervention, tazemetostat, which is exposure was 7.6 months. An interest- tance to anti-CD20 antibodies. These an EZH2 inhibitor. Tazemetostat is a ing finding was that the adverse event important data confirm that umbral- first-in-class agent approved by the US (AE) profile of umbralisib appeared isib is effective in follicular lymphoma, Food and Drug Administration for the to be more limited compared with with an acceptable tolerability profile. treatment of lymphoid malignancies. other PI3K inhibitors.5-7 The main Dr Ryan Lynch presented results of Data for new interventions targeting grade 3/4 AEs were diarrhea and neu- the CITADEL-203 study, which evalu- different pathways brought hope for tropenia, each of which occurred in ated the PI3K inhibitor parsaclisib.8 the treatment of relapsed/refractory approximately 10% of patients. Grade This drug is administered in a unique follicular lymphoma. 3/4 elevated liver enzymes occurred in schedule compared with the other PI3K

Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 13 SPECIAL MEETING REVIEW EDITION

inhibitors. The CITADEL-203 study ASH meeting, updates were given for CAR T-Cell Therapy evaluated 2 regimens: a weekly sched- several of these compounds in lym- Another category of ule, in which parsaclisib was adminis- phoma.9-12 In these studies, the overall agents in development for follicular tered at 20 mg once daily for 8 weeks, response rates ranged from 67% to lymphoma are the CAR T-cell thera- followed by 20 mg once weekly; and a 90% in patients with relapsed/refrac- pies. At the ASH meeting, Dr Caron daily schedule, which consisted of the tory follicular lymphoma, and the Jacobson presented updated results of same loading dose for 8 weeks, followed complete response rates ranged from the ZUMA-5 study, which evaluated by 2.5 mg once daily continuously. 50% to 70%. The number of patients axicabtagene ciloleucel in patients The study recruited 125 patients in these studies remains small, and with relapsed/refractory indolent non- with relapsed/refractory follicular lym- these data are preliminary. Some of the Hodgkin lymphoma.14 Results were phoma. Most patients received the daily agents have not reached their optimal previously presented at the European regimen. The patients’ characteristics dosing and schedule. Side effects, Hematology Association congress in were typical for those with this disease. such as cytokine release syndrome, June.15 The updated analysis reported All had received prior can occur during the first infusion. results for 124 patients with follicular and anti-CD20 agents. Approximately Cytokine release syndrome should be lymphoma and 22 patients with mar- 1 out of 5 patients had undergone managed with hospitalization for a day ginal zone lymphoma. These patients prior transplant. Approximately half of or more, which can represent a burden were heavily pretreated, with almost patients were refractory to their previ- for patients in this setting. two-thirds having received more than ous line of therapy. The median dura- Dr Sarit Assouline presented 3 lines of prior therapy. In the cohort tion of treatment with parsaclisib was results from a phase 1 dose-escalation of patients with follicular lymphoma, approximately 7 months. The primary trial of mosunetuzumab, an anti-CD20 the overall response rate was extremely reason for discontinuation was disease and anti-CD3 bispecific antibody.13 high, at 94%, with 80% of patients progression. Among all patients in the The study recruited 62 patients with achieving a complete response. Among study evaluable for efficacy (n=118), the relapsed/refractory follicular lymphoma all patients, the median time to a overall response rate was 73%, which is with classic characteristics. Approxi- first response was a rapid 1 month. higher than that typically reported for mately 60% of patients were double Among the patients with follicular these types of agents. Approximately refractory, and the median number of lymphoma who initially had only a 14% of patients achieved a complete prior systemic therapies was 3. partial response, half later converted to response. Many patients had good The escalated dose schedule ranged a complete response. Responses were disease control. The median duration from 0.4 mg to 13.5 mg, administered seen regardless of the patients’ tumor of response was 15.9 months, and the every 3 weeks. The overall response rate burden, number of prior therapies, median progression-free survival (PFS) was 67.7%, with a complete response in and exposure to different agents. The was 15.8 months, confirming the effi- 51.6%. Interestingly, responses, includ- median follow-up was 17.5 months. cacy of this drug. ing complete responses, were reported The median duration of response had Approximately half of the patients among patients with an adverse prog- not been reached. Among the follicular developed a treatment-emergent AE of nosis, such as those who were refractory lymphoma patients with a complete grade 3 or higher, most commonly, to the last prior therapy and those who response, 78% were still responding at diarrhea and neutropenia. Elevations were double refractory. There was a the time of the analysis. The median in transaminase levels occurred in high response rate in patients who were PFS had not been reached. approximately one-quarter of the refractory to PI3K inhibitors. Among The AEs were typical for CAR patients, but most events were grade the 4 patients treated after chimeric T-cell therapies, and included cytope- 1 or 2. Approximately half of patients antigen receptor (CAR) T-cell therapy, nia, cytokine release syndrome, and required dose modification. Overall, all responded, including 2 patients with neurotoxicity. Frequency and severity this selective PI3Kδ inhibitor had a complete response. were somewhat lower than those seen promising efficacy in this setting, with The median duration of response in patients with diffuse large B-cell an expected safety profile. Further was 20 months, suggesting a prolonged lymphoma.16 Axicabtagene ciloleucel research is needed for parsaclisib, as efficacy for these patients. The AE profile is therefore a promising intervention well as for other agents in this class. was similar to that described for other for patients with follicular lymphoma. antibodies, but also included neutrope- Dr Nathan Fowler presented Bispecific Antibodies nia, infections, and hypophosphatemia. preliminary results of another CAR The ASH meeting provided data for Cytokine release syndrome occurred in T-cell therapy, tisagenlecleucel.17 The bispecific antibodies, a promising 17.7% of patients, with only a few seri- phase 2 ELARA trial enrolled patients intervention for patients with follicular ous cases. The median duration of hospi- with follicular lymphoma from 12 lymphoma. Many bispecific antibodies talization for cytokine release syndrome countries. The patients’ characteris- are currently in development. At the was 2 days. tics were similar to those enrolled in

14 Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 HIGHLIGHTS IN RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA FROM THE 62ND ASH MEETING

other studies. The trial recruited 97 patients with follicular lymphoma, of tazemetostat vs PI3K inhibitors.22 patients, but results were reported for either with or without the EZH2 The analysis showed that the response 52 patients evaluable for efficacy. The mutation.20 This mutation occurs in rate did not significantly differ overall response rate was 83%, with approximately one-quarter of patients between tazemetostat and the other 65% of patients achieving a complete with follicular lymphoma. compounds. The safety of tazemetostat response. The median duration of The recently published results was satisfactory, with less than 20% of response was not reached. from the phase 2 trial of tazemetostat patients experiencing mild side effects, There was a high rate of conversion demonstrated an overall response rate such as fatigue or cytopenia, and less from partial remissions to complete of 69% for patients with the EZH2 than 3% experiencing grade 3/4 events. remissions, which was also observed fre- mutation and 35% for patients with Several ongoing studies are quently in patients treated with 4-1BB wild-type disease.20 The median dura- evaluating tazemetostat. Dr Krish CAR T cells. The safety profile was as tion of response was 10.9 months in Patel presented the design of a new expected. These results are promising, the EZH2-mutated cohort and 13.0 study evaluating the combination of and longer follow-up is needed. months in the EZH2–wild-type cohort. tazemetostat plus rituximab for the At the ASH meeting, I presented treatment of relapsed or refractory Antibody-Drug Conjugates results of an analysis of the phase 2 follicular lymphoma.23 Dr Connie The antibody-drug conjugates in trial that aimed to better understand Batlevi presented the design of a large, development for follicular lymphoma the efficacy of tazemetostat in patients ongoing randomized trial that is com- include polatuzumab vedotin and lon- with relapsed follicular lymphoma, bining tazemetostat with the recently castuximab tesirine. At the ASH meet- when the status of the mutation is approved regimen of lenalidomide plus ing, Dr Francisco Hernandez-Ilizaliturri not known.21 This analysis of pooled rituximab (known as R2).24 The study presented data from a phase 1 study of data examined variables that might consists of different stages. The first TRPH-222, an antibody-drug con- influence the overall response rate or stage will identify the recommended jugate that targets the antigen CD22 the duration of response. The analysis phase 3 doses of tazemetostat in com- with a payload known as maytansine.18 found that the overall response rate bination with R2. This stage has almost TRPH-222 incorporates a new type of was similar in patients with normal been completed. The second stage will biochemical linker between the payload or high levels of lactate dehydrogenase determine the safety of this combina- and the antibody that allows a stable (LDH) and was not markedly differ- tion in a larger number of patients. antibody-drug ratio. ent for patients who were or were not The randomization with allow patients Among the 10 patients with fol- refractory to rituximab. A significantly to receive tazemetostat plus R2, and to licular lymphoma, the overall response lower overall response rate was seen in continue with tazemetostat as a single rate was 50%, with a complete patients who had received more than agent for a 24-month maintenance response rate of 40%. In some patients 2 lines of therapy; this response rate phase. Therefore, the investigative arm with a complete response, the response still remained at 40%. Patients who will consist of 6 cycles of the combi- was maintained after several cycles. developed progressive disease within nation followed by 2 years of main- TRPH-222 had a similar safety profile 24 months had an overall response rate tenance, while the control arm will as the other antibody-drug conjugates. of 39% vs 60% for the other patients. consist of the usual R2 regimen. This There were a few infusion-related reac- The variables that predicted duration important study will combine epigen- tions. The most common grade 3/4 of response included refractoriness to etic modulation with immunotherapy. events included thrombocytopenia rituximab and a high LDH level. The An interesting recent observation is and neutropenia. Peripheral neuropa- median PFS was 19 months among that tazemetostat is able to enhance the thy was infrequent and mostly low patients who were not refractory to expression of several immunomodula- grade. As with other antibodies that rituximab vs 8 months in those who tory molecules on the surface of B use maytansine, there were some ocu- were. Among patients with normal cells. Tazemetostat may increase and lar symptoms, an AE that should be LDH levels, the median PFS was 16 enhance the activity of the R2 regimen. considered in future research. months vs 7 months in those with This new study will be a registration high levels. This analysis confirmed trial for this regimen in relapsed/refrac- Tazemetostat that tazemetostat provides good con- tory follicular lymphoma. There were several presentations about trol of follicular lymphoma, which tazemetostat, which is the first EZH2 is prolonged for more than 1 year in Rituximab-Based Regimens inhibitor approved by the US Food the majority of patients. Furthermore, Dr Paolo Strati presented a study and Drug Administration for patients patients with or without the EZH2 regarding the efficacy of second-line with relapsed or refractory follicular mutation can benefit from treatment. regimens in patients treated with the lymphoma.19 Approval was based David Proudman presented data R2 regimen in the first line.25 The study on a phase 2 study that recruited 99 from a matched, indirect comparison showed that immunochemotherapy,

Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 15 SPECIAL MEETING REVIEW EDITION

rather than biologic therapy, was opti- ciloleucel (axi-cel) in patients with relapsed/refractory BMS/Celgene, Kite/Gilead, MorphoSys, (R/R) indolent non-Hodgkin lymphoma (iNHL) mal for this patient group. Novartis, and Roche. [ASH abstract 700]. Blood. 2020;136(suppl 1). A study in newly diagnosed fol- 15. Jacobson CA, Chavez JC, Sehgal AR, et al. Interim licular lymphoma compared rituximab References analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory 1. Lymphoma–Non-Hodgkin: Subtypes. https://www. plus , , indolent non-Hodgkin lymphoma. Abstract presented cancer.net/cancer-types/lymphoma-non-hodgkin/sub- at: the 25th European Hematology Association Con- , and (R-CHOP) types. Posted August 2019. Accessed January 3, 2021. gress; June 11-21, 2020. Abstract S287. vs rituximab plus with 2. Casulo C, Barr PM. How I treat early-relapsing fol- 16. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabta- licular lymphoma. Blood. 2019;133(14):1540-1547. or without rituximab maintenance gene ciloleucel CAR T-cell therapy in refractory large 3. Zinzani P, Samaniego F, Jurczak W, et al. Umbral- B-cell lymphoma. N Engl J Med. 2017;377(26):2531- among patients with high maximum isib, the once daily dual inhibitor of Pi3Kδ and casein 2544. standardized uptake value (SUV ) on kinase-1ε demonstrates clinical activity in patients with max 17. Fowler NH, Dickinson M, Dreyling M, et al. Effi- relapsed or refractory indolent non-Hodgkin lym- positron emission tomography/com- cacy and safety of tisagenlecleucel in adult patients with phoma: results from the phase 2 global UNITY-NHL 26 relapsed/refractory follicular lymphoma: interim analy- puted tomography at diagnosis. Dr trial [ASH abstract 2934]. Blood. 2020;136(suppl 1). sis of the phase 2 ELARA trial [ASH abstract 1149]. Patrizia Mondello from our institute 4. Burris HA 3rd, Flinn IW, Patel MR, et al. Umbralisib, Blood. 2020;136(suppl 1). a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed presented the results. R-CHOP might 18. Hernandez-Ilizaliturri FJ, Flinn IW, Kuruvilla J, or refractory chronic lymphocytic leukaemia and lym- et al. A phase I pharmacokinetic (PK) and safety study reduce the risk of early transformation, phoma: an open-label, phase 1, dose-escalation, first-in- of Trph-222 in patients with relapsed/refractory B-cell although this improvement was not human study. Lancet Oncol. 2018;19(4):486-496. non-Hodgkin lymphoma (R/R NHL): dose-escalation 5. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhi- statistically significant. Interestingly, results [ASH abstract 701]. Blood. 2020;136(suppl 1). bition by idelalisib in patients with relapsed indolent 19. Tazverik [package insert]. Cambridge, MA: Epi- in patients with progressive disease at lymphoma. N Engl J Med. 2014;370(11):1008-1018. zyme; 2020. 2 years, the rate of overall survival was 6. Flinn IW, Miller CB, Ardeshna KM, et al. 20. Morschhauser F, Tilly H, Chaidos A, et al. Taze- DYNAMO: a phase II study of duvelisib (IPI-145) in approximately 80%, indicating that metostat for patients with relapsed or refractory follicu- patients with refractory indolent non-Hodgkin lym- lar lymphoma: an open-label, single-arm, multicentre, we have made progress with new treat- phoma. J Clin Oncol. 2019;37(11):912-922. phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. ments in controlling this disease when 7. Magagnoli M, Carlo-Stella C, Santoro A. Copan- 21. Salles G, Tilly H, Chaidos A, et al. Analyzing effi- lisib for the treatment of adults with relapsed follicular early progression occurs. cacy outcomes from the phase 2 study of single-agent lymphoma. Expert Rev Clin Pharmacol. 2020;13(8):813- tazemetostat as third-line therapy in patients with 823. relapsed or refractory follicular lymphoma to identify 8. Lynch RC, Paneesha S, Avigdor A, et al. Phase 2 Treatment During the predictors of response [ASH abstract 2047]. Blood. study evaluating the efficacy and safety of parsaclisib 2020;136(suppl 1). COVID-19 Pandemic in patients with relapsed or refractory follicular lym- 22. Proudman D, Nellesen D, Gupta D, et al. phoma (CITADEL-203) [ASH abstract 2935]. Blood. A current concern for patients with Tazemetostat is associated with lower risk for safety 2020;136(suppl 1). follicular lymphoma is how they outcomes versus the PI3-kinases idelalisib, duvelisib 9. Budde E, Gopal AK, Flinn IW, et al. Preliminary and copanlisib, in patients with relapsed/refractory will respond to vaccinations against results of a phase 1 dose escalation study of the first- follicular lymphoma who have received at least 2 prior in-class IgM based bispecific antibody Igm-2323 COVID-19. Unfortunately, patients systemic treatments: a matching-adjusted indirect com- (anti-CD20 × anti-CD3) in patients with advanced with hematologic malignancies treated parison of single-arm trials [ASH abstract 2064]. Blood. B-cell malignancies [ASH abstract 1142]. Blood. 2020;136(suppl 1). with an anti-CD20 antibody had a 2020;136(suppl 1). 23. Patel K, Bailey N, Pagel JM. A phase 2, open-label, 10. Bannerji R, Allan JN, Arnason JE, et al. Odron- low immune response to the virus in multicenter study of tazemetostat in combination with extamab (REGN1979), a human CD20 x CD3 bispe- a study by Dr Alessandra Sottini.27 It rituximab for the treatment of relapsed or refractory cific antibody, induces durable, complete responses in follicular lymphoma [ASH abstract 2952]. Blood. will be necessary to mitigate the risk of patients with highly refractory B-cell non-Hodgkin 2020;136(suppl 1). lymphoma, including patients refractory to CAR T lymphoma progression vs treatment 24. Leonard JP, Batlevi CL, Gabrail N, et al. A phase therapy [ASH abstract 400]. Blood. 2020;136(suppl 1). with anti-CD20 antibodies, especially 1b/3 randomized, double-blind, 3-stage study of taze- 11. Kim TM, Alonso A, Prince M, et al. A phase 2 metostat or placebo plus lenalidomide and rituximab in among patients who will be candidates study of odronextamab (REGN1979), a CD20 x CD3 patients with relapsed/refractory follicular lymphoma bispecific antibody, in patients with relapsed/refractory to receive the vaccine. [ASH abstract 2052]. Blood. 2020;136(suppl 1). B-cell non-Hodgkin lymphoma [ASH abstract 3029]. 25. Strati P, Samaniego F, Gallardo M, et al. Treatment Blood. 2020;136(suppl 1). and outcome of patients with follicular lymphoma Disclosure 12. Hutchings M, Mous R, Clausen MR, et al. Subcu- relapsed or progressed after frontline lenalido- taneous epcoritamab induces complete responses with In the past 12 months, Dr Salles has mide and rituximab [ASH abstract 1128]. Blood. an encouraging safety profile across relapsed/refractory received financial compensation for par- 2020;136(suppl 1). B-cell non-Hodgkin lymphoma subtypes, including 26. Mondello P, Strati P, Merryman RW, et al. R-CHOP ticipating in advisory boards or consult- patients with prior CAR-T therapy: updated dose escala- versus R-bendamustine with or without rituximab tion data [ASH abstract 402]. Blood. 2020;136(suppl 1). ing fees from AbbVie, BeiGene, BMS/ maintenance in newly diagnosed follicular lymphoma 13. Assouline S, Kim WS, Sehn LH, et al. Mosu- Celgene, Debiopharm, , Kite/ patients with high SUV at baseline PET [ASH abstract netuzumab shows promising efficacy in patients with 2041]. Blood. 2020;136(suppl 1). Gilead, Janssen, Miltenyi, MorphoSys, multiply relapsed follicular lymphoma: updated clinical 27. Sottini AS, Imberti L, Paghera S, et al. Impaired experience from a phase I dose-escalation trial [ASH Novartis, Roche, and VelosBio. Dr Salles Sars-Cov-2 specific antibody responses in patients abstract 702]. Blood. 2020;136(suppl 1). has received financial compensation for treated with anti-CD20 antibodies [ASH abstract 14. Jacobson CA, Chavez JC, Sehgal AR, et al. Primary 2040]. Blood. 2020;136(suppl 1). participation in educational events from analysis of ZUMA-5: a phase 2 study of axicabtagene

16 Clinical Advances in Hematology & Oncology Volume 19, Issue 1, Supplement 2 January 2021 Learn more about TAZVERIK for R/R FL and how it performed in a .

Visit TAZVERIK.com today

Tazemetostat (TAZVERIK®) is recommended in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as an option for appropriate patients with relapsed or refractory follicular lymphoma.3

Important Safety Information (continued)

• Embryo-Fetal Toxicity (continued) Administration of tazemetostat to pregnant rats and rabbits during organogenesis resulted in dose-dependent increases in skeletal developmental abnormalities in both species beginning at maternal exposures approximately 1.5 times the adult human exposure (area under the plasma concentration time curve [AUC0-45h]) at the 800 mg twice daily dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAZVERIK and for 6 months after the fi nal dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TAZVERIK and for 3 months after the fi nal dose. Adverse Reactions In 99 clinical study patients with relapsed or refractory follicular lymphoma receiving TAZVERIK 800 mg twice daily: Serious adverse reactions occurred in 30% of patients who received TAZVERIK. Serious adverse reactions occurring in ≥2% were general physical health deterioration, abdominal pain, pneumonia, sepsis, and . The most common (≥20%) adverse reactions were fatigue (36%), upper respiratory tract infection (30%), musculoskeletal pain (22%), nausea (24%), and abdominal pain (20%). Drug Interactions Avoid coadministration of strong or moderate CYP3A inhibitors with TAZVERIK. If coadministration of moderate CYP3A inhibitors cannot be avoided, reduce TAZVERIK dose. Avoid coadministration of moderate and strong CYP3A inducers with TAZVERIK, which may decrease the effi cacy of TAZVERIK. Coadministration of TAZVERIK with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and reduced effi cacy of CYP3A substrates. Lactation Because of the potential risk for serious adverse reactions from TAZVERIK in the breastfed child, advise women not to breastfeed during treatment with TAZVERIK and for one week after the fi nal dose.

Before prescribing TAZVERIK, please read the Brief Summary of the Prescribing Information on the adjacent pages.

EZH2=enhancer of zeste homologue 2; ORR=overall response rate; CI=confi dence interval; CR=complete response; PR=partial response; DOR=duration of response; NE=not estimable; IWG-NHL=International Working Group Non-Hodgkin Lymphoma.

References: 1. TAZVERIK (tazemetostat) Prescribing Information. Cambridge, MA: Epizyme, Inc., July 2020. 2. Data on fi le. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-cell Lymphomas V.4.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed August 17, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

© 2020 Epizyme, Inc. All Rights Reserved. 400 Technology Square, 4th Floor, Cambridge, MA 02139 epizyme.com TZ-FL-BR-20-0133 TAZVERIK (tazemetostat) tablets 200mg BRIEF SUMMARY OF PRESCRIBING CONTRAINDICATIONS - None. INFORMATION Table 6. Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Follicular missing digits, fused vertebrae, domed heads and fused bones of the skull, and reduced WARNINGS AND PRECAUTIONS Lymphoma Who Received TAZVERIK in Cohorts 4 and 5 of Study E7438-G000-101 fetal body weights. In pregnant rabbits, no adverse maternal effects were observed after CONSULT THE PACKAGE INSERT FOR COMPLETE PRESCRIBING INFORMATION. Secondary Malignancies - The risk of developing secondary malignancies is increased (continued) once daily oral administration of 400 mg/kg/day tazemetostat (approximately 7 times the following treatment with TAZVERIK. Across clinical trials of 729 adults who received INDICATIONS AND USAGE aIncludes fatigue and asthenia adult human exposure at the 800 mg twice daily dose) from GD 7 through 19. Skeletal • TAZVERIK® (tazemetostat) is indicated for the treatment of adult patients with TAZVERIK 800 mg twice daily, myelodysplastic syndrome (MDS) or acute myeloid variations were present at doses ≥100 mg/kg/day (approximately 1.5 times the adult human relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 (AML) occurred in 0.7% of patients. One pediatric patient developed T-cell bIncludes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, upper repiratory tract exposure at the 800 mg twice daily dose), with skeletal malformations at ≥200 mg/kg/day mutation as detected by an FDA-approved test and who have received at least 2 prior lymphoblastic lymphoma (T-LBL). Monitor patients long-term for the development of infection, viral upper respiratory tract infection (approximately 5.6 times the adult human exposure at the 800 mg twice daily dose). At 400 systemic therapies. secondary malignancies. cIncludes bronchitis, lower respiratory tract infection, tracheobronchitis mg/kg (approximately 7 times the adult human exposure at the 800 mg twice daily dose), Embryo-Fetal Toxicity - Based on findings from animal studies and its mechanism of major findings included increased post implantation loss and cleft palate and snout. • TAZVERIK is indicated for the treatment of adult patients with relapsed or refractory d follicular lymphoma who have no satisfactory alternative treatment options. action, TAZVERIK can cause fetal harm when administered to pregnant women. There Includes cystitis, urinary tract infection, urinary tract infection staphylococcal Lactation - Risk Summary: There are no animal or human data on the presence of These indications are approved under accelerated approval based on overall response are no available data on TAZVERIK use in pregnant women to inform the drug-associated eIncludes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper tazemetostat in human milk or on its effects on the breastfed child or milk production. risk. Administration of tazemetostat to pregnant rats and rabbits during organogenesis Because of the potential risk for serious adverse reactions from TAZVERIK in the breastfed rate and duration of response [see Clinical Studies]. Continued approval for these f indications may be contingent upon verification and description of clinical benefit in resulted in dose-dependent increases in skeletal developmental abnormalities in both Includes back pain, limb discomfort, musculoskeletal chest pain, musculoskeletal child, advise women not to breastfeed during treatment with TAZVERIK and for one week a confirmatory trial(s). species beginning at maternal exposures approximately 1.5 times the adult human discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, after the final dose. exposure (area under the plasma concentration time curve [AUC0-45h]) at the 800 mg pain in extremity, pain in jaw, spinal pain Females and Males of Reproductive Potential - Pregnancy Testing: Verify the DOSAGE AND ADMINISTRATION twice daily dose. Advise pregnant women of the potential risk to a fetus. Advise females g pregnancy status of females of reproductive potential prior to initiating TAZVERIK [see Use Patient Selection - Select patients with relapsed or refractory (R/R) follicular Includes erythema, rash, rash erythematous, rash generalized, rash maculo-papular, of reproductive potential to use effective contraception during treatment with TAZVERIK rash pruritic, rash pustular, skin exfoliation in Specific Populations]. Risk Summary: TAZVERIK can cause fetal harm when administered lymphoma (FL) for treatment with TAZVERIK based on the presence of EZH2 mutation and for 6 months after the final dose. Advise males with female partners of reproductive h to pregnant women [see Use in Specific Populations]. Contraception: Females - Advise of codons Y646, A682, or A692 in tumor specimens [see Clinical Studies]. Information potential to use effective contraception during treatment with TAZVERIK and for 3 months Includes cough and productive cough females of reproductive potential to use effective non-hormonal contraception during on FDA-approved tests for the detection of EZH2 mutation in relapsed or refractory after the final dose[see Use in Specific Populations]. iIncludes headache, migraine, sinus headache treatment with TAZVERIK and for 6 months after the final dose. TAZVERIK can render some follicular lymphoma is available at: http://www.fda.gov/CompanionDiagnostics. hormonal contraceptives ineffective [see Drug Interactions]. Males - Advise males with Recommended Dosage - The recommended dosage of TAZVERIK is 800 mg orally ADVERSE REACTIONS - The following clinically significant adverse reactions are Clinically relevant adverse reactions occurring in <10% of patients who received described elsewhere in labeling: Secondary Malignancies [see Warnings and Precautions]. female partners of reproductive potential to use effective contraception during treatment twice daily with or without food until disease progression or unacceptable toxicity. TAZVERIK included: with TAZVERIK and for at least 3 months after the final dose. Swallow tablets whole. Do not cut, crush, or chew tablets. Do not take an additional Clinical Trial Experience - Because clinical trials are conducted under widely varying • Infection: sepsis (2%), pneumonia (2%), and herpes zoster (2%) conditions, adverse reaction rates observed in the clinical trials of a drug cannot be Pediatric Use - The safety and effectiveness of TAZVERIK in pediatric patients aged less dose if a dose is missed or vomiting occurs after TAZVERIK, but continue with the next Table 7 summarizes select laboratory abnormalities in patients with follicular lymphoma than 16 years have not been established. scheduled dose. directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of TAZVERIK was evaluated in two cohorts (Cohorts in Cohorts 4 and 5 of Study E7438-G000-101. Juvenile Animal Toxicity Data - In a 13-week juvenile rat toxicology study, animals were Dosage Modifications for Adverse Reactions - Table 1 summarizes the recommended dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to dose reductions, and Table 2 summarizes the recommended dosage modifications of 4 and 5) of Study E7438-G000-101 that enrolled patients with relapsed or refractory Table 7. Select Laboratory Abnormalities (≥10%) Worsening from Baseline follicular lymphoma [see Clinical Studies]. Patients received TAZVERIK 800 mg orally twice adulthood). Tazemetostat resulted in: TAZVERIK for adverse reactions. in Patients with Relapsed or Refractory Follicular Lymphoma Who Received • T-LBL at doses ≥50 mg/kg (approximately 2.8 times the adult human exposure at the daily (n=99). Among patients who received TAZVERIK, 68% were exposed for 6 months TAZVERIK in Cohorts 4 and 5 of Study E7438-G000-101 Table 1. Recommended Dose Reductions of TAZVERIK for Adverse Reactions or longer, 39% were exposed for 12 months or longer, and 21% were exposed for 18 800 mg twice daily dose) months or longer. The median age was 62 years (range 36 to 87 years), 54% were male, TAZVERIK* • Increased trabecular bone at doses ≥100 mg/kg (approximately 10 times the adult Dose Reduction Dosage Laboratory Abnormality human exposure at the 800 mg twice daily dose) and 95% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. All Grades (%) Grade 3 or 4 (%) First 600 mg orally twice daily The median number of prior therapies was 3 (range 1 to 11). Patients were required have • Increased body weight at doses ≥50 mg/kg (approximately equal to the adult human a creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula. Serious adverse Hematology exposure at the 800 mg twice daily dose) Second 400 mg orally twice daily* • Distended in males at doses ≥50 mg/kg (approximately equal to the adult reactions occurred in 30% of patients who received TAZVERIK. Serious adverse reactions Decreased 57 18 *Permanently discontinue TAZVERIK in patients who are unable to tolerate 400 mg orally in ≥2% of patients who received TAZVERIK were general physical health deterioration, human exposure at the 800 mg twice daily dose) twice daily. abdominal pain, pneumonia, sepsis, and anemia. Permanent discontinuation due Decreased hemoglobin 50 8 Geriatric Use - Clinical studies of TAZVERIK did not include sufficient numbers of patients with relapsed or refactory follicular lymphoma aged 65 and over to determine whether they Table 2. Recommended Dosage Modifications of TAZVERIK for Adverse Reactions to an adverse reaction occurred in 8% of patients who received TAZVERIK. Adverse Decreased platelets 50 7 reaction resulting in permanent discontinuation in ≥2% of patients was second primary respond differently from younger subjects. Decreased white blood cells 41 9 Renal Impairment - No dose adjustment of TAZVERIK is recommended for patients with Adverse Reaction Severity Dosage Modification malignancy. Dosage interruptions due to an adverse reaction occurred in 28% of patients who received TAZVERIK. Adverse reactions requiring dosage interruptions in ≥3% of Decreased neutrophils 20 7 mild to severe renal impairment or end stage renal disease [see Clinical Pharmacology]. Neutropenia [see Neutrophil • Withhold until neutrophil count is greater patients were thrombocytopenia and fatigue. Dose reduction due to an adverse reaction Hepatic Impairment - No dose adjustment of TAZVERIK is recommended for patients Adverse Reactions] count less than or equal to 1 x 109/L or baseline. Chemistry with mild hepatic impairment (total bilirubin > 1 to 1.5 times upper limit of normal [ULN] 9 occurred in 9% of patients who received TAZVERIK. The most common adverse reactions than 1 x 10 /L • For first occurrence, resume at same dose. (≥20%) were fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and Increased glucose 53 10 or AST > ULN). TAZVERIK has not been studied in patients with moderate (total bilirubin • For second and third occurrence, resume > 1.5 to 3 times ULN) or severe (total bilirubin > 3 times ULN) hepatic impairment [see abdominal pain. Table 6 presents adverse reactions in patients with relapsed or refractory Increased aspartate aminotransferase 24 0 at reduced dose. follicular lymphoma in Cohorts 4 and 5 of Study E7438-G000-101. Clinical Pharmacology]. • Permanently discontinue after fourth Increased alanine aminotransferase 21 2.3 NONCLINICAL TOXICOLOGY occurrence. Table 6. Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Follicular Lymphoma Who Received TAZVERIK in Cohorts 4 and 5 of Study E7438-G000-101 Increased alkaline phosphatase 18 1.0 Carcinogenesis, Mutagenesis, Impairment of Fertility - Dedicated carcinogenicity Thrombocytopenia Platelet count • Withhold until platelet count is greater studies were not conducted with tazemetostat, but T-LBL, MDS, and AML have been Increased creatinine 17 0 [see Adverse less than than or equal to 75 x 109/L or baseline. reported clinically and T-LBL occurred in juvenile and adult rats after ~9 or more weeks of Reactions] 50 x 109/L • For first and second occurrence, resume TAZVERIK N=99 * The denominator used to calculate the rate varied from 88 to 96 based on the number tazemetostat administration during 13-week toxicity studies. Based on nonclinical studies at reduced dose. Adverse Reaction of patients with a baseline value and at least one post-treatment value. in rats, the risk of T-LBL appears to be greater with longer duration dosing. Tazemetostat did • Permanently discontinue after third All Grades (%) Grade 3 or 4 (%) not cause genetic damage in a standard battery of studies including a screening and pivotal DRUG INTERACTIONS bacterial reverse mutation (Ames) assay, an in vitro micronucleus assessment in human occurrence. General Effect of Other Drugs on TAZVERIK - Strong and Moderate CYP3A Inhibitors: peripheral blood lymphocytes, and an in vivo micronucleus assessment in rats after oral Anemia Hemoglobin • Withhold until improvement to at least a Coadministration of TAZVERIK with a strong or moderate CYP3A inhibitor increases Fatigue 36 5 administration. Fertility and early embryonic development studies have not been conducted less than Grade 1 or baseline, then resume at tazemetostat plasma concentrations , which may increase the [see Adverse [see Clinical Pharmacology] with tazemetostat; however, an assessment of male and female reproductive organs were 8 g/dL same or reduced dose. Pyrexia 10 0 frequency or severity of adverse reactions. Avoid coadministration of strong or moderate Reactions] included in 4- and 13-week repeat-dose toxicity studies in rats and Cynomolgus monkeys. CYP3A inhibitors with TAZVERIK. If coadministration of moderate CYP3A inhibitors cannot Other adverse Grade 3 • Withhold until improvement to at least Infections Oral daily administration of tazemetostat did not result in any notable effects in the adult be avoided, reduce TAZVERIK dose [see Dosage and Administration]. Strong and Moderate b male and female reproductive organs . reactions Grade 1 or baseline. Upper respiratory tract infection 30 0 CYP3A Inducers: Coadministration of TAZVERIK with a strong or moderate CYP3A inducer [see Use in Specific Populations] • For first and second occurrence, resume [see Adverse Lower respiratory tract infectionc 17 0 may decrease tazemetostat plasma concentrations [see Clinical Pharmacology], which PATIENT COUNSELING INFORMATION - Advise the patient to read the FDA-approved Reactions] at reduced dose. may decrease the efficacy of TAZVERIK. Avoid coadministration of moderate and strong patient labeling (Medication Guide). Urinary tract infectiond 11 2 • Permanently discontinue after third CYP3A inducers with TAZVERIK. Secondary Malignancies - Advise patients of the increased risk of secondary malignancies, occurrence. Gastrointestinal Effect of TAZVERIK on Other Drugs - CYP3A Substrates: Coadministration of TAZVERIK including AML, MDS, and T-LBL. Advise patients to inform their healthcare provider if they Grade 4 • Withhold until improvement to at least Nausea 24 1 with CYP3A substrates, including hormonal contraceptives, can result in decreased experience fatigue, easy bruising, , bone pain, or paleness [see Warnings and Precautions]. Grade 1 or baseline. concentrations and reduced efficacy of CYP3A substrates[see Use in Specific Populations, Embryo-Fetal Toxicity - Advise pregnant women and females of reproductive potential of • For first occurrence, resume at Abdominal paine 20 3 Clinical Pharmacology]. the potential risk to a fetus. Advise females to inform their healthcare provider of a known reduced dose. Diarrhea 18 0 or suspected pregnancy [see Use in Specific Populations]. Advise females of reproductive USE IN SPECIFIC POPULATIONS potential to use effective non-hormonal contraception during treatment with TAZVERIK • Permanently discontinue after second Pregnancy - Risk Summary: Based on findings from animal studies and its mechanism Vomiting 12 1 and for 6 months after the final dose . Advise males with occurrence. of action , TAZVERIK can cause fetal harm when administered [see Use in Specific Populations] [see Clinical Pharmacology] female partners of reproductive potential to use effective contraception during treatment Musculoskeletal and connective tissue to pregnant women. There are no available data on TAZVERIK use in pregnant women to with TAZVERIK and for 3 months after the final dose Dosage Modifications for Drug Interactions f inform the drug-associated risk. Administration of tazemetostat to pregnant rats and rabbits [see Use in Specific Populations, Musculoskeletal pain 22 1 . Strong and Moderate CYP3A Inhibitors - Avoid coadministration of TAZVERIK with strong during organogenesis resulted in dose-dependent increases in skeletal developmental Nonclinical Toxicology] Lactation - Advise women not to breastfeed during treatment with TAZVERIK and for or moderate CYP3A inhibitors. If coadministration with a moderate CYP3A inhibitor cannot Skin and subcutaneous tissue abnormalities in both species beginning at maternal exposures approximately 1.5 times 1 week after the final dose[see Use in Special Populations]. be avoided, reduce the TAZVERIK dose as shown in Table 3 below. After discontinuation of Alopecia 17 0 the adult human exposure [AUC0-45h] at the 800 mg twice daily dose . Advise (see Data) Drug Interactions - Advise patients and caregivers to inform their healthcare provider of the moderate CYP3A inhibitor for 3 elimination half-lives, resume the TAZVERIK dose that g pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated Rash 15 0 all concomitant medications, including prescription medicines, over-the-counter drugs, was taken prior to initiating the inhibitor [see Drug Interactions, Clinical Pharmacology]. background risk of major birth defects and in clinically recognized pregnancies vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit, and Respiratory and mediastinal system is 2% to 4% and 15% to 20%, respectively. Table 3. Recommended Dose Reductions of TAZVERIK for Moderate CYP3A Inhibitors grapefruit juice while taking TAZVERIK [see Drug Interactions]. Coughh 17 0 Data - Animal Data: In pregnant rats, once daily oral administration of tazemetostat during Current Dosage Adjusted Dosage the period of organogenesis from gestation day (GD) 7 through 17 resulted in no maternal 800 mg orally twice daily 400 mg orally twice daily Nervous system adverse effects at doses up to 100 mg/kg/day (approximately 6 times the adult human i exposure at 800 mg twice daily). Skeletal malformations and variations occurred in fetuses Brief Summary [07/2020] 400 mg for first dose and 200 mg Headache 13 0 600 mg orally twice daily at doses of ≥50 mg/kg (approximately 2 times the adult human exposure at the 800 mg TZ-FL-BR-20-0133 for second dose Table 6 continues on the next page twice daily dose). At 200 mg/kg (approximately 14 times the adult human exposure at Rx Only 400 mg orally twice daily 200 mg orally twice daily the 800 mg twice daily dose), major findings included increased post implantation loss, © 2020 Epizyme®, Inc. All Rights Reserved. Table 6. Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Follicular missing digits, fused vertebrae, domed heads and fused bones of the skull, and reduced Lymphoma Who Received TAZVERIK in Cohorts 4 and 5 of Study E7438-G000-101 fetal body weights. In pregnant rabbits, no adverse maternal effects were observed after (continued) once daily oral administration of 400 mg/kg/day tazemetostat (approximately 7 times the aIncludes fatigue and asthenia adult human exposure at the 800 mg twice daily dose) from GD 7 through 19. Skeletal variations were present at doses ≥100 mg/kg/day (approximately 1.5 times the adult human bIncludes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, upper repiratory tract exposure at the 800 mg twice daily dose), with skeletal malformations at ≥200 mg/kg/day infection, viral upper respiratory tract infection (approximately 5.6 times the adult human exposure at the 800 mg twice daily dose). At 400 cIncludes bronchitis, lower respiratory tract infection, tracheobronchitis mg/kg (approximately 7 times the adult human exposure at the 800 mg twice daily dose), major findings included increased post implantation loss and cleft palate and snout. dIncludes cystitis, urinary tract infection, urinary tract infection staphylococcal Lactation - Risk Summary: There are no animal or human data on the presence of eIncludes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper tazemetostat in human milk or on its effects on the breastfed child or milk production. Because of the potential risk for serious adverse reactions from TAZVERIK in the breastfed fIncludes back pain, limb discomfort, musculoskeletal chest pain, musculoskeletal child, advise women not to breastfeed during treatment with TAZVERIK and for one week discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, after the final dose. pain in extremity, pain in jaw, spinal pain Females and Males of Reproductive Potential - Pregnancy Testing: Verify the gIncludes erythema, rash, rash erythematous, rash generalized, rash maculo-papular, pregnancy status of females of reproductive potential prior to initiating TAZVERIK [see Use rash pruritic, rash pustular, skin exfoliation in Specific Populations]. Risk Summary: TAZVERIK can cause fetal harm when administered h to pregnant women [see Use in Specific Populations]. Contraception: Females - Advise Includes cough and productive cough females of reproductive potential to use effective non-hormonal contraception during iIncludes headache, migraine, sinus headache treatment with TAZVERIK and for 6 months after the final dose. TAZVERIK can render some hormonal contraceptives ineffective [see Drug Interactions]. Males - Advise males with Clinically relevant adverse reactions occurring in <10% of patients who received female partners of reproductive potential to use effective contraception during treatment TAZVERIK included: with TAZVERIK and for at least 3 months after the final dose. • Infection: sepsis (2%), pneumonia (2%), and herpes zoster (2%) Pediatric Use - The safety and effectiveness of TAZVERIK in pediatric patients aged less Table 7 summarizes select laboratory abnormalities in patients with follicular lymphoma than 16 years have not been established. in Cohorts 4 and 5 of Study E7438-G000-101. Juvenile Animal Toxicity Data - In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to Table 7. Select Laboratory Abnormalities (≥10%) Worsening from Baseline adulthood). Tazemetostat resulted in: in Patients with Relapsed or Refractory Follicular Lymphoma Who Received • T-LBL at doses ≥50 mg/kg (approximately 2.8 times the adult human exposure at the TAZVERIK in Cohorts 4 and 5 of Study E7438-G000-101 800 mg twice daily dose) TAZVERIK* • Increased trabecular bone at doses ≥100 mg/kg (approximately 10 times the adult Laboratory Abnormality human exposure at the 800 mg twice daily dose) All Grades (%) Grade 3 or 4 (%) • Increased body weight at doses ≥50 mg/kg (approximately equal to the adult human Hematology exposure at the 800 mg twice daily dose) • Distended testicles in males at doses ≥50 mg/kg (approximately equal to the adult Decreased lymphocytes 57 18 human exposure at the 800 mg twice daily dose) Decreased hemoglobin 50 8 Geriatric Use - Clinical studies of TAZVERIK did not include sufficient numbers of patients with relapsed or refactory follicular lymphoma aged 65 and over to determine whether they Decreased platelets 50 7 respond differently from younger subjects. Decreased white blood cells 41 9 Renal Impairment - No dose adjustment of TAZVERIK is recommended for patients with Decreased neutrophils 20 7 mild to severe renal impairment or end stage renal disease [see Clinical Pharmacology]. Hepatic Impairment - No dose adjustment of TAZVERIK is recommended for patients Chemistry with mild hepatic impairment (total bilirubin > 1 to 1.5 times upper limit of normal [ULN] Increased glucose 53 10 or AST > ULN). TAZVERIK has not been studied in patients with moderate (total bilirubin > 1.5 to 3 times ULN) or severe (total bilirubin > 3 times ULN) hepatic impairment [see Increased aspartate aminotransferase 24 0 Clinical Pharmacology]. Increased alanine aminotransferase 21 2.3 NONCLINICAL TOXICOLOGY Increased alkaline phosphatase 18 1.0 Carcinogenesis, Mutagenesis, Impairment of Fertility - Dedicated carcinogenicity studies were not conducted with tazemetostat, but T-LBL, MDS, and AML have been Increased creatinine 17 0 reported clinically and T-LBL occurred in juvenile and adult rats after ~9 or more weeks of * The denominator used to calculate the rate varied from 88 to 96 based on the number tazemetostat administration during 13-week toxicity studies. Based on nonclinical studies of patients with a baseline value and at least one post-treatment value. in rats, the risk of T-LBL appears to be greater with longer duration dosing. Tazemetostat did not cause genetic damage in a standard battery of studies including a screening and pivotal DRUG INTERACTIONS bacterial reverse mutation (Ames) assay, an in vitro micronucleus assessment in human Effect of Other Drugs on TAZVERIK - Strong and Moderate CYP3A Inhibitors: peripheral blood lymphocytes, and an in vivo micronucleus assessment in rats after oral Coadministration of TAZVERIK with a strong or moderate CYP3A inhibitor increases administration. Fertility and early embryonic development studies have not been conducted tazemetostat plasma concentrations , which may increase the [see Clinical Pharmacology] with tazemetostat; however, an assessment of male and female reproductive organs were frequency or severity of adverse reactions. Avoid coadministration of strong or moderate included in 4- and 13-week repeat-dose toxicity studies in rats and Cynomolgus monkeys. CYP3A inhibitors with TAZVERIK. If coadministration of moderate CYP3A inhibitors cannot Oral daily administration of tazemetostat did not result in any notable effects in the adult be avoided, reduce TAZVERIK dose . Strong and Moderate [see Dosage and Administration] male and female reproductive organs . CYP3A Inducers: Coadministration of TAZVERIK with a strong or moderate CYP3A inducer [see Use in Specific Populations] may decrease tazemetostat plasma concentrations [see Clinical Pharmacology], which PATIENT COUNSELING INFORMATION - Advise the patient to read the FDA-approved may decrease the efficacy of TAZVERIK. Avoid coadministration of moderate and strong patient labeling (Medication Guide). CYP3A inducers with TAZVERIK. Secondary Malignancies - Advise patients of the increased risk of secondary malignancies, Effect of TAZVERIK on Other Drugs - CYP3A Substrates: Coadministration of TAZVERIK including AML, MDS, and T-LBL. Advise patients to inform their healthcare provider if they with CYP3A substrates, including hormonal contraceptives, can result in decreased experience fatigue, easy bruising, fever, bone pain, or paleness [see Warnings and Precautions]. concentrations and reduced efficacy of CYP3A substrates[see Use in Specific Populations, Embryo-Fetal Toxicity - Advise pregnant women and females of reproductive potential of Clinical Pharmacology]. the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations]. Advise females of reproductive USE IN SPECIFIC POPULATIONS potential to use effective non-hormonal contraception during treatment with TAZVERIK Pregnancy - Risk Summary: Based on findings from animal studies and its mechanism and for 6 months after the final dose . Advise males with of action , TAZVERIK can cause fetal harm when administered [see Use in Specific Populations] [see Clinical Pharmacology] female partners of reproductive potential to use effective contraception during treatment to pregnant women. There are no available data on TAZVERIK use in pregnant women to with TAZVERIK and for 3 months after the final dose inform the drug-associated risk. Administration of tazemetostat to pregnant rats and rabbits [see Use in Specific Populations, . during organogenesis resulted in dose-dependent increases in skeletal developmental Nonclinical Toxicology] Lactation - Advise women not to breastfeed during treatment with TAZVERIK and for abnormalities in both species beginning at maternal exposures approximately 1.5 times 1 week after the final dose[see Use in Special Populations]. the adult human exposure [AUC0-45h] at the 800 mg twice daily dose . Advise (see Data) Drug Interactions - Advise patients and caregivers to inform their healthcare provider of pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated all concomitant medications, including prescription medicines, over-the-counter drugs, background risk of major birth defects and miscarriage in clinically recognized pregnancies vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit, and is 2% to 4% and 15% to 20%, respectively. grapefruit juice while taking TAZVERIK . Data - Animal Data: In pregnant rats, once daily oral administration of tazemetostat during [see Drug Interactions] the period of organogenesis from gestation day (GD) 7 through 17 resulted in no maternal adverse effects at doses up to 100 mg/kg/day (approximately 6 times the adult human exposure at 800 mg twice daily). Skeletal malformations and variations occurred in fetuses Brief Summary [07/2020] at doses of ≥50 mg/kg (approximately 2 times the adult human exposure at the 800 mg TZ-FL-BR-20-0133 twice daily dose). At 200 mg/kg (approximately 14 times the adult human exposure at Rx Only the 800 mg twice daily dose), major findings included increased post implantation loss, © 2020 Epizyme®, Inc. All Rights Reserved. UNSILENCE AN EXPRESSIVE INSTRUMENT

TAZVERIK® (tazemetostat) is indicated for the treatment of: • Adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least 2 prior systemic therapies. • Adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options. TAZVERIK, the first and only These indications are approved under accelerated approval based FDA-approved EZH2 inhibitor on overall response rate and duration of response. Continued for relapsed or refractory (R/R) approval for these indications may be contingent upon verifi cation follicular lymphoma (FL)1 and description of clinical benefi t in a confi rmatory trial(s).

Effi cacy results*: • FL patients (N=95) responded to single-agent • Sustained response demonstrated in patients TAZVERIK in both cohorts1,2 with both MT and WT EZH2 1,2

12% CR 4% CR (n=5/42) (n=2/53)

% % 10.9 13.0 69 34 months months ORR ORR median DOR median DOR

30% PR 57% PR (n=16/53) (n=24/42) (range: 0.0+ to 22.1+) (range: 1.0 to 22.5+) in patients with MT EZH2 in patients with WT EZH2 in patients in patients (n=29/42; 95% CI: 7.2–NE) (n=18/53; 95% CI: 5.6–NE) with mutant-type (MT) EZH2 with wild-type (WT) EZH2 (n=29/42; 95% CI: 53%–82%) (n=18/53; 95% CI: 22%–48%) The data for the MT EZH2 cohort were not yet mature at the time of assessment.

*TAZVERIK was studied in an open-label, single-arm, multicenter, phase 2 trial with 6 cohorts of patients, including 2 cohorts with histologically-confi rmed R/R FL. Patients received 800 mg of TAZVERIK orally twice daily until confi rmed disease progression or unacceptable toxicity. The major effi cacy outcome measures were ORR and DOR according to the IWG-NHL criteria as assessed by independent review committee.1,2

Important Safety Information Warnings and Precautions • Secondary Malignancies The risk of developing secondary malignancies is increased following treatment with TAZVERIK. Across clinical trials of 729 adults who received TAZVERIK 800 mg twice daily, myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) occurred in 0.7% of patients. One pediatric patient developed T-cell lymphoblastic lymphoma (T-LBL). Monitor patients long-term for the development of secondary malignancies. • Embryo-Fetal Toxicity Based on fi ndings from animal studies and its mechanism of action, TAZVERIK can cause fetal harm when administered to pregnant women. There are no available data on TAZVERIK use in pregnant women to inform the drug-associated risk.

Important Safety Information continued on back page of this insert. Please see Brief Summary of the Prescribing Information on the adjacent pages.

*EPZM20TAZ016 - TAZVERIK Media - fi les for ASH Meeting Reporter SAKS Health Inc.

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