Interim Analysis of the Randomized Phase 1b/3 Study Evaluating the Safety and Efficacy of Tazemetostat Plus Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma
Authors: Batlevi Connie Lee , Park Steven I. , Nastoupil Loretta , Phillips Tycel , Amengual Jennifer E. , Andorsky David , Campbell Philip , McKay Pamela , Pagel John M. , Leonard John P. , Yang Jay , O'Connor Heather , Hamlett Anthony , Adib Deyaa , Morschhauser Franck 
Published: November 2021

Abstract

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 inhibitor, showed antitumor activity as monotherapy in patients with wild-type and mutant EZH2 relapsed or refractory (R/R) follicular lymphoma (FL) who received ≥2 prior lines of therapy. In clinical studies in patients with R/R FL, lenalidomide and rituximab (R 2) demonstrated an objective response rate (ORR) of 73%-78% and median progression-free survival of 36-39 months. Preclinical data demonstrated synergistic activity of TAZ + lenalidomide, and clinical experience with TAZ + rituximab in diffuse large B-cell lymphoma supports the combination of TAZ + R 2 in patients with R/R FL. This global, multicenter phase 1b/3 study (NCT04224493) is designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + R 2 in patients with R/R FL after ≥1 prior therapy. We report an interim analysis of the phase 1b safety run-in.
Methods: The methods of this randomized, double-blind, 3-stage study were previously described (Leonard JP, et al. ASH 2020). Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R 2 using a 3+3 design. The RP3D of TAZ will be selected at the dose level with a target dose-limiting toxicity (DLT; NCI CTCAE v5) rate of &lt;33%. Preliminary efficacy analysis was performed on the intent-to-treat population and reported as best overall response per investigator assessment according to Lugano 2014 response criteria.
Results: As of February 26, 2021, 15 patients were enrolled and receiving treatment with TAZ + R 2 (400 mg [n=4], 600 mg [n=4], and 800 mg [n=6]). Data for the 15th patient enrolled at 800 mg BID were not available as of the cutoff date; thus, this patient is not included in the current safety analysis. The 14 patients included had a median age of 65.5 years (range, 51-83) and received a median of 2 prior therapies (range, 1-5). Median duration of treatment exposure was 16.9 weeks (range, 8-28); dose modifications for treatment-emergent adverse events (TEAEs) are shown in the Table. No DLTs were observed in phase 1b, and no new safety signals were identified as of the February 2021 data cutoff. A summary of TEAEs is provided in the Table. Serious TEAEs were observed in 3 (21.4%) patients. Grade 3/4 TEAEs were observed in 7 (50.0%) patients; the most common grade 3/4 TEAE (≥20%) was decreased neutrophil count (21.4%). Febrile neutropenia and severe cytopenias have not been reported to date. Treatment-related TEAEs (TR-TEAEs) of any grade were observed in 12 (85.7%) patients; grade 3/4 TR-TEAEs were observed in 5 (35.7%) patients. The TR-TEAEs were attributable to either study agent. Of the 12 patients evaluable for tumor assessment, 5 (41.7%) had a complete response, 6 (50.0%) had a partial response, and 1 (8.3%) had stable disease. The ORR was 91.7% (n=11).
Conclusions: The TAZ + R 2 combination demonstrates a favorable safety profile that is consistent with the respective safety information for TAZ and for R 2. The high response rates reported from the preliminary efficacy analysis support a benefit with the combination of TAZ + R 2. The randomized phase 3 portion will further explore the efficacy and safety of TAZ + R 2 in ~500 patients with R/R FL.
Figure 1 Figure 1.

Disclosures
Batlevi: Dava Oncology: Honoraria; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; Medscape: Honoraria; TouchIME: Honoraria; Bayer: Research Funding; BMS: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Park: Seattle Genetics: Research Funding, Speakers Bureau; Takeda: Research Funding; Gilead: Speakers Bureau; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Morphosys: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nastoupil: MorphoSys: Honoraria; Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Takeda: Honoraria, Other: DSMC, Research Funding; Genentech: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Pfizer: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; IGM Biosciences: Research Funding; Denovo Pharma: Other: DSMC; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Phillips: ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Amengual: Daiichi Sankyo, Inc: Consultancy; Epizyme, Inc.: Speakers Bureau; Seagen: Consultancy; Appia Pharmaceuticals: Research Funding. Andorsky: AbbVie: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding; AstraZeneca: Other: served on steering committees; AbbVie: Consultancy. Campbell: Novartis: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; CSL Behring: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Research Funding; BMS/Celgene: Research Funding. McKay: Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pagel: Epizyme: Consultancy; BeiGene: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Actinium Pharmaceuticals: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Yang: Epizyme, Inc.: Current Employment, Other: May own stock/options. O'Connor: Epizyme, Inc.: Current Employment, Other: May own stock/options . Hamlett: Epizyme: Current Employment. Adib: Epizyme, Inc.: Consultancy. Morschhauser: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Chugai: Honoraria; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy.

OffLabel Disclosure:
Tazemetostat is not approved in combination with other therapies.