ns [see clinical pharmacology ( 12.3 )] , which may decrease the efficacy of tazverik. avoid coadministration of moderate and strong cyp3a inducers with tazverik. 7.2 effect of tazverik on other drugs cyp3a substrates coadministration of tazverik with cyp3a substrates, including hormonal contraceptives, can result in decreased concentrations and reduced efficacy of cyp3a substrates [see use in specific populations ( 8.3 ), clinical pharmacology ( 12.3 )] .

anced epithelioid sarcoma not eligible for complete resection. this indication is approved under accelerated approval based on overall response rate and duration of response [see clinical studies ( 14.1 )]. continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 1.2 relapsed or refractory follicular lymphoma tazverik is indicated for the treatment of adult patients with relapsed or refractory (r/r) follicular lymphoma (fl) 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. tazverik is indicated for the treatment of adult patients with r/r fl who have no satisfactory alternative treatment options. these indications are approved under accelerated approval based on overall response rate and duration of response [see clinical studies ( 14.2 )]. continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

arm when administered to pregnant women. there are no available data on tazverik use in pregnant women to inform the drug-associated risk. 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 [auc 0-45h ]) 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 final dose. advise males with female partners of reproductive potential to use effective contraception during treatment with tazverik and for 3 months after the final dose [see use in specific populations ( 8.1 , 8.3 )] .

rik for adverse reactions. table 1. recommended dose reductions of tazverik for adverse reactions *permanently discontinue tazverik in patients who are unable to tolerate 400 mg orally twice daily. dose reduction dosage first 600 mg orally twice daily second 400 mg orally twice daily* table 2. recommended dosage modifications of tazverik for adverse reactions adverse reaction severity dosage modification neutropenia [see adverse reactions ( 6.1 )] neutrophil count less than 1 × 10 9 /l withhold until neutrophil count is greater than or equal to 1 × 10 9 /l or baseline. for first occurrence, resume at same dose. for second and third occurrence, resume at reduced dose. permanently discontinue after fourth occurrence. thrombocytopenia [see adverse reactions ( 6.1 )] platelet count less than 50 × 10 9 /l withhold until platelet count is greater than or equal to 75 × 10 9 /l or baseline. for first and second occurrence, resume at reduced dose. permanently discontinue after third occurrence. anemia [see adverse reactions ( 6.1 )] hemoglobin less than 8 g/dl withhold until improvement to at least grade 1 or baseline, then resume at same or reduced dose. other adverse reactions [see adverse reactions ( 6.1 )] grade 3 withhold until improvement to at least grade 1 or baseline. for first and second occurrence, resume at reduced dose. permanently discontinue after third occurrence. grade 4 withhold until improvement to at least grade 1 or baseline. for first occurrence, resume at reduced dose. permanently discontinue after second occurrence. 2.4 dosage modifications for drug interactions strong and moderate cyp3a inhibitors avoid coadministration of tazverik with strong or moderate cyp3a inhibitors. if coadministration with a moderate cyp3a inhibitor cannot be avoided, reduce the tazverik dose as shown in table 3 below. after discontinuation of the moderate cyp3a inhibitor for 3 elimination half-lives, resume the tazverik dose that was taken prior to initiating the inhibitor [see drug interactions ( 7.1 ), clinical pharmacology ( 12.3 )] . table 3. recommended dose reductions of tazverik for moderate cyp3a inhibitors current dosage adjusted dosage 800 mg orally twice daily 400 mg orally twice daily 600 mg orally twice daily 400 mg for first dose and 200 mg for second dose 400 mg orally twice daily 200 mg orally twice daily

uated in a cohort (cohort 5) of study ezh-202 that enrolled patients with epithelioid sarcoma [see clinical studies ( 14.1 )]. patients received tazverik 800 mg orally twice daily (n=62). among patients who received tazverik, 44% were exposed for 6 months or longer and 24% were exposed for greater than one year. serious adverse reactions occurred in 37% of patients who received tazverik. serious adverse reactions in ≥3% of patients who received tazverik were hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress. one patient (2%) permanently discontinued tazverik due to an adverse reaction of altered mood. dosage interruptions due to an adverse reaction occurred in 34% of patients who received tazverik. the most frequent adverse reactions requiring dosage interruptions in ≥3% were hemorrhage, increased alanine aminotransferase (alt), and increased aspartate aminotransferase (ast). dose reduction due to an adverse reaction occurred in one (2%) patient who received tazverik; the dose was reduced in this patient for decreased appetite. the most common adverse reactions (≥20%) were pain, fatigue, nausea, decreased appetite, vomiting, and constipation. table 4 presents adverse reactions in patients with epithelioid sarcoma in cohort 5 of study ezh-202. table 4. adverse reactions (≥10%) in patients with epithelioid sarcoma who received tazverik in cohort 5 of study ezh-202 adverse reaction tazverik n=62 all grades (%) grade 3 or 4 (%) a includes tumor pain, pain in extremity, non-cardiac chest pain, flank pain, back pain, arthralgia, bone pain, cancer pain, musculoskeletal pain, myalgia, neck pain b includes fatigue and asthenia c includes abdominal pain, gastrointestinal pain, abdominal pain lower d includes dyspnea and dyspnea exertional e includes wound hemorrhage, rectal hemorrhage, pulmonary hemorrhage, hemorrhage intracranial, cerebral hemorrhage, hemoptysis general pain a 52 7 fatigue b 47 1.6 gastrointestinal nausea 36 0 vomiting 24 0 constipation 21 0 diarrhea 16 0 abdominal pain c 13 1.6 metabolism and nutrition decreased appetite 26 4.8 respiratory, thoracic and mediastinal cough 18 0 dyspnea d 16 4.8 vascular hemorrhage e 18 4.8 nervous system headache 18 0 investigations weight decreased 16 7 table 5 summarizes select laboratory abnormalities in patients with epithelioid sarcoma in cohort 5 of study ezh-202. table 5. select laboratory abnormalities (≥ 10%) worsening from baseline in patients with epithelioid sarcoma who received tazverik in cohort 5 of study ezh-202 *the denominator used to calculate the rate varied from 39 to 61 based on the number of patients with a baseline value and at least one post-treatment value. laboratory abnormality tazverik* all grades (%) grade 3 or 4 (%) hematology decreased hemoglobin 49 15 decreased lymphocytes 36 13 decreased white blood cell count 19 0 chemistry increased triglycerides 36 3.3 increased glucose 33 1.6 decreased sodium 30 1.7 decreased phosphate 28 1.7 decreased albumin 23 0 increased alkaline phosphatase 23 1.7 decreased potassium 20 1.7 increased aspartate aminotransferase 18 3.5 decreased calcium 16 0 decreased glucose 16 0 increased partial thromboplastin time 15 5 increased alanine aminotransferase 14 3.4 increased creatinine 12 0 increased potassium 12 0 relapsed or refractory follicular lymphoma the safety of tazverik was evaluated in two cohorts (cohorts 4 and 5) of study e7438-g000-101 that enrolled patients with relapsed or refractory follicular lymphoma [see clinical studies ( 14.2 )]. patients received tazverik 800 mg orally twice daily (n=99). among patients who received tazverik, 68% were exposed for 6 months or longer, 39% were exposed for 12 months or longer, and 21% were exposed for 18 months or longer. the median age was 62 years (range 36 to 87 years), 54% were male, and 95% had an eastern cooperative oncology group (ecog) performance status of 0-1. the median number of prior therapies was 3 (range 1 to 11). patients were required have a creatinine clearance ≥40 ml/min per the cockcroft and gault formula. serious adverse reactions occurred in 30% of patients who received tazverik. serious adverse reactions in ≥2% of patients who received tazverik were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia. permanent discontinuation due to an adverse reaction occurred in 8% of patients who received tazverik. adverse reaction resulting in permanent discontinuation in ≥2% of patients was second primary malignancy. dosage interruptions due to an adverse reaction occurred in 28% of patients who received tazverik. adverse reactions requiring dosage interruptions in ≥3% of patients were thrombocytopenia and fatigue. dose reduction due to an adverse reaction occurred in 9% of patients who received tazverik. the most common adverse reactions (≥20%) were fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain. table 6 presents adverse reactions in patients with relapsed or refractory follicular lymphoma in cohorts 4 and 5 of study e7438-g000-101. 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 adverse reaction tazverik n=99 all grades (%) grade 3 or 4 (%) a includes fatigue and asthenia b includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, upper repiratory tract infection, viral upper respiratory tract infection c includes bronchitis, lower respiratory tract infection, tracheobronchitis d includes cystitis, urinary tract infection, urinary tract infection staphylococcal e includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper f includes back pain, limb discomfort, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw, spinal pain g includes erythema, rash, rash erythematous, rash generalized, rash maculo-papular, rash pruritic, rash pustular, skin exfoliation h includes cough and productive cough i includes headache, migraine, sinus headache general fatigue a 36 5 pyrexia 10 0 infections upper respiratory tract infection b 30 0 lower respiratory tract infection c 17 0 urinary tract infection d 11 2 gastrointestinal nausea 24 1 abdominal pain e 20 3 diarrhea 18 0 vomiting 12 1 musculoskeletal and connective tissue musculoskeletal pain f 22 1 skin and subcutaneous tissue alopecia 17 0 rash g 15 0 respiratory and mediastinal system cough h 17 0 nervous system headache i 13 0 clinically relevant adverse reactions occurring in <10% of patients who received tazverik included: infection: sepsis (2%), pneumonia (2%), and herpes zoster (2%) table 7 summarizes select laboratory abnormalities in patients with follicular lymphoma in cohorts 4 and 5 of study e7438-g000-101. table 7. select laboratory abnormalities (≥10%) worsening from baseline in patients with relapsed or refractory follicular lymphoma who received tazverik in cohorts 4 and 5 of study e7438-g000-101 laboratory abnormality tazverik* all grades (%) grade 3 or 4 (%) *the denominator used to calculate the rate varied from 88 to 96 based on the number of patients with a baseline value and at least one post-treatment value. hematology decreased lymphocytes 57 18 decreased hemoglobin 50 8 decreased platelets 50 7 decreased white blood cells 41 9 decreased neutrophils 20 7 chemistry increased glucose 53 10 increased aspartate aminotransferase 24 0 increased alanine aminotransferase 21 2.3 increased alkaline phosphatase 18 1.0 increased creatinine 17 0

ns [see clinical pharmacology ( 12.3 )] , which may decrease the efficacy of tazverik. avoid coadministration of moderate and strong cyp3a inducers with tazverik. 7.2 effect of tazverik on other drugs cyp3a substrates coadministration of tazverik with cyp3a substrates, including hormonal contraceptives, can result in decreased concentrations and reduced efficacy of cyp3a substrates [see use in specific populations ( 8.3 ), clinical pharmacology ( 12.3 )] .

tat during 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 at doses of ≥50 mg/kg (approximately 2 times the adult human exposure at the 800 mg twice daily dose). at 200 mg/kg (approximately 14 times the adult human exposure at the 800 mg twice daily dose), major findings included increased post implantation loss, missing digits, fused vertebrae, domed heads and fused bones of the skull, and reduced fetal body weights. in pregnant rabbits, no adverse maternal effects were observed after once daily oral administration of 400 mg/kg/day tazemetostat (approximately 7 times the 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 exposure at the 800 mg twice daily dose), with skeletal malformations at ≥200 mg/kg/day (approximately 5.6 times the adult human exposure at the 800 mg twice daily dose). at 400 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. 8.2 lactation risk summary there are no animal or human data on the presence of 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 child, advise women not to breastfeed during treatment with tazverik and for one week after the final dose. 8.3 females and males of reproductive potential pregnancy testing verify the pregnancy status of females of reproductive potential prior to initiating tazverik [see use in specific populations ( 8.1 ) ] . risk summary tazverik can cause fetal harm when administered to pregnant women [see use in specific populations ( 8.1 )] . contraception females advise females of reproductive potential to use effective non-hormonal contraception during treatment with tazverik and for 6 months after the final dose. tazverik can render some hormonal contraceptives ineffective [see drug interactions ( 7.2 )] . males advise males with female partners of reproductive potential to use effective contraception during treatment with tazverik and for at least 3 months after the final dose. 8.4 pediatric use the safety and effectiveness of tazverik have been established in pediatric patients aged 16 years and older (adolescents) with metastatic or locally advanced epithelioid sarcoma. use of tazverik for this indication is supported by evidence from adequate and well-controlled studies in adults (including 3 adolescent patients aged 16 years) [see adverse reactions ( 6.1 ), clinical pharmacology ( 12.3 ), clinical studies ( 14.1 )] . the safety and effectiveness of tazverik in pediatric patients aged less than 16 years have not been established. 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 adulthood). tazemetostat resulted in: t-lbl at doses ≥50 mg/kg (approximately 2.8 times the adult human exposure at the 800 mg twice daily dose) increased trabecular bone at doses ≥100 mg/kg (approximately 10 times the adult human exposure at the 800 mg twice daily dose) increased body weight at doses ≥50 mg/kg (approximately equal to the adult human exposure at the 800 mg twice daily dose) distended testicles in males at doses ≥50 mg/kg (approximately equal to the adult human exposure at the 800 mg twice daily dose) 8.5 geriatric use clinical studies of tazverik did not include sufficient numbers of patients with epithelioid sarcoma or relapsed or refactory follicular lymphoma aged 65 and over to determine whether they respond differently from younger subjects. 8.6 renal impairment no dose adjustment of tazverik is recommended for patients with mild to severe renal impairment or end stage renal disease [see clinical pharmacology ( 12.3 )] . 8.7 hepatic impairment no dose adjustment of tazverik is recommended for patients with mild hepatic impairment (total bilirubin > 1 to 1.5 times upper limit of normal [uln] 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 clinical pharmacology ( 12.3 )].

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 at doses of ≥50 mg/kg (approximately 2 times the adult human exposure at the 800 mg twice daily dose). at 200 mg/kg (approximately 14 times the adult human exposure at the 800 mg twice daily dose), major findings included increased post implantation loss, missing digits, fused vertebrae, domed heads and fused bones of the skull, and reduced fetal body weights. in pregnant rabbits, no adverse maternal effects were observed after once daily oral administration of 400 mg/kg/day tazemetostat (approximately 7 times the 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 exposure at the 800 mg twice daily dose), with skeletal malformations at ≥200 mg/kg/day (approximately 5.6 times the adult human exposure at the 800 mg twice daily dose). at 400 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.

twice daily dose) increased body weight at doses ≥50 mg/kg (approximately equal to the adult human exposure at the 800 mg twice daily dose) distended testicles in males at doses ≥50 mg/kg (approximately equal to the adult human exposure at the 800 mg twice daily dose)

expression and a resulting oncogenic dependence on ezh2. tazemetostat suppressed proliferation of b-cell lymphoma cell lines in vitro and demonstrated antitumor activity in a mouse xenograft model of b-cell lymphoma with or without ezh2 gain-of-function mutations. tazemetostat demonstrated greater effects on the inhibition of proliferation of lymphoma cell lines with mutant ezh2. 12.2 pharmacodynamics tazemetostat exposure-response relationships and the time course of pharmacodynamic responses are unknown. cardiac electrophysiology the effect of orally administered tazverik, at doses ranging from 100 mg to 1600 mg twice daily (0.125 to 2 times the approved recommended dosage) for 15 days, on the heart-rate corrected qt (qtc) interval was evaluated in a dose-finding study in 38 patients with advanced malignancies. tazemetostat and its metabolite epz-6930 did not cause a large mean increase (i.e. >20 ms) on the qtc interval at the 800 mg twice daily dose. the largest mean increase (upper bound of 90% confidence interval) in qtc were 6.1 ms (8.5 ms) and 9.3 ms (12.5 ms) at a dose of 800 mg twice daily and 1600 mg twice daily, respectively. 12.3 pharmacokinetics the systemic exposure of tazemetostat is approximately dose proportional over the dose range of 200 mg to 1600 mg twice daily of tazverik (0.25 to 2 times the approved recommended dosage). following tazverik 800 mg orally twice daily, steady-state was reached by day 15. the mean (coefficient of variation [cv]%) steady-state peak plasma concentration (c max ) was 829 (56%) ng/ml and auc 0-12h was 3340 (49%) ng•h/ml. tazemetostat exhibited time-dependent pharmacokinetics (pk). the mean accumulation ratio (measured by auc) was 0.58. absorption the mean absolute oral bioavailability of tazemetostat is approximately 33%. the median time to reach the peak plasma concentration of tazemetostat is 1 to 2 hours. effect of food a high-fat, high-calorie (approximately 800 to 1000 calories) meal does not have a significant effect on tazemetostat exposure. distribution the mean (cv%) apparent volume of distribution at steady-state (v ss /f) is 1230 l (46%). tazemetostat is 88% bound to human plasma proteins in vitro. the blood-to-plasma ratio is 0.73. elimination at steady-state, the estimated mean (cv%) terminal elimination half-life of tazemetostat is 3.1 hours (14%) and the apparent total clearance (cl ss /f) is 274 l/h (49%). metabolism in vitro, tazemetostat is metabolized by cyp3a to form the inactive major metabolites m5 (epz-6930) and m3 (epz006931). m5 undergoes further metabolism by cyp3a. excretion following a single oral dose of radiolabeled tazemetostat, 94% of the total radioactivity was recovered over 12 days, with 15% excreted into urine and 79% into feces. specific populations age (16 to 91 years), sex, race (white, black, asian), body weight (37.3 to 173 kg), mild hepatic impairment (total bilirubin > 1 to 1.5 times uln or ast > uln) and renal impairment, including end stage renal disease, have no clinically meaningful effect on the pharmacokinetics of tazemetostat. the effect of moderate to severe hepatic impairment has not been studied. drug interaction studies clinical studies effect of cyp3a inhibitors on tazemetostat: coadministration of fluconazole (a moderate cyp3a inhibitor) with tazverik 400 mg twice daily in patients increased tazemetostat steady-state auc 0-8h by 3.1-fold and c max by 2.3-fold. effect of gastric acid reducing agents on tazemetostat: coadministration of omeprazole (a proton pump inhibitor) with tazverik 800 mg twice daily in patients increased tazemetostat steady-state auc 0-8h by 26% and c max by 25%, which is not expected to have clinically relevant impact. effect of tazemetostat on cyp3a substrate: coadministration of tazverik 800 mg twice daily with oral midazolam (a sensitive cyp3a substrate) in patients decreased midazolam auc 0-12h by 40% and c max by 21%. effect of tazemetostat on cyp2c8 and cyp2c19 substrates: coadministration of tazverik 800 mg twice daily with repaglinide (a sensitive cyp2c8 substrate) and omeprazole (a sensitive cyp2c19 substrate) in patients increased repaglinide auc 0-8h by 80% and c max by 51%; and had no effect on the exposure of omeprazole. in vitro studies metabolic enzymes: tazemetostat does not inhibit cyp1a2, cyp2b6, cyp2c9, and cyp2d6 at clinically relevant concentrations. drug transporters: tazemetostat is a substrate of p-glycoprotein (p-gp). tazemetostat is not a substrate of breast cancer resistance protein (bcrp); renal transporters organic cation transporter 2 (oct2), organic anion transporter 3 (oat3), and multidrug and toxin extrusion transporter 1 (mate1); or hepatic transporters organic anion transporting polypeptide 1b1 (oatp1b1) and organic anion transporting polypeptide 1b3 (oatp1b3). tazemetostat is an inhibitor of mate1 and multidrug and toxin extrusion transporter 2-k (mate2-k). tazemetostat does not inhibit p-gp, bcrp, oatp1b1, oatp1b3, organic cation transporter 1 (oct1), oct2, organic anion transporter 1 (oat1), oat3, or bile salt export pump (bsep) at clinically relevant concentrations.

88% bound to human plasma proteins in vitro. the blood-to-plasma ratio is 0.73. elimination at steady-state, the estimated mean (cv%) terminal elimination half-life of tazemetostat is 3.1 hours (14%) and the apparent total clearance (cl ss /f) is 274 l/h (49%). metabolism in vitro, tazemetostat is metabolized by cyp3a to form the inactive major metabolites m5 (epz-6930) and m3 (epz006931). m5 undergoes further metabolism by cyp3a. excretion following a single oral dose of radiolabeled tazemetostat, 94% of the total radioactivity was recovered over 12 days, with 15% excreted into urine and 79% into feces. specific populations age (16 to 91 years), sex, race (white, black, asian), body weight (37.3 to 173 kg), mild hepatic impairment (total bilirubin > 1 to 1.5 times uln or ast > uln) and renal impairment, including end stage renal disease, have no clinically meaningful effect on the pharmacokinetics of tazemetostat. the effect of moderate to severe hepatic impairment has not been studied. drug interaction studies clinical studies effect of cyp3a inhibitors on tazemetostat: coadministration of fluconazole (a moderate cyp3a inhibitor) with tazverik 400 mg twice daily in patients increased tazemetostat steady-state auc 0-8h by 3.1-fold and c max by 2.3-fold. effect of gastric acid reducing agents on tazemetostat: coadministration of omeprazole (a proton pump inhibitor) with tazverik 800 mg twice daily in patients increased tazemetostat steady-state auc 0-8h by 26% and c max by 25%, which is not expected to have clinically relevant impact. effect of tazemetostat on cyp3a substrate: coadministration of tazverik 800 mg twice daily with oral midazolam (a sensitive cyp3a substrate) in patients decreased midazolam auc 0-12h by 40% and c max by 21%. effect of tazemetostat on cyp2c8 and cyp2c19 substrates: coadministration of tazverik 800 mg twice daily with repaglinide (a sensitive cyp2c8 substrate) and omeprazole (a sensitive cyp2c19 substrate) in patients increased repaglinide auc 0-8h by 80% and c max by 51%; and had no effect on the exposure of omeprazole. in vitro studies metabolic enzymes: tazemetostat does not inhibit cyp1a2, cyp2b6, cyp2c9, and cyp2d6 at clinically relevant concentrations. drug transporters: tazemetostat is a substrate of p-glycoprotein (p-gp). tazemetostat is not a substrate of breast cancer resistance protein (bcrp); renal transporters organic cation transporter 2 (oct2), organic anion transporter 3 (oat3), and multidrug and toxin extrusion transporter 1 (mate1); or hepatic transporters organic anion transporting polypeptide 1b1 (oatp1b1) and organic anion transporting polypeptide 1b3 (oatp1b3). tazemetostat is an inhibitor of mate1 and multidrug and toxin extrusion transporter 2-k (mate2-k). tazemetostat does not inhibit p-gp, bcrp, oatp1b1, oatp1b3, organic cation transporter 1 (oct1), oct2, organic anion transporter 1 (oat1), oat3, or bile salt export pump (bsep) at clinically relevant concentrations.

l daily administration of tazemetostat did not result in any notable effects in the adult male and female reproductive organs [see use in specific populations ( 8.3 )] .

tazemetostat did not result in any notable effects in the adult male and female reproductive organs [see use in specific populations ( 8.3 )] .

were white, 11% were asian, 44% had proximal disease, 92% had an ecog ps of 0 or 1, and 8% had an ecog ps of 2. prior surgery occurred in 77% of patients; 61% received prior systemic chemotherapy. efficacy results are summarized in table 8 . table 8. efficacy results for patients with epithelioid sarcoma enrolled in cohort 5 of study ezh-202 ci = confidence interval *time to response ranged from 1.4 to 18.4 months. efficacy endpoints tazverik n=62 overall response rate (95% ci)* 15% (7%, 26%) complete response 1.6% partial response 13% duration of response % with duration ≥ 6 months 67% range in months 3.7, 24.5+ 14.2 relapsed or refractory follicular lymphoma the efficacy of tazverik was evaluated in two open-label, single-arm cohorts (cohorts 4 and 5) of a multi-center study (study e7438-g000-101, nct01897571) in patients with histologically confirmed follicular lymphoma after at least 2 prior systemic therapies. patients were required to have ecog ps of 0-2 and were enrolled based on ezh2 mutation status. ezh2 mutations were identified prospectively using formalin-fixed, paraffin-embedded tumor samples, which were centrally tested using the cobas ® ezh2 mutation test; the cobas ezh2 mutation test is designed to detect the following mutations: y646x [s,h,c], y646f, y646n, a682g, and a692v. patients received tazverik 800 mg orally twice daily until confirmed disease progression or unacceptable toxicity. tumor response assessments were performed every 8 weeks through week 24 and then every 12 weeks. the major efficacy outcome measures were orr and dor according to the international working group non-hodgkin lymphoma (iwg-nhl) criteria 1 as assessed by independent review committee. median duration of follow-up was 22 months (range 3 months to 44 months) for patients with ezh2 mt positive tumors and 36 months (range 32 months to 39 months) for patients whose tumors did not have an ezh2 mutation detected. a total of 99 patients were enrolled, including 45 patients whose tumors had one of these ezh2 mutations (mutant) and 54 patients whose tumors did not have one of these mutations (wild-type). among the 45 patients with ezh2 mutant follicular lymphoma, median age was 62 years (range 38 to 80), 58% were female, 42% had early progression following front-line therapy (pod24), and all had an ecog ps of 0 or 1. race was reported in 84% of patients; of these patients, 82% were white. based on the cobas ezh2 mutation test, 36%, 29%, 27%, 11% and 2% of patients had the following mutations: y646x [s,h,c], y646f, y646n, a682g, and a692v, respectively. the median number of lines of prior systemic therapy was 2 (range 1 to 11), with 49% refractory to rituximab, 49% refractory to their last therapy, and 9% had received prior stem cell transplant. among the 54 patients with ezh2 wild-type follicular lymphoma, median age was 61 years (range 36 to 87), 63% were male, 59% had pod24, and 91% had an ecog ps of 0 or 1. race was reported in 57% of patients; of these patients, 48% were white and 3% were asian. the median number of lines of prior systemic therapy was 3 (range 1 to 8), with 59% refractory to rituximab, 41% refractory to their last therapy, and 39% had received prior stem cell transplant. the approval of tazverik was based upon the efficacy in 95 patients (42 ezh2 mutant, 53 ezh2 wild-type) who had received at least 2 prior systemic therapies and is presented in table 9 . table 9. efficacy results for patients with relapsed or refractory follicular lymphoma enrolled into cohorts 4 and 5 of study e7438-g000-101 ci = confidence interval; ne = not estimable. *median time to response for patients with ezh2 mt follicular lymphoma was 3.7 months (range 1.6 to 10.9) and for patients with ezh2 wt follicular lymphoma was 3.9 months (range 1.6 to 16.3). efficacy endpoints tazverik n=95 ezh2 mutant follicular lymphoma n=42 ezh2 wild-type follicular lymphoma n=53 overall response rate (95% ci)* 69% (53%, 82%) 34% (22%, 48%) complete response 12% 4% partial response 57% 30% duration of response median (95% ci) in months 10.9 (7.2, ne) 13.0 (5.6, ne) range in months 0.0+, 22.1+ 1, 22.5+

dose [see use in specific populations ( 8.3 ), nonclinical toxicology ( 13.1 )]. lactation advise women not to breastfeed during treatment with tazverik and for 1 week after the final dose [see use in special populations ( 8.2 )]. drug interactions advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. inform patients to avoid st. john's wort, grapefruit, and grapefruit juice while taking tazverik [see drug interactions ( 7.1 )] . manufactured for: epizyme, inc. 400 technology square cambridge, ma 02139 ©2020 epizyme, inc.