Summary Background On the basis of various clinical and MRI measurements, the phase 3 Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study in patients with relapsing–remitting ...multiple sclerosis (RRMS) showed that short-course oral treatment with cladribine at cumulative doses of 3·5 and 5·25 mg/kg over 96 weeks was more effective than placebo. Achieving sustained freedom from disease activity is becoming a viable treatment goal in RRMS; we therefore aimed to assess the effects of cladribine on this composite outcome measure by doing a post-hoc analysis of data from the CLARITY study. Methods Freedom from disease activity is composed of three components that are commonly used individually as endpoints in clinical trials; it is defined as the patient having no relapse, no 3-month sustained change in expanded disability status scale (EDSS) score, and no new MRI lesions (no T1 gadolinium-enhancing or active T2 lesions) over a specified period. We assessed the effect of two doses of cladribine tablets versus placebo on the proportion of patients who were free from disease activity based on the individual components, all pair-wise combinations, and the composite of the three components (freedom from disease activity). Freedom from disease activity was analysed at 24, 48, and 96 weeks, and in subgroups of patients stratified according to baseline demographic and disease characteristics (age, disease duration, previous treatment with disease-modifying therapy, T1 gadolinium-enhancing lesion number, T2 lesion volume, EDSS score, number of previous relapses, and highly active disease). Findings Of the 1326 patients randomly assigned to treatment in the CLARITY study, 1192 were assessable for freedom from disease activity at 96 weeks. Over 24 weeks, 266 (67%) of 395 patients in the cladribine 3·5 mg/kg group and 283 (70%) of 406 in the cladribine 5·25 mg/kg group were free from disease activity, versus 145 (39%) of 373 in the placebo group (odds ratio OR 3·31, 95% CI 2·46–4·46 for the 3·5 mg/kg group; and 3·68, 2·73–4·97 for the 5·25 mg/kg group; both p<0·0001). Over 48 weeks, 208 (54%) of 384 patients in the cladribine 3·5 mg/kg group and 222 (56%) of 396 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 86 (24%) of 360 patients in the placebo group (OR 3·80, 2·77–5·22 for the 3·5 mg/kg group; 4·13, 3·02–5·66 for the 5·25 mg/kg group; both p<0·0001). Over 96 weeks, 178 (44%) of 402 patients in the cladribine 3·5 mg/kg group and 189 (46%) of 411 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 60 (16%) of 379 patients in the placebo group (OR 4·28, 3·05–6·02 for the 3·5 mg/kg group; 4·62, 3·29–6·48 for the 5·25 mg/kg group; both p<0·0001). The effects of cladribine tablets on freedom from disease activity were significant across all patient subgroups. Interpretation Treatment with cladribine tablets significantly increased the proportion of patients with sustained freedom from disease activity over 96 weeks compared with placebo. Sustained freedom from disease activity could become an important measure of therapeutic response in RRMS. Funding Merck Serono SA–Geneva, Switzerland; an affiliate of Merck, Darmstadt, Germany.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We herein provide a comprehensive assessment of magnetic resonance imaging (MRI) outcomes from CLARITY, a 96-week, double-blind study demonstrating significant clinical and MRI improvements in ...patients with relapsing–remitting multiple sclerosis (RRMS) treated with cladribine tablets. Patients with RRMS were randomized 1:1:1 to annual short-course therapy with cladribine tablets cumulative dose 3.5 or 5.25 mg/kg or placebo. MRI endpoints included mean number of T1 gadolinium-enhancing (Gd+), active T2 and combined unique (CU) lesions/patient/scan. MRI-measured disease activity was significantly reduced in both cladribine tablets groups versus placebo. The proportion of patients with no active lesions at study end was: T1 Gd+ lesions: 86.8 and 91.0 versus 48.3 % (
p
< 0.001); active T2 lesions: 61.7 and 62.5 versus 28.4 % (
p
< 0.001); CU lesions: 59.6 and 60.7 versus 26.1 % (
p
< 0.001). Clinically meaningful and significant reductions in active lesion counts and increases in proportions of active lesion-free patients were achieved consistently in cladribine tablet groups when data were stratified by baseline disease characteristics. For example, the percentage of patients who remained lesion-free over the study was significantly greater in cladribine tablet groups than in the placebo group for all lesion types regardless of relapse category at baseline (
p
< 0.001 for all analyses of patients with ≤1 or 2 relapses;
p
≤ 0.022 for analyses of patients with ≥3 relapses). MRI-measured disease activity was greatly reduced by both doses of cladribine tablets, with consistent effect across clinically relevant patient populations. These findings add to our scientific understanding of the neurological impact of this therapeutic modality in patients with RRMS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this 96-week, placebo-controlled trial, oral cladribine reduced relapse rates and lowered the risk of sustained disability in patients with relapsing–remitting multiple sclerosis. Patients who ...were treated with cladribine had large reductions in lymphocyte counts and more infections, including herpes zoster and one death from reactivation of tuberculosis.
Oral cladribine reduced relapse rates and lowered the risk of sustained disability in patients with relapsing–remitting multiple sclerosis. Patients had large reductions in lymphocyte counts and more infections, including herpes zoster and one death from reactivation of tuberculosis.
Multiple sclerosis is a chronic and debilitating autoimmune disorder of the central nervous system, in which T and B cells are believed to play a major pathophysiological role.
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–
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Treatment benefits and disease modification can be obtained with the currently approved parenteral immunomodulatory and immunosuppressant therapies: interferon beta, glatiramer acetate, mitoxantrone, and natalizumab. However, treatment responses are often less than complete, and concern regarding safety and side-effect profiles may limit the general use of these drugs. The need for parenteral administration may present relative or absolute barriers to access, limiting treatment adherence and long-term outcomes.
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Intracellular accumulation of the active . . .
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TPS11573
Background: Epithelioid sarcoma (ES) is characterized by loss of inhibitor of integrase 1 (INI1), allowing enhancer of zeste homologue 2 (EZH2) to repress cell differentiation ...and promote tumorigenesis. Tazemetostat (TAZ) is an EZH2 inhibitor approved by the FDA as monotherapy for the treatment of patients (pts) aged ≥16 years with metastatic or locally advanced ES ineligible for complete resection. The most common ( > 20%) adverse events include pain, fatigue, nausea, decreased appetite, vomiting, and constipation. TAZ demonstrated anti-cancer activity in ES pts who previously received doxorubicin (dox), a commonly used front line FDA approved therapy for soft tissue sarcomas (STS), including ES. Preclinical studies have demonstrated synergy between TAZ and dox. This phase 1b/3 study (NCT04204941) is assessing the safety and efficacy of TAZ + dox in pts with advanced ES. Methods: This study is enrolling treatment-naïve adult pts with histologically confirmed STS (phase 1b) or INI1-deficient ES pts (phase 3) with ECOG performance status of 0-2 and life expectancy of ≥3 months. The open-label phase 1b portion is currently enrolling up to 24 patients with STS. The primary objectives are to evaluate the safety and tolerability of TAZ + dox, and to identify the recommended phase 3 dose (RP3D). Using a standard 3 + 3 design, TAZ will be evaluated at 3 dose levels (400 mg, 600 mg, and 800 mg orally BID) with standard fixed dose of dox (75 mg/m
2
on day 1 of 21-day cycles for up to 6 cycles). After completion of dox, pts will continue to receive TAZ monotherapy until disease progression or intolerable toxicity. Up to 12 additional pts will be enrolled at the maximum tolerated dose for collection of additional safety and pharmacokinetic (PK) data. The double-blind phase 3 study will randomize (1:1) up to 140 pts to receive either TAZ (RP3D) + dox (75 mg/m
2
) or placebo + dox. The adaptive study design will allow sample size re-estimation (at interim analysis) to up to 200 pts. Pts may continue TAZ or placebo monotherapy after completing 6 cycles of TAZ + dox. Tumor assessments will be performed at screening and every 6 weeks from the start of dosing. The primary objective of phase 3 will be to evaluate the progression-free survival (PFS) by independent review committee. Secondary objectives will include assessment of PFS by investigators, overall survival, safety, disease control rate, overall response rate, duration of response, time to subsequent anticancer therapy, PFS on next treatment, quality of life, and PK. Clinical trial information: NCT04204941 .
▪
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 <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.
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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.
Tazemetostat is not approved in combination with other therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract only
TPS255
Background: The histone methyltransferase EZH2 is overexpressed in many cancers. In prostate cancer (PC), EZH2 inhibition may reverse acquired resistance to androgen inhibitors ...(AIs). Pts may initially respond to AIs, but pts who progress have limited treatment options. In phase 2 trials, TAZ, a selective, orally bioavailable, investigative small molecule EZH2 inhibitor, has demonstrated encouraging objective responses in B-cell lymphomas and molecularly defined solid tumors and a favorable safety profile. In PC preclinical models, TAZ + E or A/P showed a greater reduction in tumor growth than either drug alone. This study will evaluate the safety and efficacy of TAZ + E or A/P vs E or A/P alone in mCRPC. Methods: This phase 1b/2 study will enroll pts ≥18 years with progressive mCRPC, with or without prior second-generation AI treatment, and no prior chemotherapy. Phase 1b will identify the recommended phase 2 dose (RP2D) of TAZ when combined with E (160 mg/day) or A/P (A: 1000 mg/day; P: 5 mg twice-daily BID) and evaluate the safety and tolerability of each combination in treatment-naïve pts and pts previously treated with a second-generation AI. Using a modified 3+3 design (up to 48 pts: 18 for TAZ+A/P and 30 for TAZ+E), TAZ dosing will start at 400 mg BID, escalating to 800 mg BID in the TAZ+A/P group or 1600 mg BID in the TAZ + E group, if no dose-limiting toxicities are observed. Phase 2 will begin once the RP2D for each combination is determined. Efficacy and safety results from phase 1b will inform the final design for phase 2. Phase 2 will be an open label study where pts will be randomized to either E or A/P alone or in combination with TAZ. TAZ will be administered at the RP2D in continuous 28-day cycles for as long as pts tolerate treatment and continue AI therapy. Tumor assessments will be performed every 9 weeks for 6 months and every 12 weeks thereafter. Efficacy assessments include radiographic progression-free survival (primary endpoint), prostate-specific antigen (PSA) ≥50% response rate, time to PSA progression, time to subsequent systemic therapy, and objective response rate. Safety is a secondary endpoint.
Abstract only
11563
Background: ES is a rare, aggressive subtype of STS for which cytotoxic chemotherapy has limited effectiveness. TAZ, an FDA-approved EZH2 inhibitor, has shown single-agent ...clinical activity and a favorable safety profile in patients with metastatic or locally advanced ES. In preclinical studies, TAZ has shown synergistic antitumor activity with DOX, which is often used as frontline treatment for STS. Here, we present results of the phase 1b study (NCT04204941), designed to assess the recommended phase 3 dose (RP3D), safety, and efficacy of TAZ + DOX in patients with advanced STS. Methods: The open-label, phase 1b portion of this study enrolled adult patients with previously untreated advanced STS. A standard 3 + 3 design was used to assess TAZ 400 mg, 600 mg, and 800 mg orally twice daily in combination with DOX (75 mg/m
2
intravenously on day 1 of each cycle, for up to 6 cycles) as frontline therapy. Dose-limiting toxicities (DLTs) were predefined in the protocol. The RP3D of TAZ was determined by Scientific Review Committee review of the safety and pharmacokinetic data from the phase 1b trial, with a target DLT rate of < 33%. Results: As of February 1, 2021, 16 patients are enrolled, including 2 with ES; 10 are still receiving TAZ + DOX and 6 have discontinued (5 due to disease progression, 1 due to patient withdrawal). The median age was 49.5 years (range, 2982) and all had unresectable STS. Median (range) time on treatment was 13 (0.151.1+) weeks across all dose levels evaluated. Two DLTs, both of febrile neutropenia, were observed, one in the TAZ 600 mg + DOX cohort (n = 1/6, 17%), and one in the TAZ 800 mg + DOX cohort (n = 1/3, 33%). When used in combination with DOX, the RP3D of TAZ was 800 mg. Grade 3 or 4 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 13/16 (81.3%) patients. The most common (≥ 20%) TR-TEAEs were neutropenia (n = 11, 69%), anemia (n = 10, 63%), fatigue (n = 10, 63%), stomatitis (n = 9, 56%), nausea (n = 8, 50%), febrile neutropenia (n = 7, 44%), constipation (n = 6, 38%), vomiting (n = 6, 38%), and decreased appetite (n = 5, 31%). TR-TEAEs were defined as attributable to either study agent. Conclusions: The combination of TAZ + DOX was generally well tolerated in this dose finding study in patients with advanced STS. The RP3D to be tested in the phase 3 randomized, double blind, placebo controlled study is TAZ 800 mg twice daily + DOX. The safety profile of this combination is consistent with the respective safety information for TAZ and for DOX. The TR-TEAEs include known toxicities of DOX or TAZ. Further comparison with DOX + placebo in the phase 3 trial will aid in assessing efficacy and safety of the combination of TAZ + DOX. The global phase 3 confirmatory trial will enroll patients with ES who have unresectable disease and have had no prior systemic therapy. Clinical trial information: NCT04204941.
Background: Tazemetostat, a first-in-class, oral, enhancer of zeste homolog 2 (EZH2) inhibitor was recently approved by the US Food and Drug Administration in patients with relapsed/refractory (R/R) ...follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type (WT) or mutant (MT) EZH2. Progression of disease within 24 months (POD24), exposure to multiple lines of prior therapy, and refractoriness to rituximab therapy have been shown to adversely affect the prognosis of patients receiving second- or third-line regimens for R/R FL, including chemoimmunotherapy. We performed a post hoc exploratory analysis to better understand how these factors impact the outcomes in patients receiving tazemetostat.
Methods: This open-label, multicenter study (NCT01897571) evaluated tazemetostat 800 mg administered orally twice daily in patients with MT or WT EZH2 R/R FL. The primary endpoint was objective response rate (ORR; complete response + partial response) as assessed by an independent review committee (IRC); secondary efficacy endpoints included duration of response (DOR) by IRC, progression-free survival (PFS) by IRC, and overall survival (OS) by investigator assessment. Predictive modeling using baseline demographic and disease characteristic variables combined from patients with MT or WT EZH2 R/R FL was performed to identify variables predictive of response (ORR, DOR, PFS, and OS). Models were fitted for variables that were categorical and had no missing observations; they also were fitted with/without Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria and with the number of prior lines of therapy (1, 2, or >2, and 1 or 2 vs >2). Due to incomplete data collection, GELF criteria were analyzed with missing observations (n=28) set to “no.” Stepwise logistic and Cox regression was used to determine possible predictors; inclusion at a specified step was based on P≤0.40. Final model inclusion was based on P≤0.20. A final model was run using the possible predictors identified from the previous stepwise regressions. Contingency tables and Kaplan-Meier plots were used to examine significant variables (P≤0.05).
Results: In the phase 2 study, the efficacy outcomes by IRC in combined WT and MT EZH2 populations (N=99) were: ORR, 51% (n=50); median DOR, 11 months (95% CI: 7, 19); and median PFS, 12 months (95% CI: 8, 15). Median OS was not reached (95% CI: 38.2, not estimable). Predictive modeling using 17 baseline variables identified possible predictors of efficacy outcome. For ORR, the number (1 or 2 vs >2) of prior lines of therapy was identified as possibly predictive (Table). Patients with 1 line of prior therapy had an ORR of 66% (n=27) vs 40% (n=23) in patients with 2 prior lines of therapy. Disease refractory to rituximab and number (1, 2, or >2) of prior lines of therapy (Table) were identified as possible predictors for DOR. Disease refractory to rituximab, GELF criteria, disease refractory to any treatment, and sex (Table) were possibly predictive for PFS. However, the percentage of subjects that met GELF criteria may be underestimated due to retrospective collection of qualifying data points; therefore, the translation of GELF criteria as a predictive factor for PFS should be interpreted with caution. Other baseline demographic and disease characteristics, including patient age (≤65 y, >65 y), double refractory disease, ECOG performance status, myelosuppression, POD24, disease refractory to last therapy, prior stem cell transplant, and time since last therapy, were not found to be predictive of response, as measured by ORR, DOR, PFS, and OS.
Conclusions: In this post hoc exploratory analysis of patients with R/R FL (WT and MT EZH2 cohorts combined), variables associated with heavily pretreated patients (ie, refractory to rituximab, treatment-refractory disease, and number of prior treatments) were identified as possible predictors of response. However, in these analyses other high-risk disease characteristics, such as POD24, were not predictive, although the results may be confounded by the small number of patients in some of the groups. In addition to reinforcing the efficacy of tazemetostat in heavily pretreated patients, these data also suggest that ORR is greater in patient populations who receive treatment as an earlier line of therapy. Prospective confirmatory studies are warranted to confirm these post hoc observations.
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Salles:Kite: Consultancy, Honoraria, Other; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Bristol Myers Squibb: Consultancy, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Genmab: Consultancy; Epizyme: Consultancy; Debiopharm: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Karyopharm: Consultancy; Novartis: Consultancy, Honoraria, Other. Tilly:BMS: Honoraria. McKay:Greater Glasgow and Clyde Health Board: Current Employment; Roche, Gilead, Takeda, Janssen: Other: For lectures etc; TAKEDA: Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; BeiGene: Membership on an entity’s Board of Directors or advisory committees; Gilead: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees. Phillips:Beigene: Consultancy; Karyopharm: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy, Other: travel expenses; Seattle Genetics: Consultancy; BMS: Consultancy; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Cardinal Health: Consultancy. Assouline:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Batlevi:Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding; Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Ribrag:BAY1000394 studies on MCL: Patents & Royalties; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; argenX: Current equity holder in publicly-traded company, Research Funding; Institut Gustave Roussy: Current Employment; Immune Design: Consultancy, Membership on an entity’s Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel Expenses; arGEN-X-BVBA: Research Funding; Nanostring: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Eisai: Honoraria; Servier: Consultancy, Honoraria; Pharmamar: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; AZD: Honoraria, Other; MSD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel Expenses; Infinity: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Damaj:Roche, Takeda, Accord: Honoraria; Roche, Takeda, Iqone, Accord: Consultancy; Abbevie, Pfizer, Takeda, Roche: Other: Travel. Dickinson:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jurczak:BeiGene: Consultancy, Research Funding; Celgene: Research Funding; Epizyme: Consultancy; Gilead Sciences: Research Funding; MorphoSys: Research Funding; Nordic Nanovector: Research Funding; Servier: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Sandoz-Novartis: Consultancy; European Medicines Agency,: Consultancy; AstraZeneca: Consultancy; Takeda: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Afimed: Research Funding; Janssen China R&D: Consultancy, Research Funding; MEI Pharma: Research Funding; Acerta: Consultancy, Research Funding; Bayer: Research Funding; TG Therapeutics, Inc.: Research Funding. Kaźmierczak:Department of Hematology and Bone Marrow Transplantation Poz
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Isatuximab (ISA) targets CD38-expressing tumor cells through a combination of activities, including antibody-dependent cellular cytotoxicity, direct pro-apoptotic activity, and ...complement-dependent cytotoxicity. A phase I study evaluating ISA monotherapy demonstrated promising clinical activity in 35 patients with relapsed/refractory multiple myeloma (RRMM) (Martin T et al, J Clin Oncol 2014; 32:8532). This is an ongoing phase II study (NCT01084252) with 2 stages: stage 1 to select the dose for stage 2 of the study, and stage 2 to assess efficacy and safety of ISA monotherapy or in combination with dexamethasone in RRMM. In stage 1, patients were randomized to 1 of 3 dose groups: ISA 3 mg/kg Q2W, 10 mg/kg Q2W × 2 cycles then Q4W, or 10 mg/kg Q2W. Based on pharmacokinetic data, a fourth dose of 20 mg/kg QW × 4 doses then Q2W was added. The overall response rates (ORRs) for the 4 dosing schemes were 4% (1/23), 20% (5/25), 29% (7/24), and 24% (6/25), respectively. Based on these results, a dose of 20 mg/kg QW for cycle 1 followed by 20 mg/kg Q2W in subsequent cycles was chosen for stage 2 of the study (Richter J et al, J Clin Oncol 2016;34:8005). Here, we report the baseline characteristics and demographic data from stage 2 at the selected dosing scheme from stage 1. Full safety and efficacy data will be presented at the meeting.
Methods: This study enrolled patients with MM who had previously received an immunomodulatory drug and a proteasome inhibitor. Patients received ISA monotherapy (20 mg/kg on Day 1, 8, 15, and 22 QW of cycle 1 followed by 20 mg/kg on Day 1 and 15 Q2W of subsequent cycles) or ISA in combination with dexamethasone (40 mg/day 20 mg/day in patients ≥75 years old). The primary objective was to evaluate the activity of ISA as monotherapy and in combination with dexamethasone in patients with RRMM in terms of ORR.
Results: A total of 165 patients received at least 1 cycle of treatment. Median age was 67 (37-85) years. Median time from diagnosis to first dose was 5.35 (0.7-23.0) years. Median number of prior lines was 4 (2-11) and median number of prior regimens was 6 (2-17). Patients received a median of 5 (1-17) cycles of treatment, with a median duration of exposure of 22 (1-69) weeks. Discontinuation occurred in 106 (64.2%) patients due to adverse events (15 patients, 9.1%), disease progression (85 patients, 51.5%), or patient decision (6 patients, 3.6%).
Conclusion: The full efficacy and safety data for this heavily pre-treated RRMM population will be available for presentation at the meeting.
Funding: Sanofi
Dimopoulos:Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria. Anttila:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Capra:Janssen: Research Funding, Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Research Funding; Sanofi: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Cavo:AbbVie: 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, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria. Hungria:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Jenner:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vorobyev:Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Biocad: Consultancy; Takeda: Speakers Bureau; BMS: Speakers Bureau; Astellas: Speakers Bureau. Yanez Ruiz:Universidad de la Frontera: Employment. Yin:Sanofi: Employment. Hamlett:BDM Consulting Inc.: Employment; Sanofi: Consultancy. Vij:Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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