Jahan, Thierry

11564 Background: Epithelioid sarcoma (ES) is a rare, aggressive soft tissue sarcoma 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 a selective inhibitor of EZH2 approved by the FDA for treatment of patients (pts) aged ≥16 years with metastatic or locally advanced ES ineligible for complete resection. Methods: This open-label, multicenter, multi-cohort phase 2 study (NCT02601950) evaluated safety and efficacy of TAZ in pts with INI1-negative tumors. ES pts were enrolled in Cohorts 5 and 6; pts in Cohort 6 underwent mandatory pre-dose (at screening) and post-dose biopsies (at Day 1 of cycle 2). Herein, we report the interim efficacy and safety data from Cohort 6. Results: As of July 31 2019, 44 pts were enrolled into Cohort 6 and treated with TAZ 800 mg BID. The objective response rate (ORR) was 11.4%; 4 pts (9.1%) had a partial response and 1 pt (2.3%) had a complete response (Table). Another 17 pts (38.6%) had stable disease (SD). 18 pts had progressive disease; 13 of these pts remained on study beyond progression. Progression-free survival (PFS) and overall survival (OS) at 56 weeks were 19.4% and 59.4%, respectively. In a pooled posthoc analysis of 106 ES pts from Cohorts 5 (n = 62), and 6, ORR was 13.2%. Grade 3–4 adverse events (AEs) were reported in 16 pts (36.4%), most commonly anemia (6.8%; n = 3) and tumor pain (6.8%; n = 3). 3 pts (6.8%) experienced grade 3–4 treatment-related AEs. One pt discontinued study drug and there were no treatment-emergent dose reductions or treatment-related deaths. These safety data from Cohort 6 are consistent with previously reported data from Cohort 5. 19 paired biopsies were included for translational endpoint analyses. Preliminary RNA seq and pathway analyses are currently ongoing and updated data, including additional biomarker data will be presented. Conclusions: Consistent with previously reported data from the completed Cohort 5, TAZ demonstrated clinically meaningful, durable, single agent activity in ES pts. Efficacy data from Cohort 6 continue to mature with 8 patients still on treatment. TAZ was well tolerated with a low incidence of treatment related AEs. Clinical trial information: NCT02601950 . [Table: see text]

9058 Background: Breast cancer gene 1 (BRCA1)-associated protein 1 (BAP1), a nuclear deubiquitinase, is commonly inactivated in malignant mesothelioma. Preclinical data showed that BAP1 inactivation sensitizes mesothelial cells to inhibition of enhancer of zeste-homolog 2 (EZH2), a methyltransferase implicated as an oncogenic driver in this tumor. This study evaluated the safety and efficacy of tazemetostat (TAZ), a potent and selective EZH2 inhibitor, in relapsed/refractory (R/R) malignant mesothelioma with BAP1-inactivation. Methods: EZH-203 (NCT02860286) was a 2-part, open-label, phase 2 study that assessed the pharmacokinetics (PK), safety, and efficacy of TAZ in pts with R/R malignant mesothelioma. In part 1, pts received TAZ 800 mg QD on day 1 (D1) and 800 mg BID, beginning day 2 of cycle 1 (C1). In part 2, pts received 800 mg of TAZ BID on D1 of C1. A two-stage Green-Dahlberg design was used for part 2. Primary endpoints were PK profiling of TAZ in all pts (part 1), and disease control rate (DCR) at week 12 in pts with BAP1-deficient R/R malignant mesothelioma (part 2). Secondary endpoints included safety, overall response rate (ORR), progression-free survival, overall survival, and duration of response (DOR). Results: The study enrolled 74 pts with R/R malignant mesothelioma, 70 pts (95%) were centrally confirmed to be BAP1-deficient. Median prior lines of therapy were 2 (range, 1-9). Observed clinical data in the presence of CYP3A4 inhibitors and inducers suggest a low DDI potential of TAZ. The 12 week DCR was 47% (n = 35). The ORR per RECIST version 1.1 was 3% [complete response: 0%; partial response (PR): 3% (n = 2)]. Of the 2 patients with PR, 1 had a DOR of 21 weeks and the other is ongoing (15.3 weeks at data cut off). 47 pts (64%) and 21 pts (28%) had stable disease (SD) and progressive disease, respectively. Overall, 91% pts discontinued, either due to disease progression (n = 65), death (n = 5), or treatment discontinuation (n = 1). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in ≤5% of patients, most commonly anemia (5%) and dyspnea (4%). No pts discontinued due to TEAEs. There were no treatment related deaths. Conclusions: Based on disease control rate and stable disease, TAZ showed antitumor activity in pts with BAP1-deficient R/R malignant mesothelioma. TAZ monotherapy was generally well-tolerated. The current data support further clinical evaluation of TAZ in these pts. Furthermore, this trial presents an optimal paradigm for drug development in molecularly-enriched cohorts in mesothelioma. Clinical trial information: NCT02860286.

11003 Background: ES is a rare soft tissue sarcoma that metastasizes in approximately 30% to 50% of cases. More than 90% of ES tumors lack expression of INI1, an important component of epigenetic regulation. Loss of INI1 function allows another epigenetic modifier, EZH2, to become an oncogenic driver in tumor cells. Tazemetostat, a first-in-class, selective, oral inhibitor of EZH2, has demonstrated tumor regression and favorable safety in phase 1/2 trials. Methods: Data from a phase 2 open-label, multicenter trial of pts with locally advanced or metastatic ES are reported. Efficacy was assessed with primary and secondary endpoints including objective response rate (ORR) by RECIST 1.1, disease control rate (DCR; objective confirmed response of any duration or stable disease [SD] lasting ≥32 weeks), duration of response (DOR), progression-free survival (PFS), overall survival (OS); safety and tolerability were also evaluated. Results: As of September 17, 2018, 62 INI1-negative ES pts were enrolled and treated with tazemetostat 800 mg BID. The median number of prior lines of therapy was 1 (range: 0-9). There were 9/62 (15%) confirmed partial responses (PRs) with an ORR of 15% and DCR of 26%. The DOR ranged from 7.1+ weeks to 103.0+ weeks (median: not reached) with a median OS of 82.4 weeks (95% CI: 47.4, not estimable) for all 62 pts. Tazemetostat was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild to moderate with the most commonly reported adverse events (AEs; ≥10% incidence) regardless of attribution being fatigue (24/62; 39%), nausea (22/62; 35%), and cancer pain (20/62; 32%). Any treatment-related TEAEs of grade ≥3 were reported in 10/62 (16%) pts. TEAEs grade ≥3 reported in ≥2 pts included anemia (6%) and decreased weight (3%). There were no drug-related deaths and a low discontinuation rate (1.7%). Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat achieved disease control in 26% of pts with advanced ES who entered this study. Durable clinical response of the drug was documented. Tazemetostat demonstrated favorable safety with few pts with treatment-related AEs grade ≥3. Clinical trial information: NCT02601950.

29 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) engineered to stimulate immune response to mesothelin. In a phase I trial of 60 MPM patients, 34% of subjects had tumor reduction (range -1 to -47%) following 2 doses of CRS-207 alone. In KEYNOTE-028 pembro showed activity in PDL1+ (≥1% by IHC) MPM, with an objective response rate (ORR) of 20% (5/25) and stable disease in 52% of subjects who had failed or did not receive chemotherapy. Subsequent studies of pembro have shown similar results in MPM. Results from a pre-clinical murine lung tumor model (CT26hMeso) showed anti-PD-1 enhanced LADD-induced tumor response. The study described here evaluated the efficacy of combination therapy of CRS-207/pembro. Methods: Adults with epithelial/biphasic MPM, ≤2 prior lines, progression on pemetrexed and platinum-based therapy, and no prior immunotherapies were enrolled. CRS-207/pembro were administered IV Q3W for 4 cycles, after which pembro continued Q3W and CRS-207 changed to Q6W. Response was assessed Q6W by modified RECIST for MPM (Byrne and Nowak, 2004). The primary endpoint was ORR; secondary endpoints included DOR, disease control rate (DCR), progression-free survival (PFS) and overall survival. Pre- and on-treatment blood and tumor samples were collected. Shedding and blood clearance of CRS-207 were evaluated. Results: 9/10 subjects were evaluable for response. No responses were observed; DCR was 11% (1/9 with SD) and PFS ranged from 3.4 to 8.9 weeks. Most common treatment related adverse events were chills, pyrexia and nausea. 3/10 subjects evaluated were PDL-1 negative by IHC. Of 6 subjects who underwent clearance and shedding evaluation, CRS-207 was detected in blood in 1 at 18-24 hrs after the first CRS-207 dose and cleared by the next evaluation at Day 4; shedding samples (urine, fecal, and saliva) tested negative. Conclusions: The toxicity profile of CRS-207/pembro combination was consistent with the safety profile of each component alone. No evidence of clinical activity was observed. Based on the results and an overall evaluation of the program, the clinical development of CRS-207 was discontinued. (NCT01675765) (NCT02054806). Clinical trial information: NCT03175172.

TPS8581 Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer with a 5-year overall survival (OS) rate of < 10%. At diagnosis, most patients (pts) have unresectable disease. Combination chemotherapy of cisplatin (or carboplatin as an alternative) + pemetrexed is the approved first-line standard of care. Phase 1 and 2 data suggest that targeting immune checkpoint pathways (eg, programmed death [PD]-1/PD-ligand 1 [PD-L1] and/or cytotoxic T-lymphocyte antigen-4 [CTLA-4]) may provide benefit with acceptable safety in MPM. In pts with previously treated, malignant mesothelioma, single-agent tremelimumab (a CTLA-4 inhibitor antibody) was active but did not improve OS vs placebo. In a phase 2 study of nivo (a fully human PD-1 immune checkpoint inhibitor antibody) in 34 pts with MPM that progressed after first-line platinum-based chemotherapy, 12-week disease control rate (DCR) was 50%, 5 pts had partial response, and 12 pts had stable disease. Given the data with single-agent CTLA-4 and PD-1 inhibitors and that CTLA-4 inhibition can induce PD-L1 expression, there is reason to anticipate synergy when combining CTLA-4 and PD-1 inhibitors in MPM. A phase 2 study assessing nivo alone and nivo + ipi (a CTLA-4 inhibitor antibody) in MPM is ongoing. CheckMate 743 (NCT02899299) is a phase 3 study that will evaluate the efficacy and safety of first-line nivo + ipi vs chemotherapy for MPM. Methods: Approximately 600 adult pts with unresectable MPM and ECOG performance status 0–1 will be randomized. Pts are ineligible if they have primary peritoneal, pericardial, or tunica vaginalis testis mesotheliomas; have active, untreated CNS metastases; or had received prior systemic therapy for pleural mesothelioma or a prior PD-1/PD-L1 or CTLA-4 checkpoint inhibitor antibody. Pts are randomized 1:1 to receive nivo + ipi or pemetrexed + cisplatin/carboplatin. Primary endpoints are OS and progression-free survival (PFS), assessed by blinded independent central review. Secondary endpoints are objective response rate (ORR), DCR, and correlation of PD-L1 expression level and efficacy (ORR, PFS, and OS). Clinical trial information: NCT02899299.