Tine, Brian Andrew Van

Abstract MT-5111 is a 55kD engineered toxin body targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 works by internalizing, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. This is a phase 1 study in adults with advanced HER2+ solid tumors. MT-5111 is dosed weekly IV over 30 min in every 21-day cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. The study has dose escalation (Part A) cohorts enrolling patients (pts) with any HER2+ cancer (CA) and expansion (Part B) cohorts for HER2+ breast cancer (BC), Gastric or Gastroesophageal junction adenocarcinoma (GEA), or other HER2+ solid CA. As of 30 June 2022, 42 total pts had enrolled (36 in Part A on 0.5-23 µg/kg/dose, 6 pts with BC in Part B1 on 10 µg/kg/dose). Median age 65 years, 28 (66.78%) pts were female, median of 4 prior systemic and 2 prior HER2-targeting treatment (tx). 17 pts with BC, 6 with biliary CA, 9 with GEA, and 10 with other solid CA have enrolled. Of the 17 BC pts, 15 received ≥ 10 µg/kg/dose. Tx emergent adverse events (TEAEs) have been reported in 40 (95%) pts, and tx-related AEs (TRAE) occurred in 23 (55%) pts. No pt experienced G4-G5 TRAE. G1 troponin elevations were noted in 5 pts without clinical signs of cardiotoxicity (1 pt 6.75 µg/kg, 2 pts 10 µg/kg, 1 pt 17 µg/kg, 1 pt 23 µg/kg). Reversible G1/G2 infusion-related reactions were reported in 2 pts. Tx-related G1-G3 rash was observed in 5 pts (4 pts ≥ 10 µg/kg/dose); maculopapular in 2 pts, acneiform in 1 pt and associated with pruritus in 3 pts. The G3 rash developed one wk after first dose of 23 µg/kg, was declared a DLT, improved with systemic steroid therapy and the pt continued tx at the same dose without recurrence. Best overall response per RECIST thus far is stable disease (SD) in 17 pts, non-CR/non-PD in 1 pt, and progressive disease (PD) in 14 pts. 1 pt had non-CR/non-PD for 30 wks (1 μg/kg, BC); 1 pt had SD for 24wks (10 μg/kg, pancreatic); 1 pt is on tx with SD through 8 cycles (10 μg/kg, BC). Of the 10 BC pts who received ≥ 10 μg/kg/dose, the best response was 5 SD. The mean serum concentration of MT-5111 has increased in a dose-proportional manner starting at 6.75µg/kg/dose (Table 1). The soluble HER2 (sHER2) levels at end of tx were higher compared to baseline in cohorts that received ≤ 4.5µg/kg/dose, but similar or lower in cohorts that received ≥ 6.75µg/kg/dose. Higher MT-5111 doses have been well tolerated and may saturate circulating sHER2, leading to more predictable serum concentrations and tumor penetration. The Cmax in humans at doses ≥6.75 µg/kg/dose is above the in vitro IC50 for high HER2+ cell lines (0.029nM) and at 17 µg/kg/dose, above the IC50 for moderate HER2+ cells (1.6nM). In conclusion, the dose proportionate increase in serum concentration with levels above the in vitro IC50 and the leveling off/reduction of sHER2 indicate exposure to MT-5111 is at clinically therapeutic levels. Skin toxicity at higher doses may indicate on-target effect as observed in other EGFR-targeted therapies where it is associated with clinical response and a better prognosis. sHER2 biomarker data is expected for all cohorts with PK correlation and 23µg/kg safety and efficacy data. PK profile of MT-5111, C1D1 values Citation Format: Meena Okera, Brian A. Van Tine, Joleen M. Hubbard, Minal Barve, Erika Hamilton, Monica M. Mita, Frances Valdes-Albini, Daniel Ahn, Admasu Mamuye, Joshua Pelham, Amy Yuet, Diana Yurewicz, Yanning Liu, Andres Machado Sandri, William J. Edenfield, Aki Morikawa, William Gradishar, Rajiv Kumar, Zev A. Wainberg. A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+ tumors: interim results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-11-01.

11562 Background: Afami-cel is an autologous, HLA-A*02-restricted, specific peptide enhanced affinity receptor, T-cell therapy engineered to target MAGE-A4+ solid tumors. The pivotal, 2-cohort, single-arm, Phase 2, SPEARHEAD-1 trial (NCT04044768) with afami-cel met its primary endpoint based on Cohort 1 data. As of September 1, 2021, in 47 patients (pts) with metastatic synovial sarcoma (SyS) or myxoid/round cell liposarcoma (MRCLS), the overall response rate (ORR) per independent review was 34% with encouraging durability (Van Tine, et al. Paper 30: CTOS 2021; Virtual). To identify potential stratification factors for response and assess whether response is a proxy for progression-free survival (PFS), we present pooled analyses using data from the prior Phase 1 trial (NCT03132922) and Cohort 1 of the SPEARHEAD-1 trial. Methods: Eligible pts (16–75 years) were HLA-A*02+ with MAGE-A4+ tumors. Pts received afami-cel after lymphodepleting chemotherapy. The pooled analyses evaluated ORR per RECIST v1.1 by investigator review, stratified by 7 factors, and safety. Results: In the pooled data, 69 pts received afami-cel (2.12–9.99×109 transduced T-cells) and were evaluable for response (Phase 1, n = 18; Phase 2, n = 51); all expressed one eligible HLA-A*02 allele. Median (range) for: age was 42 years (19–76), number of prior lines of therapy was 2 (1–12), and tumor MAGE-A4 H-score was 230 (60–300). Median (range) H-score was higher in SyS (256 [60–300]) than in MRCLS (180 [112–230]). The pooled investigator-assessed ORR was 36.2% (40.7% in SyS; 10.0% in MRCLS). Responses occurred across a wide MAGE-A4 H-score range (134–300). Median (range) duration of response was 52 weeks (8.29–75.14). Response rate was higher in the 59 pts with SyS: with ≤2 vs ≥3 prior lines of therapy (55.2% vs 26.7%), baseline target lesion sum of longest diameters <10cm vs ≥10cm (53.1% vs 25.9%), MAGE-A4 H-score ≥200 vs <200 (46.3% vs 27.8%), without vs with bridging therapy (48.6% vs 29.2%), who were female vs male (46.4% vs 35.5%), aged ≥40 vs <40 years (45.7% vs 33.3%), and from North America vs Europe (42.6% vs 33.3%). In responders vs non-responders with SyS, respectively, median PFS was 58.3 vs 11. 0 weeks (log-rank p-value <0.0001); the probability of being progression-free at 24 weeks was 0.8 vs 0.2. The pooled benefit:risk profile of afami-cel was similar to that in the SPEARHEAD-1 trial (Van Tine, et al. Paper 30: CTOS 2021; Virtual.). Conclusions: We show that baseline tumor burden, prior systemic treatment history, and MAGE-A4 tumor expression levels are potential factors associated with response to afami-cel, although their true predictive value for response status awaits confirmation. Our findings will inform the ongoing clinical development of afami-cel in sarcoma, especially for prognostic studies with PFS or overall survival endpoints. Clinical trial information: NCT04044768, NCT03132922.

11507 Background: Leiomyosarcoma (LMS) is one of the most common subtypes of soft tissue sarcoma and is associated with high risk of relapse and a poor prognosis for advanced disease. In preclinical LMS models, unesbulin, a microtubule polymerization inhibitor, potentiated the activity of dacarbazine (DTIC) (Jernigan F, et al. Mol Cancer Ther. 2021;20:1846–1857). Here, we report preliminary safety and efficacy results from a Phase 1b dose escalation study evaluating the combination of unesbulin with DTIC in patients with advanced LMS (NCT03761095). Methods: In this single-arm, open-label, Phase 1b clinical trial, patients with advanced LMS received unesbulin orally at 200, 300, or 400 mg twice weekly (BIW) in combination with intravenous DTIC at 1,000 mg/m2 once every 21 days. The primary objectives were to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of unesbulin in combination with DTIC and to characterize the safety profile of the combination. The time-to-event continual reassessment model (TITE-CRM) was used for dose finding. An expansion cohort with up to 12 additional patients is currently being enrolled. Results: As of the data cutoff on January 6, 2022, 29 LMS patients have been treated. Median prior lines of therapy were 3 (range 1–6). Of 27 evaluable patients, 12 had non-uterine and 15 had uterine LMS. The MTD/RP2D of unesbulin was determined to be 300 mg BIW with DTIC 1,000 mg/m2 every 21 days using the TITE-CRM. At the RP2D, the most common treatment-related adverse events included fatigue, diarrhea, neutropenia, and thrombocytopenia. In the intent-to-treat population, the overall response rate (ORR) was 17.2% (5/29) and the disease control rate (DCR) (DCR = complete response + partial response + stable disease at 12 weeks) was 58.6%. At the 300 mg dose level, the ORR was 19% (4/21) and the DCR was 57.1%. Patients received a median of four cycles (range 1–12). The study is ongoing, with patients continuing to receive treatment. Conclusions: Unesbulin 300 mg BIW in combination with DTIC 1,000 mg/m2 every 21 days was well tolerated and demonstrated promising efficacy in a heavily pre-treated patient population with advanced LMS; these results support further investigation. Updated clinical results will be presented as the data mature. A randomized, placebo-controlled, Phase 2/3 trial is planned. Clinical trial information: NCT03761095.

2583 Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death or withdrawn consent. Results: As of Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUClast data match PK simulations in non-human primate studies. Cmax at 10 µg/kg/dose is ≥5 times the IC50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.

Abstract Background: Engineered toxin bodies (ETBs) are composed of a de-immunized Shiga-like Toxin A subunit genetically fused to an antibody-like binding domain. ETBs can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other therapeutics. MT-5111 is a 55 kD ETB targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of MT-5111 monotherapy in adult pts with advanced HER2+ solid tumors. Secondary objectives are pharmacokinetics (PK), efficacy, and immunogenicity. Using a modified 3+3 design, the dose-escalation part of the study enrolls pts with HER2+ tumors into 7 cohorts: 0.5, 1, 2, 3, 4.5, 6.75, and 10 µg/kg/dose. Three dose-expansion cohorts will follow for HER2+ breast cancer, gastro-esophageal cancer, and other HER2+ tumors. All pts receive MT-5111 weekly as 30-min IV infusions in each 21-day treatment (tx) cycle (C) until disease progression (PD), unacceptable toxicity, death, or withdrawn consent (NCT04029922). Results: Per data cut in June 2021, 21 pts (mean age 64 years, range 34-78; 38% male) in cohorts 1-6 with breast (n=7), biliary (n=6), gastric (n=3), pancreatic (n=2), lung (n=2), and colon (n=1) cancer were treated (Table 1). Pts had a median of 4 prior lines of systemic therapies (range, 1-8) and 2 prior lines of HER2-targeting treatments (range, 0-6). No Grade (G)4 or 5 tx-emergent (TE) adverse events (AEs) occurred. Tx-related AEs occurred in 11 (52%) pts; the most common was fatigue (n=7, 33%). One pt (4.5 µg/kg) had a possibly (per PI) related G3 serious AE (SAE) of dyspnea and hypoxia, but also lymphangitic carcinomatosis and H. influenzae infection. The other related SAE occurred in a pt (6.75 µg/kg) who had a G1 transient troponin increase without concomitant cardiac symptoms or ECG/ECHO changes. All other related AEs were ≤G2. There were no clinically significant changes in cardiac biomarkers (troponin, ECG, left ventricular ejection fraction) nor were there cases of capillary leak syndrome. Two pts (3 µg/kg and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies, and Cmax data at 6.75 µg/kg indicated that current in-human exposure was between the IC50 values of high and medium HER2-expressing cell lines (approximately 10-89 ng/mL). Thus, a dose of at least 10 µg/kg may be required to achieve effective exposure. To date, no dose-limiting toxicities have been observed and the 10 µg/kg/dose cohort is now accruing. Conclusions: MT-5111 was well tolerated with no clinically significant immuno- or cardiotoxicity. Dose escalation is ongoing and nearing levels expected to be required for efficacious exposure. Table 1.Metastatic HER2 status and MT-5111 treatment by cohortDose0.5 µg/kg1.0 µg/kg2.0 µg/kg3.0 µg/kg4.5 µg/kg6.75 µg/kgCohort123456Number of patients treated with MT-5111433335Metastatic HER2 2+ by IHC: ALL/BC1/11/11/01/10/04/0Metastatic HER2 3+ by IHC: ALL/BC3/12/02/12/13/01/1BC, breast cancer. Citation Format: Brian A. Van Tine, Monica Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel Ahn, Joleen Hubbard, Jason Starr, Angela Georgy, Joshua Pelham, Banmeet S. Anand, Thomas Strack, Andrés Machado Sandri, Zev A. Wainberg. Interim results of a phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+tumors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-45.

297 Background: MT-5111 is a 55 kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction and does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: This is a phase 1 study in adult pts with advanced HER2+ solid tumors. The dose-escalation portion (modified 3+3 design) enrolls pts into sequential cohorts followed by expansion cohorts for HER2+ breast cancer (BC), gastric or gastroesophageal junction adenocarcinoma (GEA), and other HER2+ tumors. MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. Results: As of Sep 2021 (contains preliminary data), 24 pts (mean age 64 yrs) were treated, 13 (54%) of whom had gastrointestinal (GI) tumors (6 biliary, 3 GEA, 2 pancreatic, 2 colo/rectal) (Table). Pts with GI tumors had a median of 3 prior systemic tx and 1 prior HER2-targeting tx. No Grade (G) 4/5 tx-emergent adverse events (AEs) occurred. Tx-related AEs occurred in 13 (54%) pts, most commonly fatigue (n=7, 29%). One pt with biliary cancer and concurrent lymphangitic carcinomatosis and H. influenzae infection (4.5 µg/kg) had a possibly related G3 serious AE (SAE) of dyspnea, which resolved 9 days later. Another related SAE occurred in a pt with GEA (6.75 µg/kg) who had a G1 transient troponin increase that resolved during hospitalization, with no clinical symptoms or ECG/ECHO changes; the pt withdrew from study before further dosing. All other related AEs were ≤G2. No other clinically significant changes in cardiac biomarkers (troponin, ECG, LVEF) or cases of capillary leak syndrome occurred. Two pts (3 and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies. Cmax data at 10 µg/kg indicate that current in-pt exposure was between IC50 values of high and medium HER2-expressing cell lines (approx 10-89 ng/mL). Thus, at least 10 µg/kg may be required to achieve effective exposure. No dose-limiting toxicities have been observed. The 10 µg/kg cohort is now accruing. Following this cohort, an expansion cohort for pts with BC will open. Conclusions: MT-5111 was well tolerated with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing and is nearing levels expected to be required for efficacious exposure. Clinical trial information: NCT04029922. [Table: see text]

TPS11582 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell product using a genetically modified T-cell receptor to target cancer cells expressing the cancer testis antigen New-York esophageal squamous cell carcinoma 1 (NY-ESO-1). Lete-cel is currently being investigated alone and in combination in multiple tumor types [1,2]. NY-ESO-1 is expressed in 70‒80% of synovial sarcoma (SS) and 80‒90% of myxoid/round cell liposarcoma (MRCLS) tumors [3,4], suggesting these tumors may be prime lete-cel targets. This master protocol design (IGNYTE-ESO; NCT03967223) enables evaluation of multiple cell therapies in multiple tumor types and treatment stages in separate substudies, beginning with lete-cel in Substudies 1 and 2 for SS and MRCLS. Methods: Substudy 1 is a single-arm study assessing lete-cel in treatment-naïve patients (pts; ie, anthracycline therapy-naïve for metastatic disease) with advanced (metastatic/unresectable) NY-ESO-1+ SS or MRCLS as a first line of therapy (n=10 planned). Substudy 2 is a pivotal, single-arm study assessing lete-cel in pts with NY-ESO-1+ SS or MRCLS who progressed after anthracycline therapy (n=70 planned). Key eligibility criteria are age ≥10 y and NY-ESO-1 and HLA-A*02 positivity. Exclusion criteria include prior NY-ESO-1–specific/gene therapy, allogeneic stem cell transplant, and central nervous system metastases. Screened pts undergo leukapheresis for lete-cel manufacture, lymphodepletion, lete-cel infusion, and follow-up (FU). Long-term FU (15 y) may be done under a separate protocol. The Substudy 2 primary endpoint is overall response rate (ORR) per RECIST v1.1 assessed by central independent review. Substudy 1 is not testing any formal hypotheses; statistical analysis will be descriptive. Substudy 2 is comparing ORR with the historical control assuming at least 90% power with 0.025 one-sided type I error. Secondary endpoints include efficacy (time to/duration of response, disease control rate, progression-free survival), safety (adverse event [AE] frequency/severity, serious AEs, AEs of special interest), and pharmacokinetic (maximum transgene expansion [Cmax], time to Cmax, area under the time curve from zero to time t as data permit). Enrollment began in December 2019. References: 1. Reckamp KL, et al. Ann Oncol 2019;30(Suppl_5):v602–v660. 2. Rapoport A, et al. J Clin Oncol 2020 38:15_suppl, TPS8555. 3. D’Angelo SP, et al. Cancer Discov 2018;8(8):944–957. 4. D’Angelo SP, et al. J Clin Oncol 2018 36:15_suppl, 3005. Funding: GSK. Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Previously presented at BSG 2021 (P914542). Clinical trial information: NCT03967223.

11517 Background: Doxorubicin (doxo) remains standard first-line therapy for advanced STS. Doxo in combination with olaratumab (O) demonstrated superior clinical activity compared to doxo alone in a Ph 2 trial (NCT01185964), although this was not confirmed in the subsequent Ph 3 trial (NCT02451943). Gemcitabine (G) plus docetaxel (D) is a second line therapy for advanced STS. Here, we report a concurrent Ph 2 study that explored a second-line addition of O to G and D for advanced STS (ANNOUNCE 2 NCT02659020). Methods: Adult patients (pts) with unresectable locally advanced or metastatic STS, ≤ 2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. Pts were enrolled from 2 cohorts: O-naïve and O-pretreated. In both cohorts, pts were randomized 1:1 to either O, G plus D or placebo (PBO), G plus D. Pts received 21-day cycles of O (20 mg/ kg cycle 1 and 15 mg/kg other cycles, day (d) 1 and d8), G (900 mg/m2, d1 and d8) and D (75 mg/m2, d8). Pts continued treatment until progression, toxicity, or withdrawal. Randomization was stratified by histology (leiomyosarcoma [LMS] vs non-LMS), prior systemic therapy, ECOG PS, and prior pelvic radiation. The primary objective was overall survival (OS) in the O-naïve population using an alpha level of 0.20. Secondary endpoints included OS (O-pretreated) and other efficacy parameters, as well as safety and pharmacokinetics (PK). Results: 167 pts were enrolled in the O-naïve cohort and 89 pts in the O-pretreated cohort. Baseline patient characteristics were well balanced. OS for O-naïve pts was 16.8 vs 18.0 months (m) (hazard ratio [HR] = 0.95, 95% CI: 0.64-1.40; p = 0.78) for the investigational vs control arm, respectively. Other efficacy outcomes are presented in the table. Safety was manageable across treatment arms. PK parameter estimates for O were consistent with previous studies. Conclusions: There was no statistically significant difference in OS between the two arms in the O-naïve population. However, while not statistically significant, the combination of O, G and D demonstrated favorable OS in the O-pretreated cohort, and PFS and objective response rate (ORR) in both cohorts. For O-naïve pts, a clinically meaningful progression-free survival (PFS) improvement was observed. Further investigations in specific histological subtypes are ongoing. Clinical trial information: NCT02659020. [Table: see text]

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

11504 Background: This phase 2, open-label trial (SPEARHEAD-1; NCT04044768) is designed to evaluate the efficacy, safety, and tolerability of afamitresgene autoleucel in 45 patients (pts) with advanced/metastatic synovial sarcoma or Myxoid/Round Cell Liposarcoma (MRCLS). Methods: Eligible pts are HLA-A*02 positive with MAGE-A4-expressing tumors. Pts undergo leukapheresis for collection of autologous T-cells for processing and manufacture into afamitresgene autoleucel cells. Pts were treated with afamitresgene autoleucel doses between 1–10 × 109 transduced T-cells after receiving lymphodepleting chemotherapy. The primary endpoint is overall response rate per RECIST v1.1 by independent review. An independent Data Safety Monitoring Board reviews ongoing safety and benefit: risk during the interventional phase. Results: As of Feb 4, 2021, 32 pts received afamitresgene autoleucel. Of these pts, 59% were male, 87.5% had synovial sarcoma, the median age was 43 yrs (range: 24–73), and they had a median of 3 prior systemic lines of therapy. The MAGE-A4 antigen expression level (histoscore) ranged from 112–300, and the transduced cell dose ranged from 2.7–9.9 x 109. At the data cutoff, 25 pts were evaluable for preliminary efficacy (23 with synovial sarcoma and 2 with MRCLS) and 7 pts (5 with synovial sarcoma and 2 with MRCLS) had insufficient follow-up (<8 weeks follow-up and/or awaiting first scan). Of the 25 evaluable pts, the investigator-assessed responses were: complete response (2 pts), partial response (8 pts), stable disease (11 pts), and progressive disease (4 pts). All responses were confirmed. Nine of the 10 responders had ongoing response at the data cutoff and 3 responders had MAGE-A4 antigen histoscores <200. The most common AEs of any grade (>30% pts) were neutropenia, lymphopenia, nausea, cytokine release syndrome, leukopenia, fatigue, pyrexia, and anemia. Cytokine release syndrome of any grade occurred in 19/32 pts; 95% of those events were ≤Grade 2. No immune effector cell-associated neurotoxicity syndrome (ICANS) has been reported to date. Cytopenia (≥G3) at 4 wks post-infusion was observed in 6 pts (anemia 3 pts, neutropenia 2 pts, and thrombocytopenia 1 pt). Conclusion: These preliminary data demonstrate afamitresgene autoleucel is efficacious and well tolerated in heavily pre-treated pts. Objective responses are reported across a wide range of MAGE-A4 antigen levels and deep responses have been observed. Initial durability data is encouraging. Preliminary response data in SPEARHEAD-1 is comparable to the findings of the prior Phase 1 trial [1]. To date, the safety profile of afamitresgene autoleucel has been favorable, with mainly low-grade cytokine release syndrome and tolerable/reversible hematologic toxicities. [1]. Van Tine BA, et al. CTOS; November 18-21, 2020; Virtual. Clinical trial information: NCT04044768.