Thistlethwaite, Fiona

Abstract Purpose: AXL, a receptor tyrosine kinase related to oncogenic processes, is aberrantly expressed in various cancers and associated with treatment resistance. Enapotamab vedotin (EnaV), a novel anti-AXL human IgG1 and monomethyl auristatin E antibody–drug conjugate, demonstrated antitumor activity in preclinical models, including non–small cell lung cancer (NSCLC). This phase 1/2 study assessed the safety and preliminary efficacy of EnaV in solid tumors. Patients and Methods: This study comprised dose-escalation and dose-expansion phases; both phases investigated EnaV once every 3 weeks (Q3W) and EnaV on days 1, 8, and 15 of a 28-day cycle (3Q4W). Primary objectives determined the maximum tolerated dose (dose escalation) and safety (dose expansion). Pharmacokinetic profile, antitumor activity, and AXL expression were also assessed. Results: During dose escalation, 32 patients received EnaV Q3W; 15 received EnaV 3Q4W. The maximum tolerated dose and recommended phase 2 dose were 2.2 mg/kg in Q3W and 1.0 mg/kg in 3Q4W schedules. In dose expansion, 189 patients received EnaV Q3W; 70 received EnaV 3Q4W. Common adverse events in dose expansion included fatigue, constipation, nausea, decreased appetite, and diarrhea. Overall response rates ranged from 4.5% to 12.5% with Q3W dose schedule and from 9.1% to 11.5% with 3Q4W dose schedule. Disease control rates for NSCLC cohorts were 40.9% to 50.0%. NSCLC subset analysis demonstrated correlation between radiomics signature and disease control. The relationship between clinical activity and AXL expression was not apparent. Conclusions: EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued. Significance: EnaV, an anti-AXL human IgG1 and monomethyl auristatin E antibody–drug conjugate, showed single-agent antitumor activity in preclinical models. This phase 1/2 study of EnaV demonstrated a manageable safety profile and antitumor activity in selected tumor types. Further studies exploring alternative targeting modalities, patient selection, and/or combinations are needed.

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.