Background NY-ESO-1–specific T cells (letetresgene autoleucel [lete-cel]; GSK3377794) are autologous T cells transduced with a self-inactivating lentiviral vector to express an engineered NY-ESO-1–specific TCR that recognizes HLA-A*02–presented peptides derived from NY-ESO-1, a cancer/testis antigen expressed in 70%–80% of SS. NCT01343043 was a Phase I, open-label trial assessing safety, efficacy, and pharmacokinetics of lete-cel in patients with SS; activity was evaluated after different lymphodepletion conditioning regimens and in patients with differing levels of NY-ESO-1 expression.

Methods Patients with unresectable, metastatic, or recurrent SS who were intolerant/nonresponsive to standard first-line chemotherapy enrolled in 4 cohorts based on NY-ESO-1 tumor expression were lymphodepleted and received lete-cel infusion (table 1). Primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1; secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Transduced cell persistence was measured by qPCR of transgene vector copies in DNA extracted from PBMCs. Study was not designed/powered to compare cohorts.

Results Overall, 50 patients enrolled; 45 received lete-cel infusion (modified intent-to-treat population). Demographics were similar between cohorts. Median time in study was 480/278/605/643 days in Cohorts 1/2/3/4, respectively. At study completion, ORR ranged from 20%–50% between cohorts, with 1 complete (lasting 34 weeks) and 14 partial responses (table 1). In Cohorts 1/2/3/4, respectively, median DoR was 31.0/8.6/32.1/16.4 weeks; median PFS was 15.4/13.1/8.6/22.4 weeks (table 1). As of 27Jan2020, median OS for Cohorts 1/2/3 was 24.3/9.9/19.9 months; Cohort 4 median OS was immature (table 1). Across cohorts, Grade ≥3 adverse events (AEs) in ≥40% of patients were mostly hematologic in nature; Grade ≥3 serious AEs (SAEs) were most frequently febrile neutropenia, dyspnea, and neutropenia (table 2). AEs of special interest included cytokine release syndrome in 44% of patients (n=20; maximum Grade 1/2/3/4 in 9/7/3/1 patients, respectively; 5 patients had SAEs [Grade ≥3 in 2 patients]; all AEs/SAEs resolved); Guillain-Barré syndrome in 2 patients (Grade 3 SAEs; resolved with sequalae); and multilineage cytopenias in 96% of patients (n=43; maximum Grade 5 in 1 patient, Grade 3/4 in others). Peak persistence of transduced cells was generally higher in responders vs non-responders (table 1); time to peak persistence was similar between these groups (median 8 days). No patients tested positive for replication-competent lentivirus.

Conclusions In patients with advanced SS who need effective treatment, lete-cel had a manageable safety profile; responses occurred in all cohorts, but patients with high NY-ESO-1 expression and more intensive lymphodepletion regimen received greatest benefit.

Acknowledgements This study (208466) was funded by GlaxoSmithKline. Medical writing assistance was provided by Gemma Corr, DPhil, and Tiffany Brake, PhD, of Fishawack Indicia, UK, and funded by GlaxoSmithKline. We thank Ran Ji for contributions to statistical analysis.

Trial Registration Clinicaltrials. gov NCT01343043

Ethics Approval This study was approved by the appropriate institutional review boards and independent ethics committees.