Lete-Cel Generates Durable Responses in Synovial Sarcoma and Myoxid/Round Cell Liposarcoma

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Treatment with letetresgene autoleucel (lete-cel; GSK3377794) generated durable responses in patients with previously treated advanced or metastatic myxoid/round cell liposarcoma (MRCLS) or synovial sarcoma (SyS) expressing NY-ESO-1, meeting the primary efficacy end point of the ongoing phase 2 IGNYTE-ESO trial (NCT03967223).¹

​​Results from the primary analysis of IGNYTE-ESO presented during the 2024 CTOS Annual Meeting showed that in the overall population (n = 64), lete-cel produced an overall response rate (ORR) of 42% (95% CI, 29.9%-55.2%) by central independent review assessment, including a complete response (CR) rate of 9% and partial response (PR) rate of 33%. Stable disease (SD) was achieved by 47% of patients, and 9% experienced progressive disease (PD). One patient was not evaluable (NE).

When broken down by sarcoma subgroup, the ORRs were 41% (95% CI, 24.6%-59.3%) for patients with SyS (n = 34) and 43% (95% CI, 25.5%-62.6%) for those with MRCLS (n = 30). Respective CR rates were 9% and 10%; respective PR rates were 32% and 33%. SD was observed in 41% of patients with SyS and 53% of those with MRCLS. PD occurred in 15% and 3% of patients in these subgroups, respectively. One patient in the SyS group was NE.

The median duration of response (DOR) was 12.2 months (95% CI, 6.8-19.5) in the overall population, 18.3 months (95% CI, 3.3-not reached [NR]) in the SyS group, and 12.2 months (95% CI, 5.3-NR) in the MRCLS group. The median progression-free survival (PFS) was 5.3 months (95% CI, 4.0-8.0), 3.9 months (95% CI, 2.6-7.8), and 7.7 months (95% CI, 5.2-9.2) in these respective patient populations.

“These results support the advancement of lete-cel as a novel therapy for patients with unresectable or metastatic SyS and MRCLS, [and submission of a] biologics license application to the FDA planned,” Sandra P. D’Angelo, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and study coauthors wrote in a presentation of the data. “Further analyses of translational correlates are pending.”

Lete-cel comprises autologous CD4- and CD8-positive T cells that have been genetically modified to express a T-cell receptor (TCR) capable of recognizing the NY-ESO-1 peptide. This peptide is often present on HLA-A*02:01, A*02:05, or A*02:06 surface markers. The agent has over 12-fold greater binding affinity for NY-ESO-1:HLA complexes compared with naturally occurring TCRs.

Lete-cel previously demonstrated clinical activity in 2 phase 1 pilot studies of patients with SyS (NCT01343043) and MRCLS (NCT02992743), respectively; ORRs ranged from 20% to 50% and 20% to 40% across cohorts in these respective studies. IGNYTE-ESO was subsequently designed to further evaluate lete-cel in these populations. Findings from substudy 1 of IGNYTE-ESO showed an ORR of 80% in treatment-naive patients with SyS.² Accordingly, a second substudy of IGNYTE-ESO was conducted in patients with previously treated SyS or MRCLS whose disease progressed following treatment with anthracycline-based chemotherapy.¹

Overview of IGNYTE-ESO Substudy 2 Design

IGNYTE-ESO is a master protocol composed of 2 independent substudies.² Substudy 1 was an open-label pilot study of lete-cel in treatment-naive patients with metastatic or unresectable SyS or MRCLS.

Substudy 2 is an open-label, international trial evaluating the agent in patients at least 10 years of age with NY-ESO-1–expressing metastatic or unresectable SyS or MRCLS, defined as 30% or greater staining at 2+/3+ per immunohistochemistry.1 Patients are also required to be HLA-A*02:01, *02:05, or *02:06 positive; have started or received an anthracycline-based chemotherapy prior to apheresis; have progressed on their last prior line of therapy, excluding bridging therapy; and have measurable disease per RECIST 1.1 criteria before undergoing lymphodepletion.

Following HLA and NY-ESO-1 screening of 407 patients, 98 eligible patients enrolled onto the study who underwent leukapheresis and awaited lete-cel manufacturing between days –17 to –8. Bridging therapy was permitted during this period, and baseline tumor measurements were obtained.

Lymphodepletion chemotherapy was administered to 78 patients on days –7 to –4. Reasons for not undergoing lymphodepletion included physician decision (n = 9), death (n = 7), not meeting eligibility criteria (n = 3), or patient withdrawal (n =1).

On day 1, 77 of these patients received lete-cel at a dose of 1 to 15 x 109 transduced cells alongside a cumulative 120 mg/m2 of fludarabine and 2700 to 3600 mg/m2 of cyclophosphamide over 3 to 4 days. Dose reductions of fludarabine and cyclophosphamide were permitted when given after the infusion of lete-cel. Scans were performed at weeks 6, 12, 18, and 24 before being conducted every 3 months until the end of intervention. Follow-up is planned for up to 15 years.

The study’s primary end point is ORR per RECIST 1.1 criteria by central independent review; to meet this end point, the ORR in the study population needed to be at least 40%. Secondary end points include safety ORR by investigator assessment, time to response, DOR, disease control rate, PFS, and overall survival.

At the data cutoff date of March 1, 2024, 66 patients had received the intended commercial supply of lete-cel; 64 received a lete-cel–conforming product. These patients comprised the safety and efficacy populations, respectively. Notably, all HLA-eligible patients with MRCLS were also NY-ESO-1 eligible compared with 65% of HLA-eligible patients with SyS.

In the efficacy evaluable population, the majority of patients were male (56%), White (97%), and had metastatic disease at screening (98%). The median age of patients was 46 years (range, 18-70), and the median dose of transfused cells was 6.7 x 109 (range, 1.1-11.4).

Prior to leukapheresis, 11% of patients received no prior systemic therapy regimens for advanced/metastatic disease, 30% received 1 prior line of therapy, 41% received 2 prior lines of therapy, and 19% had 3 or more prior lines of therapy. All patients had previously received anthracyclines before lymphodepletion, and 77% had previously received ifosfamide. Half of patients received anticancer therapy between leukapheresis and lymphodepletion; only 8% received radiotherapy during this time.

Safety Results

Any-grade treatment-related adverse effects (TRAEs) were reported in 98% of patients in the safety population, including 89% who had grade 3 or higher TRAEs. TRAEs occurring in at least 15% of patients included neutropenia (any-grade, 73%; grade ≥3, 73%), thrombocytopenia (64%; 48%), anemia (62%; 44%), leukopenia (48%; 47%), febrile neutropenia (29%; 27%), fatigue (21%; 0%), alopecia (20%; 0%), diarrhea (20%; 0%), decreased appetite (18%; 3%), nausea (18%; 0%), increased aspartate aminotransferase (AST) levels (17%; 9%), and hypophosphatemia (17%; 3%).

Notably, 1 grade 5 treatment-emergent, lymphodepletion-related AE was observed. This patient had a pulmonary alveolar hemorrhage in the setting of pancytopenia, and they had a platelet count of 0 despite HLA-matched platelets and platelet-stimulating agents.

Any-grade and grade 3 or higher T-cell–related AEs were reported in 97% and 85% of patients, respectively. Cytokine release syndrome (CRS) and rash were common and manageable.

The median time of onset to CRS was 2 days (range, 1-9), and the median duration was 7 days (range, 2-51). Tocilizumab (Actemra), corticosteroids, and anakinra were administered to 79%, 27%, and 6% of patients who experienced CRS, respectively. Four patients experienced grade 1 immune effector cell–associated neurotoxicity syndrome.

Maculopapular rash was the most commonly-reported AE with a median time of onset of 7 days (range, 2-332) and median duration of 22 days (range, 1-498). One grade 5 T-cell–related AE of cardiac arrest was reported; this was attributed to primary pulmonary etiology.

T-cell–related AEs reported in at least 15% of patients included CRS (any grade, 92%; grade ≥3, 12%), rash (64%; 35%), neutropenia (45%; 42%), anemia (39%; 33%), thrombocytopenia (35%; 30%), increased alanine aminotransferase levels (32%; 17%), pyrexia (30%; 3%), increased AST levels (29%; 9%), diarrhea (24%; 0%), leukopenia (24%; 23%), nausea (24%; 0%), hypophosphatemia (20%; 0%), febrile neutropenia (18%; 17%), pruritis (18%; 0%), dyspnea (17%; 5%), and headache (15%;0%).

References

1. Furness A, Thistlethwaite F, Burgess M, et al. Primary analysis of the pivotal IGNYTE-ESO trial of lete-cel in patients with synovial sarcoma or myxoid/round cell liposarcoma. Presented at: 2024 CTOS Annual Meeting. November 13-16, 2024; San Diego, California. Abstract P84.
2. Burgess M, Noujaim J, John S, et al. Primary analysis of efficacy and safety of letetresgene autoleucel (Lete-cel) as first-line treatment for unresectable or metastatic Synovial Sarcoma (SyS); Substudy 1 of IGNYTE-ESO. Presented at: 2023 CTOS Annual Meeting. November 1-4, 2023; Dublin, Ireland. Abstract P114.