New phase 1 SURPASS trial cohort: Early-line ADP-A2M4CD8 T-cell receptor T-cell therapy plus pembrolizumab in urothelial carcinoma.
Authors: Aggen David H , Garcia Alejandro , Saro Suarez Jose M , Sauer Amy , Cristiani Sebastiano , Brophy Francine Elizabeth , Streets Sharon , Norry Elliot , Nelson Ariel Ann , Kilari Deepak , Garmezy Benjamin , Charlson John A. , Zugazagoitia Jon , Calvo Emiliano , Moreno Irene , Moreno Victor , Hoimes Christopher J. , Hong David S. , Cervantes Andres 
Published: January 2024

TPS708 Background: ADP-A2M4CD8 T-cell receptor (TCR) T-cell therapy consists of autologous CD4+ and CD8+ T-cells genetically modified to target melanoma-associated antigen A4 (MAGE-A4) in patients (pts) with advanced cancers who are human leukocyte antigen A*02 eligible. In the late-line setting, ADP-A2M4CD8 monotherapy has demonstrated an acceptable benefit-to-risk profile and clinical responses across multiple tumor types in the ongoing Phase 1 SURPASS trial (NCT04044859). As of November 23, 2022, there were encouraging signs of antitumor activity in the 7 pts with advanced urothelial carcinoma (UC) treated in SURPASS, with best overall responses of 1 complete response, 3 partial responses, and 3 stable disease, giving an overall response rate of 57.1% and a disease control rate of 100% (Aggen DH. et al., Poster 517, ASCO-GU 2023; San Francisco, CA, USA). Furthermore, inhibiting immunosuppressive pathways may enhance antitumor activity. Thus, a new SURPASS cohort consisting of early-line ADP-A2M4CD8 TCR T-cell therapy combined with pembrolizumab in participants with UC has been opened. Methods: A dedicated UC cohort will enroll ≤15 pts with unresectable locally advanced or metastatic UC who have received first-line cisplatin-based standard-of-care (SOC) chemotherapy and are either currently receiving second-line SOC pembrolizumab or have received avelumab maintenance therapy and no second-line therapy. Key eligibility criteria include >30% of tumor cells expressing MAGE-A4 (≥2+ by immunohistochemistry); positivity for HLA-A*02:01, 02:02, 02:03, or 02:06 alleles; measurable disease per RECIST v1.1 prior to lymphodepletion; and ECOG performance status of 0 or 1. T-cells are collected by leukapheresis, transduced with a lentiviral vector expressing the MAGE-A4-specific TCR and an additional CD8α co-receptor designed to increase functionality of CD4+ T-cells, and expanded ex vivo. Pts receive lymphodepletion chemotherapy consisting of cyclophosphamide 600 mg/m2/day for 3 days and fludarabine 30 mg/m2/day for 4 days followed by ADP-A2M4CD8 infusion (1x109 to 10x109 transduced T-cells) and subsequent pembrolizumab 400 mg (administered every six weeks for ≤2 years, until unacceptable toxicity or disease progression). Primary and secondary endpoints include evaluation of adverse events (AEs), serious AEs, AEs of special interest, and overall response rate per RECIST v1.1 by investigator review, respectively. Trial registration number: NCT04044859. Editorial acknowledgement:This study is sponsored by Adaptimmune (Philadelphia, PA, USA). Writing and editorial support was from Excel Scientific Solutions (Fairfield, CT, USA); funding was provided by Adaptimmune. Clinical trial information: NCT04044859 .