Portal de Periódicos da CAPES

64MO A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM)

2020; Elsevier BV; Volume: 31; Linguagem: Inglês

10.1016/j.annonc.2020.10.552

1569-8041

Joseph J. Sacco, Richard D. Carvajal, Marcus O. Butler, Alexander N. Shoushtari, Jessica C. Hassel, Alexandra P. Ikeguchi, Leonel F. Hernandez‐Aya, Paul Nathan, Omid Hamid, J.M. Piulats Rodriguez, Matthew J. Rioth, Douglas B. Johnson, Jason J. Luke, Enrique Espinosa, Serge Leyvraz, Howard Goodall, Christopher P. Holland, Shaad E. Abdullah, Takami Sato,

Cancer Immunotherapy and Biomarkers

mUM is a historically treatment-refractory tumor with high expression of gp100 and 12 month (mo) OS rate of 43% (Khoja L, et al. Ann Oncol. 2019; 30(8):1370-1380). Tebe is a bispecific consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells (melanocytes and melanoma). An intra-patient escalation regimen evaluated in Ph1 of the current study identified 68 μg as the phase 2 dose (Sato T et al. J. Clin. Oncol. 2018; 36(15_suppl): 9521). We conducted a Ph2 study of tebe in mUM pts. HLA-A*0201+ pts were treated at 24 centers with a regimen of QW iv dosing (20μg C1D1; 30μg C1D8; 68μg C1D15). 1° objective was ORR by RECIST 1.1 using independent central review (ICR). 2° objectives included safety, OS and PFS. 127 pts were treated (50% male; 70% ECOG 0, 58% LDH >ULN). All pts received ≥1 prior therapy in metastatic setting (34% ≥2 lines; 45% LDT; 73% immunotherapy (65% anti PD1, 31% anti CTLA4)). ORR (all PRs) was 5% (95% CI: 1.8%, 10.0%); median duration of response 8.7 mos. 45% pts achieved stable disease. Of pts with evaluable tumors (n=116), 44% had reduction in target lesions (TL) including immune-related responses. With median follow-up of 19.6 mos, median OS (mOS) was 16.8 mos (95% CI: 12.9, 21.3). 12 mo OS rate was 62%, 18 mo was 45%. 12 mo OS rate of pts with any TL reduction was 86%. Median PFS was 2.8 mos. Most common treatment related AEs (TRAEs) were generally cutaneous (gp100+ melanocytes) or cytokine mediated (T cell activation) and included pyrexia (80%), pruritus (67%), and chills (64%) with Grade ≥3 TRAE of rash maculo-papular (13%), hypotension (8%), increased aspartate aminotransferase (AST), and hypophosphatemia (5% each). TRAEs decreased in frequency and severity after first 3 doses. 86% pts experienced cytokine release syndrome (CRS) by ASTCT criteria (Lee DW, et al. Biol Blood Marrow Transplant. 2019; 25(4): 625-638); 3% Grade 3; 1% Grade 4. There were no grade 5 TRAEs. Pts who developed rash within 7 days of tebe start (64%) had superior mOS, 22.5 mos vs other pts, 10.3 mos. While the 1° endpoint of ORR was 5%, 44% pts had reduction in TL. 12 mo OS rate (62% all pts, 86% in pts with TL reduction) was promising. Related AEs were generally predictable, manageable, decreased in frequency and severity over first few doses and were consistent with proposed MoA. Tebe is being evaluated in a randomised pivotal trial with 1° endpoint of OS.