Safety, efficacy and biology of the gp100 TCR-based bispecific T cell redirector IMCgp100 in advanced uveal melanoma

Abstract

Purpose : Uveal melanoma (UM) is characterized by low PD-L1 expression, low mutational burden and limited efficacy with checkpoint inhibition. IMCgp100 is a bispecific T cell redirector with an affinity-enhanced TCR recognizing gp100 and an anti-CD3 scFV. Two phase 1 trials evaluated safety, pharmacokinetics, pharmacodynamics and efficacy for IMCgp100 administered IV weekly in HLA-A2+ patients (pts): (1) a first in human study enrolling pts with melanoma including a cohort with advanced UM (n=16) where the intra-patient escalation (IE) dosing regimen was defined and (2) a second study with dose escalation of the IE regimen for pts with advanced UM 9N=19) in vestigating increasing exposures with the altered regimen, and is reported here.

Methods : Endpoints included overall response rate (ORR) by RECISTv1.1, progression free survival (PFS), and overall survival (OS). THe IE phase 1 trial allowed treatment beyond progression assessed by modified immune-related response criteria in specific settings. The IE regimen was designed to mitigate toxicity with reduced doses of 20 mcg and 30 mcg administered at weeks 1 and 2 and dose escalation implemented at dose 3 (day 15).

Results : The most frequent adverse events (AE, any grade) were rash (90%), pruritus (90%) and edema (63%). The most frequent grade 3 or 4 AE was hypotension (16%). The RP2D was 68 mcg defined with DLT of transaminase elevations. The ORR was 11% (2/19 evaluable) with an additional 5 patients achieving minor (-10 to -29% reduction) responses (26%) including pts treated with prior checkpoint inhibiton and elevated LDH. Median PFS by RECISTv1.1 was 5.6 months and the 1 year PFS rate by irRC was 62%. The 1 year OS rate in the IE trial was 73% (95% CI [46, 88]) and median OS has not been reached with median follow up of 12.8 months. With 3 doses of IMCgp100, immunofluorescence studies demonstrate an influx of PD-1+/CD8+ T cells in the tumor bed associated with strong PD-L1 expression. Further, increased T cells are observed in the setting of resistance and tumor progression.

Conclusions : These studies demonstrate preliminary safety and immune biology as well as promising efficacy in advanced UM. The pivotal trials evaluating the IE regimen in advanced UM are enrolling (NCT03070392; NCT02570308).

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.