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Richard D. Carvajal, Joseph Sacco, Paul Nathan, Marlana Orloff, Nicola Little, Cheryl McAlpine, David Krige, Namir Hassan, Ann-Marie Hulstine, Christina Coughlin, Takami Sato; Safety, efficacy and biology of the gp100 TCR-based bispecific T cell redirector IMCgp100 in advanced uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3622.
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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.
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).
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.
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.
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