In the phase 3 OPTiM trial, overall response (OR) and durable response (DR: OR lasting ≥ 6 months) rates were 26.4% and 16.3%, respectively, in pts with advanced melanoma treated with T-VEC. The primary endpoint of this study was the correlation between baseline (BL) CD8+ density and OR. Key secondary and exploratory endpoints included correlation between BL CD8+ density and DR, efficacy, safety, and correlation of outcome with other biomarkers.
Pts with unresectable stage IIIB–IVM1c melanoma were treated with T-VEC at the approved dose. Tumor biopsies were collected at BL (n = 91) and week (W) 6 (n = 59) from uninjected lesions. All biopsies were analyzed for CD8+ density by immunohistochemistry. In a substudy of paired BL–W6 biopsies (n = 25), additional immunophenotypes were analyzed by multiparameter immunofluorescence (IF).
112 pts were enrolled; 111 received ≥ 1 T-VEC dose. BL CD8+ density did not predict OR (odds ratio, 95% CI; P value: 1.06, 0.83–1.34; 0.64) but correlated with DR (1.38, 1.00–1.88; 0.047). The median increase in tumor CD8+ density from BL to W6 was 2.4-fold (P < 0.0001). Intratumoral changes included an increase in effector CD8+ T-cells and NK cells but not macrophages (Table). In addition, tumorinfiltrating CD8+ T-cells had a memory phenotype (CD45RO+) and/or expressed immune checkpoint markers PD-1 and CTLA-4. Efficacy and safety were similar to OPTiM.Table: 1246PD
Changes in intratumoral density of immune-cell subsets*
|Cell type, markers||Fold increase||P value|
|Helper T cells, CD3+ CD4+||1.72||0.050|
|Effector CTL, CD3+ CD8+ granzyme B+||3.10||0.005|
|Effector NK cells, CD3- CD56+ granzyme B+||3.77||0.020|
IF substudy included 25 paired BL–W6 biopsies
T-VEC treatment was associated with infiltrates of effector CD8+ T-cells and NK cells in uninjected lesions, indicating a systemic effect. BL tumor CD8+ density correlated with DR but not OR. Data also support studies of T-VEC combined with checkpoint inhibitors. Correlations of outcome with changes in other immune markers are under investigation.
Clinical trial identification
EudraCT: 2013-005552-15, Sponsor Protocol: 20120325
Legal entity responsible for the study
Medical writing was provided by Yang Li, Ph.D. (Amgen Inc.).
H. Gogas: Honoraria: BMS, MSD, Roche, Novartis, Amgen; Research funding: BMS, MSD, Roche, Novartis. I. Samoylenko: Consulting or advisory role, speakers’ bureau: BMS, MSD, Roche, Novartis, R-Farm; Research funding: BMS. D. Schadendorf: Honoraria, Consulting or advisory role: BMS, MSD, Roche, Novartis, Amgen, Pfizer, Sanofi; Speakers’ bureau: BMS, Roche, Novartis; Research funding (self and institution): BMS, Novartis. R. Gutzmer: Honoraria: BMS, MSD/Merck, Roche, Novartis, Amgen, GSK, Boehringer Ingelheim, AstraZeneca, Merck Serono, Pierre Fabre, Almirall; Consulting or advisory role: BMS, MSD/Merck, Roche, Novartis, Amgen, Merck Serono, Pierre Fabre, Almirall, LEO, Incyte, 4SC; Research funding (self and institution): Pfizer, Novartis, J&J; Travel, accomodations, expense: BMS, Roche, Pierre Fabre, Merck Serono. J.J. Grob: Consulting or advisory role: BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer. J.J. Sacco: Honoraria: BMS; Consulting or advisory role: Immunocore; Research funding (self and institution): BMS, MSD, AstraZeneca, Immunocore, Amgen, Replimmune; Travel, accomodations, expense: BMS, MSD. K. Gorski, A. Anderson: Employee, Stock, Patents: Amgen. C. Liu: Employee, Stock: Amgen. J. Malvehy: Speakers’ bureau (self and immediate family member): BMS, Novartis, Amgen, Pierre Fabre, Leo Pharma, Almirall, MSD; Research funding (self, immediate family member, institution): BMS, Amgen, Leo Pharma, Almirall, GSK; Patents (self, immediate family member, institution): ISDIN.