1757O - Early reduction in ctDNA, regardless of best RECIST response, is associated with overall survival (OS) on tebentafusp in previously treated metastatic uveal melanoma (mUM) patients

Background

Tebentafusp (tebe), an investigational TCR–anti-CD3 bispecific fusion protein that targets gp100 and activates T cells, has shown OS benefit in 1^st line mUM. OS was improved in patients (pts) regardless of RECISTv1.1 best response, suggesting better surrogate efficacy endpoints are needed.

Methods

2L+ HLA-A*02:01+ mUM pts were treated weekly with 68mcg tebe after intra-patient dose escalation (NCT02570308). RECISTv1.1 was assessed by an independent radiographic committee. Serum samples (N=118) collected at baseline (BL) and at weeks (wks) 5, 9 on tebe were analyzed for ctDNA using a targeted mPCR-NGS assay for mutations in 15 genes including mUM oncogenes GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX. 0.1-3 log reductions in mean tumour molecules (MTM) per ml of serum observed on treatment were tested for association with OS.

Results

109/118 (92%) of pts had detectable ctDNA. MTM at BL was correlated with tumor burden as assessed by sum of longest diameters (Spearman’s r=0.61, P=10^-10). By wk 9, in 99 pts with BL and on-treatment MTM measurements, any (>0) ctDNA reduction was observed in 69 (70%). In 97 pts that were evaluable by RECISTv1.1, any ctDNA reduction was observed in 31/48 with progressive disease (PD), 34/45 with stable disease (SD) and 2/4 with partial response (PR). Magnitude of ctDNA reduction by wk 9 was strongly associated with improvement in OS (R²=0.87, P<0.0001): 0.1 log reduction hazard ratio HR 0.8; 0.5 log reduction HR 0.5; 1 log reduction HR 0.4; 2 log reduction HR 0.3, 3 log reduction HR 0.2 and undetectable ctDNA (clearance) HR 0.1. 1 yr OS was 100% in pts with ctDNA clearance (N=14) vs 57% in those with increased ctDNA (N=30). Best overall response among those with ctDNA clearance was PD in 4 (29%), SD in 8 (57%) and PR in 1 (7%).

Conclusions

ctDNA was detected in most mUM pts, associated with tumor burden at BL and reduced in 70% of pts on tebe, despite a RECIST response rate of <10%. ctDNA reduction as early as 9 wks on tebe was strongly associated with improved OS, even in pts with RECIST PD or SD. Early ctDNA reduction may be a better surrogate of tebe efficacy than RECIST objective response in mUM.

Clinical trial identification

NCT02570308.

Editorial acknowledgement

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore Ltd.

Disclosure

A.N. Shoushtari: Financial Interests, Institutional, Research Grant: Immunocore Ltd.; Financial Interests, Institutional, Research Grant: BMS; Non-Financial Interests, Personal, Other: Castle Biosciences; Financial Interests, Institutional, Research Grant: Xcovery; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer. L. Collins: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. E. Espinosa: Non-Financial Interests, Personal, Advisory Role: BMS; Non-Financial Interests, Personal, Advisory Role: MSD; Non-Financial Interests, Personal, Advisory Role: Novartis; Non-Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Research Grant: Roche; Non-Financial Interests, Institutional, Principal Investigator: Immunocore. H. Sethi: Financial Interests, Institutional, Full or part-time Employment: Natera Inc.; Financial Interests, Institutional, Stocks/Shares: Natera Inc.. S. Stanhope: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. S. Abdullah: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. A. Ikeguchi: Non-Financial Interests, Institutional, Principal Investigator: Immunocore. K. Ranade: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. O. Hamid: Non-Financial Interests, Personal, Advisory Board: Aduro; Non-Financial Interests, Personal, Advisory Board: Akeso; Non-Financial Interests, Personal, Advisory Board: Amgen; Non-Financial Interests, Personal, Advisory Board: BeiGene; Non-Financial Interests, Personal, Advisory Board: Bioatla; Non-Financial Interests, Personal, Invited Speaker: BMS; Non-Financial Interests, Personal, Advisory Board: BMS; Non-Financial Interests, Personal, Advisory Board: GSK; Non-Financial Interests, Personal, Advisory Board: Idera; Non-Financial Interests, Personal, Advisory Board: Immunocore; Non-Financial Interests, Personal, Advisory Board: Incyte; Non-Financial Interests, Personal, Advisory Board: Janssen; Non-Financial Interests, Personal, Advisory Board: Merck; Non-Financial Interests, Personal, Advisory Board: Nextcure; Non-Financial Interests, Personal, Invited Speaker: Novartis; Non-Financial Interests, Personal, Advisory Board: Novartis; Non-Financial Interests, Personal, Invited Speaker: Pfizer; Non-Financial Interests, Personal, Advisory Board: Pfizer; Non-Financial Interests, Personal, Advisory Board: Roche Genentech; Non-Financial Interests, Personal, Advisory Board: Sanofi / Regeneron; Non-Financial Interests, Personal, Invited Speaker: Sanofi / Regeneron; Non-Financial Interests, Personal, Advisory Board: Seagen; Non-Financial Interests, Personal, Advisory Board: Tempus; Non-Financial Interests, Personal, Advisory Board: Zelluna; Non-Financial Interests, Institutional, Principal Investigator: Aduro; Non-Financial Interests, Institutional, Principal Investigator: Akeso; Non-Financial Interests, Institutional, Principal Investigator: Amgen; Non-Financial Interests, Institutional, Principal Investigator: Arcus; Non-Financial Interests, Institutional, Principal Investigator: Bioatla; Non-Financial Interests, Institutional, Principal Investigator: BMS; Non-Financial Interests, Institutional, Principal Investigator: CytomX; Non-Financial Interests, Institutional, Principal Investigator: Exelixis; Non-Financial Interests, Institutional, Principal Investigator: GSK; Non-Financial Interests, Institutional, Principal Investigator: Idera; Non-Financial Interests, Institutional, Principal Investigator: Immunocore; Non-Financial Interests, Institutional, Principal Investigator: Incyte; Non-Financial Interests, Institutional, Principal Investigator: Iovance; Non-Financial Interests, Institutional, Principal Investigator: Merck; Non-Financial Interests, Institutional, Principal Investigator: Merck Serono; Non-Financial Interests, Institutional, Principal Investigator: Moderna; Non-Financial Interests, Institutional, Principal Investigator: Nextcure; Non-Financial Interests, Institutional, Principal Investigator: Novartis; Non-Financial Interests, Institutional, Principal Investigator: Pfizer; Non-Financial Interests, Institutional, Principal Investigator: Roche Genentech; Non-Financial Interests, Institutional, Principal Investigator: Sanofi / Regeneron; Non-Financial Interests, Institutional, Principal Investigator: Seagen; Non-Financial Interests, Institutional, Principal Investigator: Torque; Non-Financial Interests, Institutional, Principal Investigator: Zelluna.