Abstract 1018P
Background
Tebentafusp (tebe) is a bispecific gp100-targeted T-cell receptor fusion protein that can redirect and activate polyclonal T-cells leading to release of inflammatory mediators. In this randomized phase III study in 1L mUM [NCT03070392], tebe demonstrated OS benefit vs. investigator’s choice (IC). Increases in liver function tests (LFTs) were common; however, gp100 is not expressed on hepatocytes and tebe did not redirect T-cells against normal hepatocytes in vitro. Here we describe LFT kinetics and outcomes for tebe and IC-treated patients.
Methods
In this open-label, Ph3 trial, 1L HLA-A*02:01+ pts with mUM were randomized 2:1 to receive tebe or IC (pembrolizumab, ipilimumab or dacarbazine). LFTs were measured at baseline (BL) and serially on-treatment prior to dosing. Analysis was conducted on primary analysis snapshot (Jan 2021).
Results
At BL, 98% (241/245) of tebe pts and 99% (110/111) of IC pts had ALT/AST Grade (G)≤1 and nearly all pts had liver metastases (96% tebe vs 93% IC). Increases in post-BL grade of ALT, AST or both occurred in 158 (65%) tebe pts and 53 (48%) IC pts, of which 63% vs 70% increased to G1, 16% vs 23% to G2, 19% vs 6% to G3, and 3% vs 2% to G4, respectively. For the majority of tebe-treated pts (71% [112/158]), increases to worst post-BL grade occurred during the first 3 wks of treatment, with 38% at wk1, 20% at wk2, and 13% at wk3. In the remaining 46 pts, ALT/AST increases occurred at or after wk4, and most of these (59%) were temporally associated with an increase in size of liver metastases. Most tebe-treated pts continued treatment beyond the time of worst ALT/AST elevation (91% [143/158]).
Conclusions
Greater than 90% of pts had BL liver metastases and nearly 2/3 of tebe-treated pts and approximately 1/2 of IC-treated pts had an increase in post-BL grade of AST/AST. Although numerically higher, the majority of ALT/AST elevations in the tebe arm were mild, occurred early, and did not result in treatment discontinuation. Since most patients had pre-existing liver metastases, LFT elevations may be secondary to T-cell redirection into the liver metastases.
Clinical trial identification
NCT03070392.
Editorial acknowledgement
Legal entity responsible for the study
Immunocore.
Funding
Immunocore.
Disclosure
B. Chmielowski: Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Advisory Board: Epizme; Financial Interests, Personal, Advisory Board: IDEAYA Bioscience; Financial Interests, Personal, Advisory Board: Iovance Biotherapeutics; Other, Personal, Other, Data monitoring committee: Nektar; Financial Interests, Personal, Advisory Board: OncoSec; Financial Interests, Personal, Advisory Board: Sanofi-Genzyme; Financial Interests, Personal, Advisory Board: Sanofi-Regeneron; Financial Interests, Institutional, Other, Clinical Trial Support: Advenchen Biotherapeutics; Financial Interests, Institutional, Other, Clinical Trial Support: Aeglea Biotherapeutics; Financial Interests, Institutional, Other, Clinical Trial Support: Array BioPharma; Financial Interests, Institutional, Other, Clinical Trial Support: Ascentage; Financial Interests, Institutional, Other, Clinical Trial Support: Atreca; Financial Interests, Institutional, Other, Clinical Trial Support: Biothera; Financial Interests, Institutional, Other, Clinical Trial Support: BMS; Financial Interests, Institutional, Other, Clinical Trial Support: Compugen; Financial Interests, Institutional, Other, Clinical Trial Support: Daiichi Sankyo; Financial Interests, Institutional, Other, Clinical Trial Support: EMD Serono; Financial Interests, Institutional, Other, Clinical Trial Support: IDEAY Biosciences; Financial Interests, Institutional, Other, Clinical Trial Support: Idera; Financial Interests, Institutional, Other, Clinical Trial Support: Immunocore; Financial Interests, Institutional, Other, Clinical Trial Support: Incyte; Financial Interests, Institutional, Other, Clinical Trial Support: Infinity Pharmaceuticals; Financial Interests, Institutional, Other, Clinical Trial Support: Iovance; Financial Interests, Institutional, Other, Clinical Trial Support: Karyopharm Therapeutics; Financial Interests, Institutional, Other, Clinical Trial Support: Lilly; Financial Interests, Institutional, Other, Clinical Trial Support: Macrogenics; Financial Interests, Institutional, Other, Clinical Trial Support: Merck; Financial Interests, Institutional, Other, Clinical Trial Support: Neon Therapeutics; Financial Interests, Institutional, Other, Clinical Trial Support: PACT Pharma; Financial Interests, Institutional, Other, Clinical Trial Support: RAPT Therapeutics; Financial Interests, Institutional, Other, Clinical Trial Support: Replimune; Financial Interests, Institutional, Other, Clinical Trial Support: Rgenix; Financial Interests, Institutional, Other, Clinical Trial Support: Tolero Pharmaceuticals; Financial Interests, Institutional, Other, Clinical Trial Support: Xencor. P.A. Ascierto: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Roche Genentech; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Array; Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: Newlinks Genetics; Financial Interests, Personal, Advisory Role: Genmab; Financial Interests, Personal, Advisory Role: MedImmune; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Sindax; Financial Interests, Personal, Advisory Role: Sun Pharma; Financial Interests, Personal, Advisory Role: Sanofy; Financial Interests, Personal, Advisory Role: Idera; Financial Interests, Personal, Advisory Role: Ultimovacs; Financial Interests, Personal, Advisory Role: Sandoz; Financial Interests, Personal, Advisory Role: Immunocore; Financial Interests, Personal, Advisory Role: 4SC; Financial Interests, Personal, Stocks/Shares: PrimeVax; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Roche Genentech; Financial Interests, Institutional, Research Grant: Array; Financial Interests, Personal, Other, Travel expenses: MSD; Financial Interests, Personal, Advisory Role: Alkermes; Financial Interests, Personal, Advisory Role: Italfarmaco; Financial Interests, Personal, Advisory Role: Nektar. S.E. Abdullah: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. S. Lockwood: Financial Interests, Personal, Other, Consultant: Immunocore. P. Mendez: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. I. Puzanov: Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Iovance; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Nektar; Non-Financial Interests, Personal, Other, Data and Safety Monitoring Committee: Nouscom; Non-Financial Interests, Personal, Other, Trial Steering Committee: Amgen. All other authors have declared no conflicts of interest.