The PRADO trial (n=99) tested different surgical and adjuvant therapy strategies based on the pathologic response after neoadjuvant IPI 1mg/kg and NIVO 3mg/kg in stage III melanoma patients (pts). The pathologic response rate (pRR: ≤50% viable tumor) was 72%, including 61% major pathologic responses (MPR: ≤10% viable tumor). After a median follow-up of 28.1 months, the 2-year (2y) event-free survival (EFS) rate was 80%. Here, we report the response and EFS data of PRADO according to the IFN-γ signature and TMB.
TMB and the IFN-γ gene expression signature (GES) were examined in baseline tumor biopsies by whole exome sequencing (n=76) and mRNA sequencing (n=80). Association with pRR, MPR or EFS was examined by logistic/Cox regression analyses. Cutoffs between high (H) and low (L) were calculated using ROC curves.
The table shows the association between IFN-γ GES and TMB with pRR, MPR, and EFS. IFN-γ GES and logTMB were not correlated (R = 0.065; p = 0.579). Pts with a high IFN-γ GES had a higher pRR and MPR rate than pts with a low IFN-γ GES (87% vs 50%, p=0.001 and 77% vs 35%, p<0.001, respectively), and also a higher 2y EFS rate (87% vs 68%, log-rank p=0.015). Pts with a high TMB were more likely to achieve a pathologic response (pRR 83% vs 58%, p=0.024) and MPR (80% vs 38%, p<0.001), but did not have a lower risk of relapse (2y EFS 77% vs 76%, log-rank p=0.531). When combined, the pRR for pts with IFN-γ H/TMB H was 90%, IFN-γ H/TMB L 79%, IFN-γ L/TMB H 67% and IFN-γ L/TMB L 42%. For MPR rates this was 85%, 63%, 67% and 19%, respectively.
Univariable analysis OR / HR 95% CI p-value pRR IFN-γ score (continuous) 1.089 (1.027-1.156) 0.004 IFN-γ high vs low 6.800 (2.208-20.944) 0.001 logTMB (continuous) 1.311 (0.988-1.741) 0.061 TMB high vs low 3.654 (1.183-11.286) 0.024 MPR IFN-γ score (continuous) 1.092 (1.031-1.157) 0.003 IFN-γ high vs low 6.190 (2.304-16.634) <0.001 logTMB (continuous) 1.376 (1.037-1.826) 0.027 TMB high vs low 6.588 (2.240-19.374) 0.001 EFS IFN-γ score (continuous) 0.965 (0.922-1.011) 0.130 IFN-γ high vs low 0.308 (0.112-0.846) 0.022 logTMB (continuous) 0.935 (0.726-1.205) 0.604 TMB high vs low 0.747 (0.298-1.872) 0.533
Similar to findings in our previous trials, baseline IFN-γ GES and TMB were independent biomarkers for pathologic response and MPR, and the IFN-γ GES was associated with EFS. However, TMB was not associated with risk of relapse, possibly owing to the different response-driven surgical and adjuvant therapy strategies in PRADO.
NCT02977052.
Netherlands Cancer Institute.
BMS.
R. Saw: Financial Interests, Personal, Invited Speaker: Bristol Myers Squib, Novartis; Financial Interests, Personal, Advisory Board: Novartis, MSD, Qbiotics; Financial Interests, Personal, Other, On Faculty, support of University of Sydney salary: Melanoma Institute Australia. E. Kapiteijn: Financial Interests, Institutional, Advisory Board: BMS, Novartis, Pierre Fabre, Merck, Delcath, Bayer; Financial Interests, Institutional, Invited Speaker: BMS. A.A.M. Van der Veldt: Financial Interests, Institutional, Advisory Board: BMS, MSD, Merck, Roche, Eisai, Pfizer, Sanofi, Novartis, Pierre Fabre, Ipsen. K. Suijkerbuijk: Financial Interests, Institutional, Advisory Board: Novartis, BMS, AbbVie, Pierre Fabre, MSD; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Research Grant: Novartis, TigaTx. G. Hospers: Financial Interests, Institutional, Advisory Board: Amgen, Roche, MSD, BMS, Novartis, Pierre Fabre, Pfizer; Financial Interests, Institutional, Research Grant: BMS, Seerave. W. Van Houdt: Financial Interests, Institutional, Invited Speaker: Amgen, BMS; Financial Interests, Institutional, Advisory Board: Belpharma; Financial Interests, Institutional, Expert Testimony: Sanofi, MSD; Financial Interests, Personal, Other, travel grant: Novartis. R. Scolyer: Financial Interests, Institutional, Advisory Board: F. Hoffmann-La Roche, Evaxion, Provectus Biopharmaceuticals Australia, QBiotics, Novartis, MSD, NeraCare, Amgen, BMS, Myriad Genetics, GlaxoSmithKline. A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. A.C.J. van Akkooi: Financial Interests, Institutional, Advisory Board: Amgen, Bristol Myers Squibb, Novartis, MSD - Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC, Provectus; Financial Interests, Institutional, Research Grant, NIVEC study: Amgen; Financial Interests, Institutional, Research Grant: Merck-Pfizer. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc., Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Merck Sharpe & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc; Financial Interests, Personal, Advisory Board, Consultant Advisor: Highlight Therapeutics S.L. C.U. Blank: Financial Interests, Institutional, Advisory Board: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre; Financial Interests, Personal, Expert Testimony: Third Rock Ventures; Financial Interests, Personal, Stocks/Shares: Immagene; Financial Interests, Personal, Stocks/Shares, intention to develop IFN signature algorithm: NewCo, no name yet; Financial Interests, Institutional, Invited Speaker: BMS, Novartis, NanoString, 4SC; Other, Personal, Other, pending patent: WO 2021/177822 A1. All other authors have declared no conflicts of interest.