1095P - Associations between baseline biomarkers and 3-year survival in the PRADO trial testing neoadjuvant ipilimumab and nivolumab in stage III melanoma

Background

PRADO tested neoadjuvant ipilimumab plus nivolumab in 99 stage III melanoma patients (pts) followed by omission of therapeutic lymph node dissection (TLND) and adjuvant therapy in pts achieving a major pathologic response (MPR) in their index lymph node, and addition of adjuvant therapy after TLND in non-responding (pNR) pts. Previous analyses of PRADO and its previous OpACIN-neo trial showed that a high interferon-gamma (IFN-y) signature, PD-L1 expression and tumor mutational burden (TMB) were associated with major pathologic response (PD-L1 expression only in PRADO). Here, we report the association between these biomarkers and 3-year (3y) survival of PRADO.

Methods

The IFN-y signature, PD-L1 expression and TMB were analyzed on baseline tumor biopsies using mRNA sequencing (n=80), anti-PD-L1 mAb (clone 22C3) (n=76), and whole exome sequencing (n=75). Cutoffs between high and low cohorts were calculated using ROC curves on MPR. Event-free (EFS), relapse-free (RFS), distant metastasis-free (DMFS) and overall (OS) survival curves were generated and compared using the Kaplan-Meier and log-rank method.

Results

Pts with a high baseline IFN-y signature or a PD-L1 expression of ≥1% had a significantly higher 3y EFS rate than pts with low levels (85% vs 61%, p=0.006 and 91% vs 67%, p=0.005, respectively) (Table). Pts with a high TMB had a numerically higher 3y EFS rate (81% vs 64%, p=0.072). The correlation between baseline IFN-y signature and PD-L1 expression and EFS translated into a numerical benefit in RFS, DMFS and OS (OS was statistically significant for PD-L1). However, no association with RFS, DMFS or OS was observed for TMB. Table: 1095P

*Patients with an event prior to surgery (n=6) or who did not undergo surgery (n=1) were excluded.

Conclusions

The IFN-y signature seems to be the most robust baseline biomarker for long-term (event-free) survival across different cohorts. In contrast to results from the previous OpACIN-neo trial, PD-L1 expression was also associated with survival in PRADO, while TMB was not significantly associated.

Clinical trial identification

NCT02977052.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

BMS.

Disclosure

I. Reijers: Financial Interests, Personal, Licensing Fees, I.L.M.R reports financial interest in Signature Oncology, and will receive some possible revenues if the IFN-γ signature is being developed as clinical companion diagnostic: Signature Oncology. P. Dimitriadis: Financial Interests, Personal, Licensing Fees, P.D. reports financial interest in Signature Oncology, and will receive some possible revenues if the IFN-γ signature is being developed as clinical companion diagnostic: Signature Oncology. A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre Fabre, QBiotics. E. Kapiteijn: Financial Interests, Institutional, Advisory Board: BMS, Novartis, Pierre Fabre, Merck, Delcath, Bayer, Lilly; Financial Interests, Institutional, Coordinating PI: BMS, Pierre Fabre, Delcath. A.A.M. Van der Veldt: Financial Interests, Institutional, Advisory Board: BMS, MSD, Merck, Roche, Eisai, Pfizer, Sanofi, Novartis, Pierre Fabre, Ipsen. K.P.M. 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.A.P. Hospers: Financial Interests, Institutional, Advisory Board: Amgen, Roche, MSD, BMS, Pfizer, Novartis, Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS, Seerave. W. Van Houdt: Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Advisory Board: Belpharma, Sanofi, MSD; Financial Interests, Personal, Other, travel grant: Novartis; Financial Interests, Institutional, Local PI: BMS. R. Saw: Financial Interests, Institutional, Advisory Board: MSD, Novartis, QBiotics; Financial Interests, Institutional, Speaker, Consultant, Advisor: BMS, Novartis. B. van de Wiel: Financial Interests, Institutional, Advisory Board: BMS. R. Scolyer: Financial Interests, Institutional, Advisory Board: F. Hoffmann-La Roche, Evaxion, Provectus Biopharmaceuticals Australia, QBiotics, Novartis, MSD, NeraCare, Amgen, BMS, Myriad Genetics, GSK. 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, Institutional, Advisory Board: Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, BMS, Evaxion, Hexal AG, Highlight Therapeutics, Innovent Biologics, MSD, Novartis, OncoSec, PHMR Ltd., Pierre Fabre, Provectus, QBiotics, Regeneron Pharmaceuticals. C.U. Blank: Financial Interests, Institutional, Advisory Board: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre; Financial Interests, Personal, Advisory Board: 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, Coordinating PI: BMS, Novartis, NanoString, 4SC; Other, pending patent: WO 2021/177822 A1. All other authors have declared no conflicts of interest.