1121P - Interferon-gamma (IFNy) gene signature as a predictive biomarker for response in lactate dehydrogenase (LDH) low advanced melanoma patients

Background

In current clinical practice, LDH level is widely used as decision tool between anti-PD1 monotherapy (LDH low) versus combination of anti-PD1 and anti-CTLA4 (LDH high). However, approximately only 50% of LDH low patients respond to anti-PD1. In stage III melanoma patients (generally LDH low) the interferon (IFN)g signature has been identified as strongest baseline marker for response to neoadjuvant combination immunotherapy. Therefore, we addressed the question whether an IFNg signature could serve as additional biomarker for treatment decisions in LDH low advanced melanoma patients.

Methods

Advanced melanoma patients participating in biobank study in the Netherlands Cancer Institute (NKI), treated with anti-PD1 monotherapy between April 2014 and June 2016 were retrospectively identified. The IFNg-signature was analyzed on baseline paraffine tumor biopsies using mRNA sequencing. The cutoff between IFNg-high and IFNg-low cohorts was calculated using ROC curves on the objective response (OR).

Results

Forty-nine patients were included: the majority had cutaneous (98%) and BRAF wild type (53%) melanoma and stage M1c disease (39%, AJCC 8th edition). Patients with a high IFNg-signature at baseline showed a higher response rate to anti-PD1 (OR 86% vs 43%; p=0.016) and an improved progression free survival (p=0.046) and overall survival (p=0.064). Table: 1121P

PFS, progression free survival; OS, overall survival; m, months; IQR, interquartile range; CI, 95% confidence interval.

Conclusions

Our results suggest that the IFNg-signature could become a biomarker for treatment decisions in LDH low patients directing towards anti-PD1 monotherapy (in IFNg high patients) versus combination therapy, with either anti-LAG3 or anti-CTLA-4 in IFNg low patients. However, confirmation in larger cohorts and in other combination therapies is needed.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Christian Blank's group.

Funding

Has not received any funding.

Disclosure

P. Dimitriadis: Financial Interests, Personal, Advisory Role, will receive some possible revenues if the IFN-γ signature is being developed as clinical companion diagnostic: Signature oncology. D. Peeper: Financial Interests, Personal, Ownership Interest, o-founder, shareholder, and advisor: Immagene. 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.