KEY TAKEAWAYS
- A study leveraged Aster Insights’ ORIEN Avatar® database to establish criteria for estimating a melanoma cohort’s real-world progression-free survival (rwPFS).
- Researchers assessed the association between rwPFS and a validated IFN-γ-related gene signature from clinical trial patients.
- Extended rwPFS in high IFN-γ-related signature aligned with favorable ICI response. Recent real-world data validation reinforced rwPFS utility.
The swift progression of immunotherapies in oncology necessitates clinicogenomic databases to validate published findings and enhance related discoveries. Real-world data (RWD) sources, such as Aster Insights’ ORIEN Avatar® database, offer valuable opportunities.
Utilizing this RWD source, criteria were established to estimate real-world progression-free survival (rwPFS) endpoints. These criteria were applied to a melanoma cohort, examining the correlation between rwPFS and a published, validated, prognostic gene signature associated with IFN-γ, developed from clinical trial patients.
From the April 2023 release of the ORIEN Avatar® database, a cohort of 239 melanoma patients with RNA-seq data was identified. Aster Insights maintains this pan-cancer database, which receives comprehensive submissions from ORIEN members— a research consortium comprising 18 U.S. cancer centers. The submissions include specimens and data, encompassing whole-exome tumor/germline sequencing, RNA sequencing, and lifetime follow-up. Melanoma samples were procured from either the primary tumor site or a metastasis.
Normalized clinical data identified rwPFS endpoints, with the following events considered uncensored: 1) annotated progression/recurrence in clinical records, 2) cessation of drug therapy due to progression, 3) discovery of new metastases, and 4) death. Patients without an event were right-censored at the last follow-up.
For RNA-seq analysis, a pipeline incorporating RSEM was employed. Gene expression, quantified as Transcript Per Million (TPM), underwent log2(TPM+1) transformation and ComBat normalization to address batch effects related to preservation methods. A summary score was computed for an 18-gene IFN-γ-related signature previously documented to predict clinical response in PD-1 blockade.
In the melanoma cohort, 112 patients underwent immune-checkpoint inhibitor (ICI) therapy, had RNA-seq prior to ICI treatment, and possessed an assessable rwPFS endpoint. The cohort had a median follow-up of 4.4 years, with a median rwPFS of 1.5 years. Groups categorized based on a median cut of the IFN-γ-related signature displayed a marginally significant association with rwPFS (p=0.059).
Higher expression of the signature correlated with extended survival. While determining an optimal cutpoint for defining risk groups was beyond the study’s scope, a stronger separation of groups was observed with lower cutpoints.
The noted prolonged rwPFS in the high IFN-γ-related signature group aligned with the original findings of the signature, where heightened expression correlated with a favorable response to ICI treatment. The derivation of PFS endpoints from real-world data was recently demonstrated, and the present study offered further confirmation of the efficacy of rwPFS.
Source: https://jitc.bmj.com/content/11/Suppl_1/A1000
Clinical Trial: https://clinicaltrials.gov/study/NCT03977402
Radmacher MD, Agius P, Hampton OA, et al898 Demonstration of the utility of real-world progression-free survival (rwPFS) by application of an IFN-γ-related signature in a real-world cohort of patients with melanomaJournal for ImmunoTherapy of Cancer 2023;11:doi: 10.1136/jitc-2023-SITC2023.0898
