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898 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 melanoma
  1. Michael D Radmacher1,
  2. Phaedra Agius2,
  3. Oliver A Hampton2,
  4. David M McKean2,
  5. Daniel R Elgort2,
  6. Robert J Rounbehler2,
  7. Michelle Churchman2,
  8. Donghai Dai3,
  9. Tingyi Li4,
  10. Abdul Rafeh Naqash5,
  11. Margaret E Gatti-Mays6,
  12. Aakrosh Ratan7,
  13. Martin D McCarter8,
  14. John Carpten9,
  15. Howard Colman10,
  16. Igor Puzanov11,
  17. Susanne M Arnold12,
  18. Issam El Naqa4,
  19. Aik Choon Tan10,
  20. Timothy I Shaw4,
  21. Xuefeng Wang4,
  22. William S Dalton2,
  23. George J Weiner13 and
  24. Ahmad A Tarhini4
  1. 1Aster Insights, Laconia, IN, USA
  2. 2Aster Insights, Hudson, FL, USA
  3. 3University of Iowa, Iowa City, IA, USA
  4. 4H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
  5. 5Stephenson Cancer Center Oklahoma University, Greenville, NC, USA
  6. 6The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
  7. 7University of Virginia, Charlottesville, VA, USA
  8. 8University of Colorado Cancer Center, Aurora, CO, USA
  9. 9University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
  10. 10Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
  11. 11Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
  12. 12Markey Cancer Center, Lexington, KY, USA
  13. 13Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background The rapid advancement of immunotherapies in oncology precipitates the need for clinicogenomic databases to verify published findings and to augment related discoveries. Growing bodies of real-world data (RWD) present such opportunities. We used one RWD source, Aster Insights’ ORIEN Avatar® database, to develop criteria for estimating real-world progression-free survival (rwPFS) endpoints and applied these criteria to a melanoma cohort, investigating association of rwPFS with a published, validated, prognostic, IFN-γ-related gene signature developed from clinical trial patients.1

Methods A cohort of 239 patients with melanoma and RNA-seq data were identified from the ORIEN Avatar® database (April 2023 release). This pan-cancer database is maintained by Aster Insights, which receives specimens and data submissions (comprised of whole-exome tumor/germline sequencing, RNA sequencing, and lifetime follow-up) from ORIEN members, a consortium research network of 18 U.S. cancer centers. Melanoma samples were collected from either the primary tumor site or a metastasis.

rwPFS endpoints were identified from normalized clinical data. The following were considered uncensored events: 1) annotated progression/recurrence in clinical records, 2) drug therapy annotated as stopped due to progression, 3) identification of new metastases, and 4) death. Patients without an event were right-censored at last follow-up.

RNA-seq analysis utilized a pipeline incorporating RSEM. Gene expression was quantified as Transcript Per Million (TPM), log2(TPM+1) transformed, and ComBat normalized to adjust for batch effects related to preservation method. A summary score was calculated for an 18 gene, IFN-γ-related signature previously reported to predict clinical response in PD-1 blockade.1

Results 112 patients in the melanoma cohort had immune-checkpoint inhibitor (ICI) therapy, RNA-seq prior to ICI therapy, and an evaluable rwPFS endpoint. Patient characteristics are shown in table 1. Median follow-up for the cohort was 4.4 years; median rwPFS was 1.5 years. Groups derived from a median cut of the IFN-γ-related signature demonstrated a marginally significant association with rwPFS (p=0.059). Higher expression of the signature associated with longer survival (figure 1). Identifying an optimal cutpoint for defining risk groups was outside the scope of this study, but stronger separation of groups was observed with lower cutpoints.

Conclusions The observation of longer rwPFS in the high IFN-γ-related signature group corresponds with the original report of the signature, in which high expression of the signature was associated with a favorable response to ICI treatment.1 Derivation of PFS endpoints from real-world data has recently been demonstrated2; the current study provides additional confirmation of the utility of rwPFS.


  1. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, Piha-Paul SA, Yearley J, Seiwert TY, Ribas A, McClanahan TK. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930–2940.

  2. Griffith SD, Tucker M, Bowser B, Calkins G, Chang C-H. Generating Real-World Tumor Burden Endpoints from Electronic Health Record Data: Comparison of RECIST, Radiology-Anchored, and Clinician-Anchored Approaches for Abstracting Real-World Progression in Non-Small Cell Lung Cancer. Adv Ther. 2019;36:2122–2136.

Ethics Approval For this study, ORIEN members utilized a standard protocol, Total Cancer Care (TCC®; NCT03977402), to which patients provided an IRB-approved written informed consent at their participating institutions.

Abstract 898 Table 1

Patient characteristics of ICI-treated Subgroup

Abstract 898 Figure 1

rwPFS for IFN-gamma-Related Signature Groups

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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