Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden. Issue 1 (9th May 2018)

• Record Type: Journal Article
• Authors: Morrison, Carl; Pabla, Sarabjot; Conroy, Jeffrey M.; Nesline, Mary K.; Glenn, Sean T.; Dressman, Devin; Papanicolau-Sengos, Antonios; Burgher, Blake; Andreas, Jonathan; Giamo, Vincent; Qin, Moachun; Wang, Yirong; Lenzo, Felicia L.; Omilian, Angela; Bshara, Wiam; Zibelman, Matthew; Ghatalia, Pooja; Dragnev, Konstantin; Shirai, Keisuke; Madden, Katherine G.; Tafe, Laura J.; Shah, Neel; Kasuganti, Deepa; de la Cruz-Merino, Luis; Araujo, Isabel; Saenger, Yvonne; Bogardus, Margaret; Villalona-Calero, Miguel; Diaz, Zuanel; Day, Roger; Eisenberg, Marcia; Anderson, Steven M.; Puzanov, Igor; Galluzzi, Lorenzo; Gardner, Mark; Ernstoff, Marc S.;
• Is Part Of: Journal for immunotherapy of cancer. Volume 6:Issue 1(2018)
• Publication Date: 2018-05-09
• Subjects: Pembrolizumab -- Nivolumab -- Ipilimumab -- Algorithmic analysis -- Inflamed -- Borderline -- Immune Desert; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-018-0344-8
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma. Methods: Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8 + T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort ( n = 48) and subsequently tested in a separate eight institution validation cohort ( n = 29) to mimic a real-world clinical scenario. Results: PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity. Conclusions: In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.