Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden

• Main Authors: Carl Morrison, Sarabjot Pabla, Jeffrey M. Conroy, Mary K. Nesline, Sean T. Glenn, Devin Dressman, Antonios Papanicolau-Sengos, Blake Burgher, Jonathan Andreas, Vincent Giamo, Moachun Qin, Yirong Wang, Felicia L. Lenzo, Angela Omilian, Wiam Bshara, Matthew Zibelman, Pooja Ghatalia, Konstantin Dragnev, Keisuke Shirai, Katherine G. Madden, Laura J. Tafe, Neel Shah, Deepa Kasuganti, Luis de la Cruz-Merino, Isabel Araujo, Yvonne Saenger, Margaret Bogardus, Miguel Villalona-Calero, Zuanel Diaz, Roger Day, Marcia Eisenberg, Steven M. Anderson, Igor Puzanov, Lorenzo Galluzzi, Mark Gardner, Marc S. Ernstoff
• Format: Article
• Language: English
• Published: BMJ Publishing Group 2018-05-01
• Series: Journal for ImmunoTherapy of Cancer
• Subjects: Pembrolizumab; Nivolumab; Ipilimumab; Algorithmic analysis; Inflamed; Borderline
• Online Access: http://link.springer.com/article/10.1186/s40425-018-0344-8

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.