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

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 M.; Bogardus, Margaret; Villalona-Calero, Miguel; Diaz, Zuanel; Day, Roger; Eisenberg, Marcia; Anderson, Steven M.; Puzanov, Igor; Galluzzi, Lorenzo; Gardner, Mark; Ernstoff, Marc S.

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.

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Also Published In

Title
Journal for ImmunoTherapy of Cancer
DOI
https://doi.org/10.1186/s40425-018-0344-8

More About This Work

Academic Units
Medicine
Published Here
August 20, 2018

Notes

Pembrolizumab, Nivolumab, Ipilimumab, Algorithmic analysis, Inflamed, Borderline, Immune Desert

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