Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients
Tian Zhang, Sarabjot Pabla, Felicia L. Lenzo, Jeffrey M. Conroy, Mary Nesline, Sean T. Glenn, Antonios Papanicolau‐Sengos, Blake Burgher, Vincent Giamo, Jonathan Andreas, Yirong Wang, Wiam Bshara, Katherine G. Madden, Keisuke Shirai, Konstantin H. Dragnev, Laura J. Tafe, Rajan T. Gupta, Jason Zhu, Matthew Labriola, Shannon J. McCall, Daniel J. George, Pooja Ghatalia, Farshid Dayyani, Robert A. Edwards, Michelle S Park, Rajbir Singh, Robin Jacob, Saby George, Bo Xu, Matthew R. Zibelman, Razelle Kurzrock, Carl Morrison
Abstract
Background Biomarkers predicting immunotherapy response in metastatic renal cell cancer (mRCC) are lacking. PD-L1 immunohistochemistry is a complementary diagnostic for immune checkpoint inhibitors (ICIs) in mRCC, but has shown minimal clinical utility and is not used in routine clinical practice.Methods Tumor specimens from 56 patients with mRCC who received nivolumab were evaluated for PD-L1, cell proliferation (targeted RNA-seq), and outcome.Results For 56 patients treated with nivolumab as a standard of care, there were 2 complete responses and 8 partial responses for a response rate of 17.9%. Dividing cell proliferation into tertiles, derived from the mean expression of 10 proliferation-associated genes in a reference set of tumors, poorly proliferative tumors (62.5%) were more common than moderately (30.4%) or highly proliferative (8.9%) counterparts. Moderately proliferative tumors were enriched for PD-L1 positive (41.2%), compared to poorly proliferative counterparts (11.4%). Objective response for moderately proliferative (29.4%) tumors was higher than that of poorly (11.4%) proliferative counterparts, but not statistically significant (p = .11). When cell proliferation and negative PD-L1 tumor proportion scores were combined statistically significant results were achieved (p = .048), showing that patients with poorly proliferative and PD-L1 negative tumors have a very low response rate (6.5%) compared to moderately proliferative PD-L1 negative tumors (30%).Conclusions Cell proliferation has value in predicting response to nivolumab in clear cell mRCC patients, especially when combined with PD-L1 expression. Further studies which include the addition of progression-free survival (PFS) along with sufficiently powered subgroups are required to further support these findings.