Cell proliferation as a biomarker for response to immune checkpoint inhibitors in PD-L1 negative renal cell carcinoma.

Abstract

62 Background: Cell proliferation is an important marker of survival in many tumors, and we hypothesized that this attribute could be related to response to immune checkpoint inhibitors (ICIs) in RCC. Previously we reported (SITC 2018) that moderately proliferative lung cancer have a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE RCC tumor samples were evaluated by RNA-seq to measure transcript levels of 394 immune related genes. Cell proliferation was defined as the mean mRNA expression of 10 genes (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A) which was evaluated for association with ORR to ICIs by RECIST v1.1 criteria for both PD-L1 IHC positive and negative cases. Cell proliferation for each case was split into 3 tertiles of poorly ( < 33), moderately (33-66) and highly ( > 66) proliferative versus a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. PD-L1 IHC was performed using DAKO 22C3 antibody and scored by FDA guidelines and considered positive if TPS ≥1% and negative if < 1%. Results: In our cohort of 69 patients, the overall ORR was 18.8. The majority, 91% of tumors were PD-L1 negative, with ORR of 14.8%, as opposed to ORR of 50% in PD-L1 positive cases. 62.2% of tumors were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately proliferative. ORR in moderately proliferative tumors was 30% and 14.2% in poorly/highly proliferative tumors. In PD-L1 negative tumors the ORR in moderately proliferative tumors was 20% and 13% in poorly/highly proliferative tumors. For the 5 moderately proliferative, PD-L1 positive tumors, there were 2 PR and 1 CR, and in the 3 poorly/highly proliferative tumors there was 1 PR. Conclusions: Cell proliferation may play a crucial role in distinguishing RCC patients who may have a clinical benefit to ICI, including the important subgroup of PD-L1 negative tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.