1891P - Determinants of exceptional response to immune checkpoint inhibition in metastatic clear cell renal cell carcinoma

Background

In a subset of patients (pts), immune checkpoint inhibitors (ICIs) hold the potential to achieve lasting and sustainable responses, or even complete recoveries in pts with clear cell renal cell carcinoma (ccRCC). We sought to understand the immunogenomic determinants of these exceptional responses to ICIs.

Methods

We analyzed pre-therapy genomic and transcriptomic data in treatment-naive metastatic ccRCC pts treated with standard-of-care immunotherapies: (1) combination of PD-1/PDL1 and CTLA-4 (IO/IO), or (2) PD-1/PD-L1 inhibitor and VEGF-receptor (IO/VEGF) combination. We also compared baseline characteristics and outcomes between these cohorts and the International Metastatic RCC Database Consortium (IMDC) dataset. We defined 3 groups of pts in each cohort: (a) extreme responders (ER): pts with complete response (CR) and progression free survival (PFS) ≥ 12 months or partial response (PR) with tumor shrinkage 50% and PFS ≥ 24 months or PR with PFS ≥ 36 months; (b) intermediate responders, pts with CR and PR who were not exceptional responders (IR); (c) pts with progressive disease (PD).

Results

550 pts on IO/IO had available whole exome sequencing (WES) data while 434 pts in the IO/VEGF cohort had available WES and RNA-sequencing data. A greater proportion of pts from clinical trials had ER (25%) when compared to real-world data (6%) in the IO/IO cohort. Neither tumor mutation burden, mean HLA-I evolutionary divergence, whole genome integrity index, tumor purity nor tumor ploidy were associated with ER in the trial cohorts. In the IO/IO cohort, clonal neoantigen load (CNL) was significantly higher in ER pts (vs. IR: p=0.043; vs. PD: p=0.017). In a multivariate Cox regression, only CNL remained associated with improved PFS (p = 0.007). In the IO/VEGF cohort, ER pts had high expression of signatures for plasma cells, memory B-cell inside, and tertiary lymphoid structures (TLS). Pts with ER had higher TLS signature score compared to IR and PD using 3 different gene expression signatures.

Conclusions

Our results suggest that ER is partly mediated by clonal neoantigen-driven cytotoxic T-cell responses and TLS formation in the tumor microenvironment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.