ASCO 2018: Correlation of Degree of Tumor Immune Infiltration and Insertion-and-Deletion Burden with Outcome on Programmed Death 1 Therapy in Advanced Renal Cell Cancer

Chicago, IL ( The clinical benefit of anti-PD1 therapy can be predicted by the amount of mutational load and neoantigen burden in most cancer. Notably, In RCC these are specifically known to be low. However, when comparing RCC to other cancers, RCC was noted to be enriched with tumor immune infiltrate and a high proportion of insertion and deletion burden, which might have an immunogenic potential.

In this study, the authors investigated these RCC specific immunologic phenomena in patients who were treated with anti-PD1 therapy, compared to patients undergoing treatment with tyrosine kinase inhibitors (TKI).

This study analyzed tumors from 112 patients across 3 cohorts:
1. PD1-A – 54 patients treated with a single agent (nivolumab)
2. PD1-B – 23 patients treated with PD-1 directed regimens at three academic institutions
3. PD1-A+PD1-B – vary in regards to clinical setting (extent of prior treatment). The cohorts were analyzed separately and then jointly in a pooled stratified analysis.
4. TKI – 35 patients treated with 1st line TKI therapy and with no prior exposure to checkpoint inhibitor (CPI) therapy. These patients were treated across 5 academic institutions.

For this study, whole exome sequencing (WES) was performed to all 112 patients. Quantification of the overall mutation burden, insertion and deletion burden, and predicted neoantigens was performed. The ESTIMATE and CIBERSORT algorithms were used to infer abundances of immune infiltrate and detailed immunophenotypes from RNA sequencing. The correlation of molecular features with overall survival (OS) and durable clinical benefit (DCB), which was defined as progression free survival > 6mo, was assessed.

The authors presented their results, showing that patients with a tumor insertion and deletion burden >=median was associated with improved overall survival (OS) in PD-1 treated patients (Figure 1).

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Insertion and deletion count above the median is associated with improved overall survival

RNA sequence analysis demonstrated that increasing overall immune infiltration in RCC patients was correlated favorably with durable clinical benefit in the PD1 cohort (p = 0.053), but not in the TKI treated patients (p = 0.845). The most abundant infiltrating immune cell type was analyzed (M2 macrophage). This cell was associated with durable clinical benefit in anti PD1 therapy (p=0.017). However, it was not associated with favorable outcome in the TKI patients (p = 0.1733).

In conclusion, this interesting study demonstrated that in contrast to other cancers, in RCC the mutation and neoantigen load did not correlate with outcomes to PD1-directed therapy. However, higher insertion and deletion count appeared to confer superior OS with PD1-directed therapy. In RCC patients treated with PD1, higher extent of tumor immune infiltration at baseline demonstrated a trend towards superior outcome. This was not shown in the TKI treated patients. These important findings are of great potential in the biomarker development field and should be validated in other larger cohorts.

Presented by: Martin Henner Voss, Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

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