Higher Indel Counts Linked to Improved OS in RCC

In RCC patients on anti–PD-1 therapy, besides the indel count link to better OS, baseline tumor infiltration with M2 macrophages predicted improved PFS.

Baseline tumor immune infiltration, particularly by M2 macrophages, appears to be associated with favorable outcomes in renal cell carcinoma (RCC) patients receiving anti–programmed death 1 (PD-1) immunotherapy, according to new data presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. Investigators found that, in contrast to other cancers, in this RCC populations, mutation and neoantigen load did not affect the outcomes of anti–PD-1 agents. In addition, the study showed that higher insertions and deletions (indel) counts appeared to be associated with superior overall survival (OS).

Mutational load and neoantigen burden have been shown to be predictive of benefit from anti–PD-1 therapy in several tumor types.  However, the tumor mutational load and neoantigen burden tend to be low in patients with RCC. Martin Henner Voss, MD, from Memorial Sloan Kettering Cancer Center, New York City, and colleagues, investigated these anomalies in anti-PD1 treated RCC patients, comparing anti–PD-1–treated RCC patients with RCC patients receiving tyrosine kinase inhibitors (TKIs).

Voss et al conducted whole-exome sequencing for 77 tumors from 2 anti–PD-1–treated patient cohorts. The investigators were also able to analyze RNA sequence data in 25 of these patients. The team quantified the overall mutation burden, indel, and predicted neoantigens. The researchers investigated the correlation of molecular features with OS and durable clinical benefit, which was defined as progression free survival > 6 months. The investigators used a cohort of TKI-treated RCC patients with no prior anti–PD-1treatment as a comparator. The second group included 35 patients who had undergone whole-exome sequencing and 33 who had undergone RNA sequencing.

The researchers found that higher overall immune infiltration correlated favorably with durable clinical benefit (progression-free survival lasting 6 months or longer) in the PD-1 cohort. However, that was not the case in TKI-treated patients (P = .84). The study showed conflicting results with the two most abundant infiltrating cell types. The M2 macrophages were associated with a durable clinical benefit, but the opposite was true regarding the CD8+ T cells (P = .22) in RCC patients in the anti–PD-1therapy arm. Neither M2 macrophages nor CD8+ T cells were associated with outcomes in the arm with the TKI patients, according to the researchers.

They reported that the mutation counts were low and neither mutation nor neoantigen burden appeared to have an impact on OS in the arm with patients on anti–PD-1 therapy. However, they found that the association with OS was significant for frameshift indel count. These findings may have implications for better stratifying RCC patients, however much more research is warranted.