Study Probes Genomic Factors Affecting Outcomes in Advanced Renal Cancer

Researchers trying to understand the response to programmed death 1 (PD-1) inhibitors in clear cell renal cell carcinoma (ccRCC) have identified several influencing factors, according to a recently published study.

The research, led by the Dana-Farber Cancer Institute, was presented during the American Society of Clinical Oncology (ASCO) Annual Meeting and published simultaneously in Nature Medicine.

By analyzing 592 tumors from patients treated with immunotherapy for advanced kidney cancer in 3 clinical trials, the researchers said they have more information about which patients may be more likely to benefit from the immunotherapy drugs.

Features typically linked to immunotherapy response or resistance in other types of cancer don’t work the same way in advanced ccRCC, the most common form of kidney cancer. Annually, there are about 74,000 new US cases of kidney cancer and about 15,000 deaths.

The 2 FDA-approved PD-1 inhibitors, nivolumab (Opdivo) and pembrolizumab (Keytruda) work by blocking PD-1, a protein on immune T cells. But the therapy does not work for all patients. Compared with other cancers, where the drugs are more effective against tumors with a high mutational burden, ccRCC has a moderate number of mutations but is relatively responsive to checkpoint inhibitors.

In addition, in melanoma and some other cancers, tumors that are infiltrated with large numbers of immune CD8 T cells respond better to PD-1 blockade. But ccRCC, the worse is true—high infiltration by CD8 T cells is associated with a worse outcome.

Of the 592 tumors, 362 were treated with a PD-1 blocker and 230 with inhibitors of the mammalian target of rapamycin (mTOR). They were analyzed by whole-exome (n = 454) and RNA-sequencing (n = 311), integrated with CD8 immunofluorescence analysis (n = 219) in order to understand how genomic changes and other factors were associated with progression-free survival (PFS) and overall survival (OS). Researchers looked for biomarkers in the genomes of the kidney cancer cells that might be correlated with patient outcomes.

Conventional genomic markers (tumor mutation burden, P = .81; neoantigen load, P = .47 for clinical benefit vs. no clinical benefit) and degree of CD8+ T cell infiltration (P = .88 for PFS; P = .65 for OS) were not associated with clinical response or altered survival with PD-1 blockade.

The ccRCC tumors were highly CD8+ T cell infiltrated, with only 22% having an immune desert phenotype and 5% with an immune excluded phenotype. CD8+ T cell infiltrated tumors were depleted of clinically favorable PBRM1 mutations (P = .013) and enriched for unfavorable chromosomal losses of 9p21.3 (P < .001) when compared with non-infiltrated tumors.

When found within infiltrated tumors, deletions of 9p21.3 were associated with worse clinical benefit rate and worse survival.

Reference

Braun DA, Hou Y, Bakouny Z, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med (2020). hdoi.org/10.1038/s41591-020-0839-y