Genomic correlates of response and resistance to immune checkpoint inhibitors in carcinomas of unknown primary.

Abstract

Cancers of unknown primary (CUP) are highly aggressive tumours with limited molecular characterization. These tumours can be particularly sensitive to immune checkpoint inhibitors (ICI) by mounting a seemingly more effective anti-tumour immune response. Unlike other tumour lineages, the biological basis and clinical efficacy of ICI in CUP remain largely unknown. The cBioPortal database was accessed to select eligible cases from the MSK-IMPACTTM Clinical Sequencing Cohort. The tumour cell genomic correlates of response and resistance to ICI in patients with CUP were compared to those with ICI-eligible tumours: cervical cancer, gastric cancer, renal cell carcinoma, hepatocellular carcinoma, non-small-cell lung cancer, melanoma, Merkel cell carcinoma and urothelial bladder cancer. Among a total of 234 patients with CUP, the identified genomic alterations were mainly mutation correlates of resistance to ICI, notably mutations in oncogenic signalling pathways including KRAS, STK11 and EGFR (24.7%, 10.9% and 4.2%, respectively). Compared to other tumours considered eligible for ICI, CUP presents a higher prevalence of alterations in the oncogenic signalling pathways KRAS and STK11. CUP patients treated with ICI had similar median overall survival with and without genomic correlates of response and resistance to ICI. An exploratory analysis showed that patients with TMB >10 mutations had a trend for better outcomes. A tumour mutation burden >10 mutations per megabase can provide a potential genomic correlate of response to ICI in patients with CUP. Further research is warranted to validate these findings.