Mutations linked to checkpoint inhibitor response in RCC

Truncating mutations in the gene for a protein involved in chromatin structure and transcription appear to identify patients with metastatic clear cell renal cell carcinoma (ccRCC) who respond to treatment with nivolumab (Opdivo) or other immune checkpoint inhibitors in a derivation and validation study involving a total of 98 patients.

This finding “has important implications as a molecular tool for considering immunotherapy responsiveness” in patients with ccRCC and possibly patients with other cancer types, wrote Eliezer M. Van Allen, MD, of Dana Farber Cancer Institute in Boston and coauthors.

The derivation cohort included 35 patients with metastatic ccRCC treated with nivolumab in a prospective clinical trial. Genome sequencing of pretreatment tumor specimens showed that improved survival after treatment was significantly linked with truncating mutations in a gene, PBRM1, that codes for a protein in the SWI/SNF chromatin-remodeling complex. Patients in the derivation cohort who had these mutations were nearly 13-fold more likely to have clinical benefit from treatment, compared with those without these mutations.

The validation study included specimens and treatment-outcome results from 63 patients with metastatic ccRCC treated with either nivolumab or a different checkpoint inhibitor, such as atezolizumab (Tecentriq). In the validation study, PBRM1 mutations linked with a sixfold higher rate of clinical benefit from treatment.

The researchers noted that the types of mutations they identified as likely involved occur in more than 20% of all cancer types. Results from mouse studies have suggested that tumor cells with these types of mutations are more sensitive to T cell–mediated cytotoxicity, an observation that “lends a mechanistic basis” to the observed findings.

The study received funding in part from Bristol-Myers Squibb, the company that markets nivolumab (Obdivo). Several researchers involved in this study have received honoraria and research support from Bristol-Myers Squibb and from several other drug companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

SOURCE: Miao D et al. Science. 2018 Jan 4. doi: 10.1126/science.aan5951