• Key objective: To determine whether high tumor mutational burden and homologous recombination repair mutations in microsatellite-stable colorectal cancer can confer sensitivity to PD-1/ICOS bispecific checkpoint blockade. • Knowledge generated: Genomic profiling identified a POLE mutation, very high TMB (82 mut/Mb), and co-occurring pathogenic BRCA1/2 mutations in a patient with metastatic MSS CRC. Treatment with a PD-1/ICOS bispecific antibody led to a durable partial response lasting over 2 years without dose modification. • Relevance: These findings suggest a potential role for biomarker-selected MSS CRC patients to benefit from novel bispecific checkpoint inhibitors. They support the clinical investigation of PD-1/ICOS bispecific therapies in MSS solid tumors with features of increased immunogenicity. Microsatellite-stable (MSS) or mismatch repair proficient (MMRp) colorectal cancer typically exhibits resistance to immune checkpoint blockade. Tumor mutational burden (TMB) and DNA repair defects may increase immunogenicity and sensitivity to novel immunotherapies. We present a patient with metastatic MSS colorectal adenocarcinoma, previously treated with multiple standard regimens, who demonstrated an exceptional and durable partial response to an investigational bispecific PD-1/ICOS antibody. XmAb23104 was initially given in combination with ipilimumab on a clinical trial (DUET-3) and subsequently via an expanded-access investigational new drug (IND) application. Genomic profiling revealed extremely high TMB and pathogenic BRCA1/2 mutations. He achieved a partial response which was sustained for more than 2 years without dose reductions. This case highlights a novel therapeutic opportunity for MSS CRC, in which high TMB and homologous recombination deficiency may sensitize tumors to bispecific checkpoint blockade. Further investigation of PD-1/ICOS bispecific antibodies in biomarker-selected MSS solid tumors is warranted.
Jung et al. (Sun,) studied this question.