Mismatch Repair Deficiency as a Predictive Biomarker for Immunotherapy Efficacy

Table 1

Ongoing clinical trial with immune-checkpoint inhibitors alone or in a combination regimen according to mismatch repair status for different solid tumors. Last updated, April 2017.

Experimental arm	Active comparator regimen	Disease	Setting	Phase	Comments	ClinicalTrials.gov Identifier
Atezolizumab + FOLFOX	FOLFOX	CRC	Adjuvant, stage III	3	CT plus IO up to 25 courses	NCT02912559
Pembrolizumab	FOLFOX; FOLFIRI; Bevacizumab; Cetuximab	CRC	IV	3	KEYNOTE-177; IO for up to 35 treatments	NCT02563002
GVAX°; Pembrolizumab; Cyclophosphamide	Single arm	CRC	Advanced	2	MMRp	NCT02981524
AZD9150; Durvalumab	Single arm	Pancreatic, NSCLC, and MMRd CRC	Advanced	2	—	NCT02983578
Pembrolizumab; Poly-ICLC	Single arm	MMRp CRC	IV	1/2	IO for 1 year	NCT02834052
DS-8273; Nivolumab	NA	MMRp CRC	IV	1	—	NCT02991196
Nivolumab	Single arm	Hypermutated malignancies	Recurrent or refractory disease	1/2	Pediatric patients (12 months to 18 years of age); Biallelic; MMRd	NCT02992964
Nivolumab	Single arm	mCRPC with mutations in DNA repair defects	IV	2	ImmunoProst Trial; IO until progression or unacceptable toxicity	NCT03040791
Avelumab; Ad-CEA vaccine; Standard of care	FOLFOX; Bevacizumab Capecitabine	CRC	IV	2	CT and IO with maintenance	NCT03050814
Pembrolizumab	Single arm	High-grade gliomas, diffuse intrinsic pontine gliomas, or hypermutated brain tumors	NA	2	IO for 34 courses	NCT02359565

FOLFOX: Fluorouracil, Leucovorin, and Oxaliplatin combination regimen. CRC: colorectal cancer. CT: chemotherapy. IO: immunotherapy. FOLFIRI: Fluorouracil, Leucovorin, and Irinotecan. MMRp: mismatch repair proficient profile. MMPd: mismatch repair deficient profile. NSCLC: non-small cell lung carcinoma. mCRPC: metastatic castration-resistant prostate cancer; °GVAX, cancer vaccine composed of irradiated tumor cells genetically modified to secrete granulocyte-macrophage colony-stimulating factor; AZD9150, antisense oligonucleotide inhibitor of STAT3; Poly-ICLC (carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA), ligand of TLR3; DS-8273a, anti-human death receptor 5 (DR5) agonistic antibody; patients must have evidence of biallelic mismatch repair deficiency either in their tumor tissue (by immunohistochemistry or sequencing) or in their germline (by sequencing) and/or evidence of hypermutant malignancy by whole exome sequencing with a mutation load > 100 per exome; the germline and somatic DRD (BRCA1, BRCA2, ATM, PTEN, CHEK2, RAD51C, RAD51D, PALB2, MLH1, MSH2, MSH6, and PMS2) will be assessed by T-NGS of metastatic sites or by liquid biopsy.