Table 6.
Study | Study Type | Treatment | Setting | Primary Endpoint | Results |
---|---|---|---|---|---|
KEYNOTE-164 1NCT02460198 [134] |
Phase II, open-Label | Pembrolizumab (anti-PD-1)2 | Previously treated MSI-H/dMMR3 mCRC4: -Cohort A: ≥2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan ± anti-VEGF45/EGFR6 monoclonal antibodies -Cohort B: ≥1 prior line of therapy |
ORR7 by RECIST8 version 1.1 by independent central review | -Cohort A: *ORR: 33% (95% CI9: 21–46%); median duration of response not reached *mPFS10: 2.3 months (95% CI, 2.1–8.1 months) *mOS11: 31.4 months (95% CI, 21.4 months-not reached) -Cohort B: *ORR: 33% (95% CI: 22–46%); median duration of response not reached *mPFS: 4.1 months (95% CI, 2.1–18.9 months) *mOS: not reached (95% CI, 19.2 months—not reached) |
CheckMate-14212 trial NCT02060188 [135,136,137] |
Phase II, open-label, non-randomized, multicohort | Nivolumab (anti-PD-1) | MSI-H/dMMR recurrent/mCRC progressed on/after, or intolerant of at least one previous line of treatment, including fluoropyrimidine and oxaliplatin or irinotecan | ORR - investigator-assessed per RECIST 1.1 | *ORR: 31.1% (95% CI: 20.8–42·9%) of patients * disease control for ≥12 weeks: 68.9% of patients (95% CI: 57.1–79.2%) *median duration of response: not yet reached |
Nivolumab + ipilimumab (anti-CTLA-413) | First line MSI-H/dMMR mCRC | *ORR: 60% | |||
2 – NIMBLe14 study NCT0346195 |
Phase II, open-label, randomized, non-comparative trial | Nivolumab vs.15 nivolumab+ipilimumab | Advanced hypermutated solid tumors with POLE16 or POLD117 mutations progressing after at least 1 standard cancer therapy | ORR by RECIST 1.1 | Ongoing |
NCT03428802 | Basket, open-label trial | Pembrolizumab | Metastatic, recurrent. or locally advanced cancer and genomic instability, including POLE and POLD1 mutations | RR18 | Ongoing |
NCT03150706 | Phase II, open-label | Avelumab (anti-PD-L1)19 | MSI-H/dMMR or POLE mutant mCRC progressed after at least first-line systemic chemotherapy | Serum CEA20, TSH21, T322, free T423, EKG24, CT25 (or MRI26) scans of evaluable/measurable lesions by RECIST 1.1 | Ongoing |
NCT03435107 | Phase II, open-label | Durvalumab (anti-PD-L1) | MSI-H/dMMR or POLE mutant mCRC progressed after at least first-line systemic chemotherapy for metastatic setting (or within 6 months after completion of adjuvant chemotherapy) | ORR by RECIST 1.1 | Ongoing |
Note: 1KEYNOTE-164 = A Phase II Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects with Previously Treated Locally Advanced Unresectable or Metastatic (Stage IV) Mismatched Repair Deficient or Microsatellite Instability-High Colorectal Carcinoma; 2anti-PD1 = anti-programmed cell death protein 1; 3MSI-H/dMMR = microsatellite instability-high/defective mismatch repair; 4mCRC = metastatic colorectal cancer; 45anti-VEGF = anti-vascular endothelial growth factor; 6EGFR = epidermal growth factor receptor; 7ORR = objective response rate; 8RECIST = response evaluation criteria in solid tumors; 9CI: = confidence interval; 10mPFS = median progression-free survival; 11mOS = median overall survival; 12CheckMate-142 = Nivolumab in Patients With Metastatic DNA Mismatch Repair-Deficient or Microsatellite Instability-High Colorectal Cancer; 13anti-CTLA4 = anti -cytotoxic T-lymphocyte antigen-4; 14NIMBLe = Nivolumab Ipilimumab in Patients With hyperMutated Cancers Detected in Blood; 15vs. = versus; 16POLE = DNA polymerase epsilon, catalytic subunit; 17POLD1 = DNA polymerase delta 1, catalytic subunit; 18RR = response rate; 19anti-PD-L1 = anti-programmed death-ligand 1; 20CEA = carcinoembryonic antigen; 21TSH = thyroid-stimulating hormone; 22T3 = triiodothyronine; 23T4 = thyroxine; 24EKG = electrocardiogram; 25CT = computed tomography; 26MRI = magnetic resonance imaging.