Table 6.

Immunotherapy trials involving metastatic colorectal cancer patients.

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.