Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions

Table 1 List of clinical trials with immune check point inhibition therapy

Trial identified (number of patients)	Treatment groups	Patients enrolled	Primary and secondary outcomes
Checkpoint inhibitor: Pembrolizumab
NCT01876511 (n = 113)	Pembrolizumab	Cohort A: MSI positive (pMMR) CRC	Cohort A: ORR: 54.0% (95%CI: 37.0–69.0); PFS: 70% (95%CI: 57–86); OS: NA (95%CI: 151.86-NA)
		Cohort B: MSI negative (dMMR) CRC	Cohort B: ORR: 0% (95%CI: 0.0–14.0); PFS: 16% (95%CI: 6–41); OS: 36.71 (95%CI: 21.29-69.43)
NCT02460198 (n = 124)	Pembrolizumab	mCRC with dMMR or MSI–H status Cohort A: Participants must have received prior treatment with standard therapies	Cohort A: ORR: 32.8 (95%CI: 21.3 to 46.0); PFS: 2.3 (95%CI: 2.1–8.1); OS: 31.4 (95%CI: 21.4–58)
		Cohort B: Participants must have undergone at least one line of systemic standard of care therapy	Cohort B: ORR: 34.9 (95%CI: 23.3–48.0); PFS: 4.1 (95%CI: 2.1–18.9); OS: 47 (19.2–NA)
NCT02563002 (n = 307)	Arm A: Pembrolizumab	mCRC with high MSI–H or dMMR	Arm A: ORR: 45.1% (95%CI: 37.1–53.3); PFS: 16.5 (95%CI: 5.4–38.1); OS: NA (95%CI: 49.2–NA)
	Arm B: mFOLFOX6/FOLFIRI/Bevacizumab/Cetuximab/Pembrolizumab		Arm B: ORR: 33.1% (95%CI: 25.8–41.1); PFS: 8.2 (95%CI: 6.1–10.2); OS: 27.6 (95%CI: 27.6–NA)
Checkpoint inhibitor: Nivolumab + Regorafenib
NCT04126733 (n = 94)	Regorafenib and Nivolumab	Patients with pMMR or MSS CRC	ORR: 7% (95%CI: 2.4–15.9); PFS: 1.8 (95%CI: 1.8–2.4); OS: 11.9 (95%CI: 7.0 to NA)
Checkpoint inhibitor: Nivolumab + Ipilimumab
NCT02060188 (n = 119)	Arm A: Nivolumab	MSI–H or dMMR mCRC	Arm A: No results posted
	Arm B: Nivolumab + Ipilimumab		Arm B: ORR: 55% (95%CI: 45.2%–63.8%); PFS: 71% (95%CI: 61.4 to 78.7); OS: 85% (95%CI: 77.0 to 90.2)
	Arm C: Cobimetinib + Nivolumab + Ipilimumab		Arm C: No results posted
	Arm D: Nivolumab + Daratumumab		Arm D: No results posted
	Arm E: Nivolumab + BMS–986016		Arm E: No results posted
Checkpoint inhibitor: Atezolizumab
NCT02788279 (n = 363)	Arm A: Atezolizumab	Patients with mCRC (MSI or MSS status unknown)	Arm A: PFS: 1.94 (95%CI: 1.91 to 2.10); OS: 7.10 (95%CI: 6.05–10.05)
	Arm B: Cobimetinib + Atezolizumab		Arm B: PFS: 1.91 (95%CI: 1.87 to 1.97); OS: 8.87 (95%CI: 7.00–10.61)
	Arm C: Regorafenib		Arm C: PFS: 2 (95%CI: 1.87–3.61); OS: 8.51 (95%CI: 6.41–10.71)
NCT01988896 (n = 84)	Atezolizumab + Cobimetinib	Patients having BRAF/KRAS mutation in mCRC	ORR: 8% (7/84) (6 patients: MSS, 1 patient: MSI)
NCT01633970 (n = 10)	Arm A: Atezolizumab + Bevacizumab	No results posted	No results posted
	Arm B: Atezolizumab + Bevacizumab + FOLFOX
	Arm C: Atezolizumab + Carboplatin + Paclitaxel
	Arm D: Atezolizumab + Carboplatin + Pemetrexed
	Arm E: Atezolizumab + Carboplatin + Nab–paclitaxel
	Arm F: Atezolizumab + Nab–paclitaxel
Checkpoint inhibitor: Durvalumab + Tremelimumab
NCT03122509 (n = 25)	Arm A: Durvalumab + Tremelimumab + Radiotherapy	Metastatic Colorectal Cancer (MSI or MSS status unknown)	Arm A: ORR: 8%; Stable response: 12%; Progressive disease: 76%
	Arm B: Durvalumab + Tremelimumab + Ablation		Arm B: No participants enrolled
Checkpoint inhibitor: Dostarlimab
NCT04165772 (n = 200)	Arm A: Dostarlimab	Patients with dMMR rectal adenocarcinoma	Arm A: Complete response: 12 patients (100%; 95%CI: 74–100)
	Arm B: Dostarlimab + Capecitabine or 5–FU + IMRT		Arm B: No participants enrolled

CRC: Colorectal cancer; mCRC: Metastatic colorectal cancer; MSI: Microsatellite-instability; MSI-H: Microsatellite instability-high; pMMR: Proficient mismatch repair; dMMR: Deficient mismatch repair; MSS: Microsatellite-stable; 5–FU: 5-fluorouracil IMRT: Intensity modulated radiotherapy.