Clinical Development of Immune Checkpoint Inhibitors

Table 1

Target molecule	Drug name	Phase	Status/NCT number	Disease	Number of patients	Study design	Response	Survival	Treatment-related adverse events (≧Gr3)	Reference
CTLA-4	Ipilimumab	III	Completed (NCT00094653)	Melanoma	676	Endpoint: safety/efficacy Ipi + gp100 versus Ipi versus gp100	Ipi + gp100: ORR 5.7%; SD 14.4%	Ipi + gp100 versus gp100: 10.1 versus 6.4 mos	Ipi + gp100: drug-related 17.4%; irAEs 10.2%; diarrhea 4.5%; fatigue 5.0%; dyspnea 3.7%; anemia 2.9%; endocrine abnl. 11%; AST↑ 0.5%; ALT↑ 0.3%	[5]
		III	Completed (NCT00324155)	Melanoma	502	Endpoint: efficacy Ipi + DTIC versus PBO + DITC	Ipi + DTIC: ORR 15.2%; SD 18.0%	Ipi + DTIC versus PBO + DTIC: 11.2 versus 9.1 mos	Ipi + DTIC: immune-related 41.7%; pruritus 2.0%; rash 1.2%; diarrhea 4.0%; colitis 6.1%; AST↑ 17.4%; ALT↑ 20.7%	[6]
	Tremelimumab	III	Completed (NCT00257205)	Melanoma	655	Endpoint: efficacy treme. versus chemo.	ORR 10.7%	Treme. versus chemo.: 12.6 versus 10.7 mos (NS)	52%; diarrhea/colitis 18%; fatigue 6%; rash 2%; pruritus 1%; dyspnea 3%; hypothalamus and pituitary disorders 1%; hepatitis 1%	[7]
PD-1	Nivolumab (BMS-936558/ONO-4538)	I	Ongoing (not recruiting) (NCT00730639)	Melanoma	107	Endpoint: safety/efficacy 5 dosing regimens	ORR 30.8%; median duration of response 104 wks; SD (≧24 wks) 6.5%	OS 16.8 mos; PFS 3.7 mos	22.4%; fatigue 1.9%; diarrhea 1.9%; abdominal pain 1.9%; lymphopenia 2.8%	[8]
		I	Ongoing (not recruiting) (NCT01176461)	Melanoma	90	Endpoint: safety/efficacy 3 dosing regimens	ORR 25%; SD (≧24 wks) 21%	PFS (at 24 wks) 46%	5.6%; rash 2.2%; interstitial pneumonitis 2.2%	[9]
		III	Ongoing (not recruiting) (NCT 01721772)	Melanoma	370	Endpoint: efficacy; Nivo. versus ICC	ORR 32% versus 11%	NA	9% versus 31%	[10]
		III	Completed (NCT01721772)	Melanoma	418	Endpoint: efficacy; Nivo. versus dacarbazine	ORR 40.0% versus 13.9%	OS (at 1 yr) 72.9% versus 42.1%, median PFS 5.1 versus 2.2 mo	11.7% versus 17.6%; fatigue 0.5%; diarrhea 1.0%; rash 0.5%; vomiting 0.5%	[11]
	Pidilizumab (CT-011)	II	Completed (NCT01435369)	Melanoma	103	Endpoint: safety/efficacy 2 dosing regimens	ORR 5.9%	OS (at 1 yr): 64.5%	NA	[12]
	Pembrolizumab (MK-3475)	I	Ongoing (not recruiting) (NCT01295827)	Melanoma	135	Endpoint: safety/efficacy 3 dosing regimens	ORR 38% by RECIST and 37% by irRC	Median PFS >7 mos	13%; hypothyroidism 1%; diarrhea 1%; fatigue 1%; AST↑ 1%; renal failure 1%; rash 2%; pruritus 1%	[13]
		I	Ongoing (not recruiting) (NCT01295827)	Untreated NSCLC	57	Endpoint: safety/efficacy 3 dosing regimens	ORR 26% by RECIST and 47% by irRC	Median OS NR; OS at 1 yr 80%; median PFS 45.6%; PFS at 24 wks 70%	CK↑ 2%; pericardial effusion 2%; pneumonitis 2%; acute kidney injury 2%	[14]
		I	Ongoing (not recruiting) (NCT01848834)	Head and neck cancer	60	Endpoint: safety/efficacy single arm	ORR 19.6% in total, 20.0% in HPV+, and 19.4% in HPV−;	NA	Gr3–5 16.7%; Rash 3.3%	[15]
		I	Ongoing (not recruiting) (NCT01848834)	Gastric cancer	39	Endpoint: safety/efficacy single arm	ORR 30.2% by RECIST	NA	7.7%; hypoxia 2.6%; peripheral neuropathy 2.6%; pneumonia 2.6%	[16]
PD-L1	BMS-936559	I	Ongoing (not recruiting) (NCT00729664)	Melanoma	52	Endpoint: safety 4 dose levels	ORR 17%; SD (≧24 wks) 27%	PFS (at 24 wks) 42%	9%; fatigue 1%; infusion reaction 1%; lymphopenia 1%	[17]
				NSCLC	49		ORR 10%; SD (≧24 wks) 12%	PFS (at 24 wks) 31%
				Ovarian cancer	17		ORR 6%; SD (≧24 wks) 18%	PFS (at 24 wks) 22%
				Renal cell carcinoma	17		ORR 12%; SD (≧24 wks) 41%	PFS (at 24 wks) 53%
	MPDL3280A	I	Recruiting (NCT01375842)	Urothelial bladder cancer	68	Endpoint: safety/efficacy/; biomarker single arm	ORR: PD-L1 + 43% (at 6 wks) and 52% (at 12  wks); PD-L1 − 11% (at 6 wks);	NA	4%; no irAE	[18]
	MEDI4736	I	Recruiting (NCT01693562)	Advanced solid tumors	26 (as of Jan 2014)	Endpoint: safety/efficacy single arm	PR 15.4%; disease control rate (≧12 wks) 46%	NA	Any Gr 34%; Gr3/4 0%; no DLT; no MTD	[19]
	MSB0019718C	I	Recruiting (NCT01772004)	Refractory malignancies	27 (as of Jan 2014)	Endpoint: safety single arm	NA	NA	Treatment discontinuation 52.2% (8.7% for AEs); drug-related AEs 11.1%; DLT 3.7% (CPK↑, myositis, and myocarditis)	[20]

Abbreviations: NSCLC, non-small cell lung cancer; Ipi, Ipilimumab; gp100, glycoprotein 100 peptide vaccine; DITC, dacarbazine; PBO, placebo; ORR, objective response rate; PR, partial response; SD, stable disease; mo, month; wk, week; RECIST, response evaluation criteria in solid tumors; irRC, immune-related response criteria; HPV, human papillomavirus; NA, not available; NS, not significant; NR, not reached; OS, overall survival; PFS, progression-free survival; AE, adverse event; irAE, immune-related adverse event; Gr, Grade; abnl., abnormality; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CPK, creatine phosphokinase; DLT, dose limiting toxicity; MTD, maximum tolerance dose; ICC, investigator’s choise chemotherapy.