PD-1 Inhibition and PD-1 Inhibitors

Programmed T cell death 1 (PD-1) is a trans-membrane protein found on the surface of T cells, which, when bound to programmed T cell death ligand 1 (PD-L1) on tumor cells, results in suppression of T cell activity and reduction of T cell-mediated cytotoxicity (Robert et al. 2014). Thus, PD-1 and PD-L1 are immune down-regulators or immune checkpoint “off switches” (Mamalis et al. 2014).

Drug class	Target	Agent	Diseases	Line of Therapy	Status	Source
PD-1 inhibitors	PD-1	nivolumab (Opdivo)	Hodgkin lymphoma	metastatic	Trials completed with results	Ansell et al. 2015
			melanoma	metastatic	FDA Approved	Hodi et al. 2014; Weber et al. 2013
			non-small cell lung cancer	metastatic	FDA Approved	Antonia et al. 2014a, Antonia et al. 2014b; Gettinger et al. 2014; Rizvi et al. 2014
			small cell lung cancer	metastatic	Trials completed with results	Antonia et al. 2015
			hepatocellular carcinoma	metastatic	Trials completed with results	El-Khoueiry et al. 2015
			renal cell carcinoma	metastatic	FDA Approved	Motzer et al. 2014
			ovarian cancer	metastatic	Trials completed with results	Hamanishi et al. 2015
		pembrolizumab (Keytruda)	melanoma	metastatic	FDA Approved	Ribas et al. 2014
			non-small cell lung cancer	metastatic	FDA Approved	Garon et al. 2014
			small cell lung cancer	metastatic	Trials completed with results	Ott et al. 2015
			head and neck cancer	metastatic	Trials completed with results	Seiwert et al. 2015
			urothelial cancer	metastatic	Trials completed with results	Plimack et al. 2015
		pidilizumab	melanoma	metastatic	Trials completed with results	Atkins et al. 2014

PD-1 inhibitor adverse effects

Treatment with PD-1 inhibitors is associated with unique adverse events due to the medication’s immune upregulation. The most common adverse effects in ≥ 20% of patients are rash, diarrhea, pruritis, and fatigue (FDA 2014; Robert et al. 2014; Weber et al. 2013). Less common but also observed are various endocrinopathies (hypophysitis, hypothyroidism), neurologic damage (altered mental status, peripheral neuropathy), and pneumonitis. Aminotransferase levels, endocrine function, and respiratory status should be closely monitored in patients receiving PD-1 inhibitors.

PD-1 inhibitors in melanoma

Three fully human anti-PD-1 monoclonal antibodies have been tested in phase I and II clinical trials in patients with metastatic melanoma: nivolumab (Hodi et al. 2014; Weber et al. 2013), pembrolizumab (Ribas et al. 2014), and pidilizumab (Atkins et al. 2014). Pembrolizumab and nivolumab are FDA-approved for the treatment of metastatic melanoma (FDA 2014).

Reference	Study Type / Phase	Line of Treatment	Treatment Agent	Mutation/Marker Status	# Patients in Study	Response Rate	PFS (months)	OS (months)
Larkin et al. 2015; Wolchok et al. 2015 (CheckMate 067)	Phase III	1st line	ipilimumab	PD-L1+ or PD-L1-	315	19.0%	2.9
				≥ 5% PD-L1 expression subgroup	75	21.3%	3.9
			nivolumab	PD-L1+ or PD-L1-	316	43.7%	6.9
				≥ 5% PD-L1 expression subgroup	80	57.5%	14
			ipilimumab + nivolumab	PD-L1+ or PD-L1-	314	57.6%	11.5
				≥ 5% PD-L1 expression subgroup	68	72.1%	14
Robert et al. 2015	Phase III	1st line	nivolumab	BRAF wild type	210	40%	5.1	72.9% (12-month)
			dacarbazine		208	13.9%	2.2	42.1% (12-month); 10.8
Robert et al. 2015 (KEYNOTE-006)	Phase III	1st or 2nd line	ipilimumab 3 mg/kg Q 3 weeks (4 cycles)		278	11.9%	26.5% (6-month)	58.2% (12-month)
			pembrolizumab 10 mg/kg Q 2 weeks		279	33.7%	47.3% (6-month)	74.1% (12-month)
			pembrolizumab 10 mg/kg Q 3 weeks		277	32.9%	46.4% (6-month)	68.4% (12-month)
Weber et al. 2015	Phase III	2nd line or greater	nivolumab	PD-L1+ or PD-L1-	120	31.7%
				≥ 5% PD-L1 expression subgroup	55	43.6%
			investigator’s choice	PD-L1+ or PD-L1-	47	10.6%
				≥ 5% PD-L1 expression subgroup	22	9.1%
Ribas et al. 2015 (KEYNOTE-002)	Phase II	Any line of therapy with confirmed progressive disease within 24 weeks after two or more ipilimumab doses	pembrolizumab 2 mg/kg Q 3 weeks		180	21%	34% (6-month)
			pembrolizumab 10 mg/kg Q 3 weeks		181	25%	38% (6-month)
			investigator-choice chemotherapy		179	4%	16% (6-month)
Hodi et al. 2014	Phase I	2nd line or greater (no prior ipilimumab)	nivolumab	PD-L1+ or PD-L1-	107	32%	9.1 (PD-L1+)	61% (12-month)
							1.9 (PD-L1-)
Ribas et al. 2014	Phase I		pembrolizumab		411	40% (no prior ipilimumab)	6 (no prior ipilimumab)	71% (12-month)
						28% (prior ipilimumab)	5.8 (prior ipilimumab)
Atkins et al. 2014	Phase II	1st-4th line	pidilizumab		103	5.9%	2.8 (prior ipilimumab)	64.5% (12-month)
							1.9 (no prior ipilimumab)

NOTE: OS = overall survival; PFS = progression-free survival

PD-1 inhibitors in non-small cell lung cancer

Two fully human anti-PD-1 monoclonal antibodies have been tested in patients with advanced non-small cell lung cancer (NSCLC): pembrolizumab (Garon et al. 2014), and nivolumab (Gettinger et al. 2014; Antonia et al. 2014a; Antonia et al. 2014b; Rizvi et al. 2014). Nivolumab and pembrolizumab are FDA-approved for the treatment of advanced NSCLC (FDA 2015).

In squamous non-small cell lung cancer, one phase III study comparing nivolumab with docetaxel demonstrated a survival benefit with nivolumab in patients after disease progression on prior platinum-based doublet chemotherapy regimen (CheckMate 017; Spigel et al. 2015).

Reference	Study Type / Phase	Line of Treatment	Treatment Agent	Mutation/Marker Status	# Patients in Study	Response Rate	PFS (months)	OS (months)
Paz-Ares et al. 2015 (CheckMate 057)	Phase III	2nd line or greater (after failure of platinum-based doublet chemotherapy and/or tyrosine kinase inhibitor)	nivolumab		292	19.2%	2.3	12.2
			docetaxel		290	12.4%	4.2	9.4
Spigel et al. 2015 (CheckMate 017)	Phase III	Squamous NSCLC; 2nd line (after disease progression on prior platinum-based doublet chemotherapy regimen)	nivolumab		135	20%	3.5	9.2
			docetaxel		137	9%	2.8	6.0
Garon et al. 2014; Rizvi et al. 2014 (KEYNOTE-001)	Phase I	3rd line or greater	pembrolizumab	PD-L1+ or PD-L1-	221	15%
				PD-L1+ subgroup	90	24%	6
				PD-L1 staining in ≥50% of tumor cells	17	47%
				PD-L1 staining in 1%-49% of tumor cells	31	19%	4.4
				PD-L1 staining in <1% of tumor cells	7	14%	3.4	7.3
Gettinger et al. 2014	Phase I	1st line	nivolumab		20	30%	7.4
						67% (PD-L1+)	not reached (PD-L1+)
						0% (PD-L1-)	5.8 ( PD-L1 -)
Antonia et al. 2014a	Phase I	1st line	nivolumab		46	22%
Antonia et al. 2014b	Phase I	1st line	nivolumab		56	33-50%	36-71% (6-month)	59-87% (12-month)
Rizvi et al. 2014	Phase I	1st line	nivolumab	EGFR mutation subset	21	19%	47% (6-month)

NOTE: OS = overall survival; PFS = progression-free survival