PD-L1 Inhibition and PD-L1 Inhibitors

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

Drug class	Target	Agent	Diseases	Line of Therapy	Status	Source
PD-L1 inhibitors	PD-L1	BMS-936559	melanoma	metastatic	Trials completed with results	Brahmer et al. 2012
			non-small cell lung cancer	metastatic	Trials completed with results	Brahmer et al. 2012
		atezolizumab (MPDL3280A)	bladder cancer	metastatic	Trials completed with results	Powles et al. 2014; Petrylak et al. 2015
			melanoma	metastatic	Trials completed with results	Herbst et al. 2014
			non-small cell lung cancer	metastatic	Trials completed with results	Besse et al. 2015; Herbst et al. 2014; Spigel et al. 2015; Spiva et al. 2015; Vansteenkiste et al. 2015
			renal cell carcinoma	metastatic	Trials completed with results	Herbst et al. 2014

PD-L1 inhibitor adverse effects

Treatment with PD-L1 inhibitors is associated with unique adverse events due to the medication’s immune upregulation. The most common adverse effects in ≥ 10% of patients are rash, diarrhea, pruritis, and fatigue (Brahmer et al. 2012). Less common but also observed are various endocrinopathies (hypophysitis, hypothyroidism) or neurologic damage (altered mental status, peripheral neuropathy). Aminotransferase levels and visual changes should be closely monitored in patients receiving PD-L1 inhibitors (Brahmer et al. 2012).

PD-L1 inhibitors in bladder cancer

One anti-PD-L1 monoclonal antibody (atezolizumab, also known as MPDL3280A) has been tested in a phase I trial of patients with metastatic urothelial bladder cancer (Powles et al. 2014). Currently, this medication is not FDA-approved for the treatment of bladder cancer.

Reference	Study Type / Phase	Line of Treatment	Treatment Agent	Mutation/ Marker Status	# Patients in Study	Response Rate	PFS (months)	OS (months)
Powles et al. 2014; Petrylak et al. 2015	Phase I	1st line or greater	atezolizumab (MPDL3280A)	PD-L1 IHC score 2/3	46	46%	6
				PD-L1 IHC score 0/1	38	16%	2

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

PD-L1 inhibitors in melanoma

A fully human anti-PD-L1 monoclonal antibody (BMS-936559) has been tested in a phase I trial of patients with advanced melanoma (Brahmer et al. 2012). In a large phase I trial, atezolizumab (MPDL3280A)demonstrated efficacy in an expansion cohort for melanoma patients (Herbst et al. 2014). Currently, these medications are not FDA-approved for the treatment of advanced melanoma.

Reference	Study Type / Phase	Line of Treatment	Treatment Agent	Mutation/ Marker Status	# Patients in Study	Response Rate	PFS (months)	OS (months)
Brahmer et al. 2012	Phase I	2nd line or greater	BMS-936559		55	17%	42% (6-month)
Herbst et al. 2014	Phase I	1st line or greater	atezolizumab (MPDL3280A)		43 (melanoma cohort)	30%	41% (6-month)

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

PD-L1 inhibitors in non-small cell lung cancer

In preliminary results reported from phase II trials in non-small cell lung cancer (NSCLC), PD-L1 status conferred predictive benefit with treatment with atezolizumab (MPDL3280A; Besse et al. 2015; Spigel et al. 2015; Spiva et al. 2015; Vansteenkiste et al. 2015). In a large phase I trial, atezolizumab demonstrated efficacy in an expansion cohort for NSCLC patients (Herbst et al. 2014; Horn et al. 2015).

In a phase I trial, a fully human anti-PD-L1 monoclonal antibody (BMS-936559) has been tested in patients with metastatic NSCLC (Brahmer et al. 2012).

Currently, these medications are not FDA-approved for the treatment of NSCLC.

Reference	Study Type / Phase	Line of Treatment	Treatment Agent	Mutation/ Marker Status	# Patients in Study	Response Rate	PFS (months)	OS (months)
Spigel et al. 2015	Phase II (FIR)	Chemo-naïve (cohort 1)	atezolizumab (MPDL3280A)	≥5% PD-L1 expressing tumor cells (TC) by IHC and ≥1% PD-L1 expressing immune cells (IC) by IHC (TC2/3 and IC2/3)	31	29%	39% (6-month PFS)
				≥50% PD-L1 expressing TC by IHC and ≥10% PD-L1 expressing IC by IHC subgroup (TC3 and IC3 subgroup)	7	29%	43% (6-month PFS)
		2nd line or greater without brain mets (cohort 2)	atezolizumab (MPDL3280A)	TC2/3 and IC2/3	71	17%	35% (6-month PFS)
				TC3 and IC3 subgroup	26	27%	49% (6-month PFS)
		2nd line or greater with treated brain mets (cohort 3)	atezolizumab (MPDL3280A)	TC2/3 and IC2/3	12	17%
				TC3 and IC3 subgroup	8	25%
Spiva et al. 2015; Vansteenkiste et al. 2015	Phase II (POPLAR)	2nd or 3rd line	atezolizumab (MPDL3280A)	All PD-L1 levels	144	15%	2.7	12.6
				TC3 and IC3 subgroup	24	38%	7.8	15.5
			docetaxel	All PD-L1 levels	143	15%	3	9.7
				TC3 and IC3 subgroup	23	13%	3.9	11.1
Besse et al. 2015	Phase II (BIRCH)	1st line	atezolizumab (MPDL3280A)	TC2/3 or IC2/3	65	26%	48% (6-month)	79% (12-month)
				TC3 or IC3	139	19%	46% (6-month)	82% (12-month)
		2nd line		TC2/3 or IC2/3	122	24%	34% (6-month)	80% (12-month)
				TC3 or IC3	267	17%	29% (6-month)	76% (12-month)
		3rd line or greater		TC2/3 or IC2/3	115	27%	39% (6-month)	75% (12-month)
				TC3 or IC3	253	17%	31% (6-month)	71% (12-month)
Herbst et al. 2014; Horn et al. 2015	Phase I	1st line or greater	atezolizumab (MPDL3280A)	All PD-L1 levels	88 (NSCLC cohort)	21%	42% (6-month)	82% (12-month)
				TC3 and IC3 subgroup	20	45%	45% (6-month)	89% (12-month)
Brahmer et al. 2012	Phase I	2nd line or greater	BMS-936559		75	10%	31% (6-month)

NOTE: IC = immune cells; TC = tumor cells; OS = overall survival; PFS = progression-free survival