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 durvalumab (Imfinzi) non-small cell lung cancer adjuvant FDA Approved Antonia et al. 2017
urothelial cancer metastatic FDA Approved Powles et al. 2017
head and neck cancer metastatic Trials completed with results Siu et al. 2018
atezolizumab (Tecentriq) urothelial cancer metastatic FDA Approved Bernard-Tessier et al. 2018; Powles et al. 2014; Petrylak et al. 2015
non-small cell lung cancer metastatic FDA Approved Besse et al. 2015; Herbst et al. 2014; Rittmeyer et al. 2017; Spigel et al. 2015; Spiva et al. 2015; Vansteenkiste et al. 2015
melanoma metastatic Trials completed with results Herbst et al. 2014
renal cell carcinoma metastatic Trials completed with results Herbst et al. 2014
avelumab (Bavencio) Merkel cell carcinoma metastatic FDA Approved D’Angelo et al. 2018
urothelial cancer metastatic FDA Approved Patel et al. 2018

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 urothelial cancer

Atezolizumab, durvalumab and avelumab all received accelerated FDA approval for the treatment of urothelial cancer in 2017 (FDA 2017).

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation/ Marker Status # Patients in Study Response Rate PFS (months) OS (months)
Powles et al. 2017 Phase I/II 1st line or greater durvalumab   191 17.8% 1.5 18.2
Patel et al. 2018 Phase I 2nd line or greater avelumab   161 17%    
Bernard-Tessier et al. 2018 Phase II 1st line atezolizumab   119 (cohort 1) 23%   15.9
Phase II 2nd line atezolizumab   310 (cohort 2) 15%   7.9
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 for non-small cell lung cancer in the metastatic setting

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 (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).

Atezolizumab received FDA approval based on a phase III study which randomized over 1000 patients to receive atezolizumab or docetaxel (Rittmeyer et al. 2017). Overall survival was improved in the atezolizumab arm, and atezolizumab received FDA approval in 2016 (FDA 2016).

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation/ Marker Status # Patients in Study Response Rate PFS (months) OS (months)
Rittmeyer et al. 2017 Phase III 2nd line or greater atezolizumab   425 14% 2.8 13.8
docetaxel   425 13% 4.0 9.6
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)
NOTE: IC = immune cells; TC = tumor cells; OS = overall survival; PFS = progression-free survival

 

PD-L1 inhibitors for non-small cell lung cancer in the adjuvant setting

Durvalumab was FDA-approved for the treatment of adjuvant non-small cell lung cancer in 2018 (FDA 2018).

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation/ Marker Status # Patients in Study Response Rate PFS (months) OS (months)
Antonia et al. 2017 Phase III adjuvant durvalumab   473 28.4% 16.8 55.9% (12-month)
placebo   236 16% 5.6 35.3% (12-month)

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

PD-L1 inhibitors in head and neck cancer

In a phase II trial, durvalumab and the combination of durvalumab and tremelimumab showed activity and efficacy in the treatment of head and neck cancer patients (Siu et al. 2018).

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation/ Marker Status # Patients in Study Response Rate PFS (months) OS (months)
Siu et al. 2018 Phase II 2nd line durvalumab PD-L1 Low/Negative 67 9.2%   6
tremelimumab 67 1.6%   5.5
durvalumab + tremelimumab 133 7.8%   7.6

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

PD-L1 inhibitors in Merkel cell carcinoma

Avelumab was granted accelerated FDA approval for the treatment of Merkel cell carcinoma in 2017 (FDA 2017).

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation/ Marker Status # Patients in Study Response Rate PFS (months) OS (months)
D’Angelo et al. 2018 Phase II 1st line avelumab   29 62.1% 93% (DOR)  

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

Contributors: Wade T. Iams, M.D., Douglas Johnson, M.D., Christine M. Lovly, M.D., Ph.D.

Suggested Citation: Iams, W.T., D. Johnson, C. Lovly. 2015. PD-L1 Inhibition and PD-L1 Inhibitors. My Cancer Genome http://www.padiracinnovation.org/content/molecular-medicine/pd-l1-inhibition-and-inhibitors/ (Updated September 3).

Last Updated: May 25, 2018

Disclaimer: The information presented at padiracinnovation.org is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.