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 FDA Approved Ansell et al. 2015
melanoma metastatic FDA Approved Hodi et al. 2014; Weber et al. 2013
adjuvant FDA Approved Weber et al. 2017
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 FDA Approved El-Khoueiry et al. 2015
renal cell carcinoma metastatic FDA Approved Motzer et al. 2018
ovarian cancer metastatic Trials completed with results Hamanishi et al. 2015
colorectal cancer (MSI-H/dMMR) metastatic FDA Approved Overman et al. 2017
urothelial cancer metastatic FDA Approved Sharma et al. 2017
head and neck cancer metastatic FDA Approval Ferris et al. 2016
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 FDA Approved Seiwert et al. 2015
urothelial cancer metastatic FDA Approved Plimack et al. 2015
Hodgkin lymphoma metastatic FDA Approval Chen et al. 2017
gastric cancer metastatic FDA Approved Fuchs et al. 2018
solid tumors (MSI-H/dMMR) metastatic FDA Approved Le et al. 2015; Diaz et al. 2017
colorectal cancer (MSI-H/dMMR) metastatic FDA Approved Diaz et al. 2017

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 Hodgkin lymphoma

Nivolumab was FDA-approved for the treatment of Hodgkin lymphoma in 2016 (FDA 2016). Pembrolizumab received accelerated approval for the treatment of Hodgkin lymphoma 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)
Ansell et al. 2015 Phase I / II relapsed/refractory nivolumab   23 87% 86% (6- month)  
Chen et al. 2017 (CA209-040) Phase II relapsed/refractory pembrolizumab   210 69%    

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

 

PD-1 inhibitors for melanoma in the metastatic setting

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 for melanoma in the adjuvant setting

Nivolumab was FDA-approved for the treatment of adjuvant melanoma 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)
Weber et al. 2017 Phase III adjuvant nivolumab   367   66.4% (18-month RFS)  
ipilimumab   366   52.7% (18-month RFS)  

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

 

PD-1 inhibitors in small cell lung cancer

Two fully human anti-PD-1 monoclonal antibodies have been tested in patients with small cell lung cancer (SCLC): nivolumab (CA209-032; Antonia et al. 2015), and pembrolizumab (Ott et al. 2015).

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation/Marker Status # Patients in Study Response Rate PFS (months) OS (months)
Antonia et al. 2015 (CA209-032) Phase I/II 2nd line nivolumab   40 15%    
nivolumab + ipilimumab   35 25%    
Ott et al. 2015 (KEYNOTE-028) Phase I 2nd line pembrolizumab PD-L1+ 16 25%    

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

 

PD-1 inhibitors in hepatocellular carcinoma (HCC)

Nivolumab was FDA-approved for the treatment of hepatocellular 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)
El-Khoueiry et al. 2015 (CA209-040) Phase I / II 1st line or greater (after failure or refusing of sorafenib) nivolumab   39 25%   72% (6-month)

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

 

PD-1 inhibitors in renal cell carcinoma (RCC)

In a phase III trial, over a thousand renal cell carcinoma patients were randomized to receive nivolumab plus ipilimumab followed by nivolumab or sunitinib. In the intermediate- and poor-risk patients, overall survival was significantly higher with the combination therapy of nivolumab plus ipilimumab (Motzer et al. 2018). Ipilimumab was approved in combination with nivolumab for the treatment of patients with intermediate and poor risk renal cell carcinoma 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)
Motzer et al. 2018 Phase III 1st line nivolumab + ipilimumab Intermediate- and Poor-Risk Patients 425 42% 11.6 months Not reached
sunitinb Intermediate- and Poor-Risk Patients 422 27% 8.4 months 26 months

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

 

PD-1 inhibitors in head and neck cancer

Pembrolizumab and nivolumab are FDA-approved for the treatment of head and neck cancer. Pembrolizumab received accelerated FDA approval in 2016, and nivolumab received regular FDA approval the same year (FDA 2016).

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation/Marker Status # Patients in Study Response Rate PFS (months) OS (months)
Seiwert et al. 2015; Chow et al. 2015 (KEYNOTE-012) Phase I 1st line or greater pembrolizumab   99 18.2%    
PD-L1+ subgroup 61 20% 2.3  
Ferris et al. 2016 Phase III 1st line or greater nivolumab   240 13.3% 2.0 7.5
methotrexate, docetaxel, or cetuximab   121 5.8% 2.3 5.1

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

 

PD-1 inhibitors in urothelial cancer

Pembrolizumab and nivolumab are FDA-approved for the treatment of urothelial cancer. Pembrolizumab received regular FDA approval, and nivolumab received accelerated FDA approval, 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)
Plimack et al. 2015 (KEYNOTE-012) Phase I 1st line or greater pembrolizumab   28 25% 19% (1-year)  
PD-L1+ subgroup   38%    
Sharma et al. 2017 (CheckMate 275) Phase II 2nd line or greater nivolumab   265 19.6%   8.7

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

 

PD-1 inhibitors in gastric cancer

Pembrolizumab received accelerated FDA approval for the treatment of gastric 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)
Motzer et al. 2018 Phase II 2nd line or greater pembrolizumab   259 11.6% 2.0 5.6

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

 

PD-1 inhibitors in colorectal cancer (MSI-H/dMMR)

Nivolumab and pembrolizumab were granted acccelrated FDA approval for the treatment of metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal 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)
Overman et al. 2017 Phase II 1st line or greater nivolumab MSI-H/dMMR 74 31% 14.3 73% (12-month)
Diaz et al. 2017 (KEYNOTE-164) Phase II 3rd line or greater pembrolizumab MSI-H/dMMR 61 28% 43% (6-month) 87% (6-month)

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

 

PD-1 inhibitors in solid tumors (MSI-H/dMMR)

Pembrolizumab was granted acccelrated FDA-approval for the treatment of metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) solid tumors 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)
Le et al. 2015 Phase II refractory pembrolizumab MSI-H/dMMR 9 (Cohort C) 71% 5.4 Not reached
Diaz et al. 2017 (KEYNOTE-158) Phase II 2nd line or greater pembrolizumab MSI-H/dMMR 77 37.7% 45% (6-month) 73% (6-month)

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. 2015. PD-1 Inhibition and PD-1 Inhibitors. My Cancer Genome http://www.padiracinnovation.org/content/molecular-medicine/pd-1-inhibition-and-inhibitors/ (Updated September 3).

Last Updated: May 25, 2018

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