- Guide to PHARMACOLOGY
Synonyms: Keytruda® | lambrolizumab | MK-3475
pembrolizumab is an approved drug (FDA (2014), EMA (2015))
Compound class: Antibody
Comment: Pembrolizumab is the first-in-class, anti-PD-1 antibody to be approved by the US FDA.
Full peptide sequence and disulphide bond information is available from the IMGT/mAb-DB entry for this antibody.
Pembrolizumab is the first immuno-oncology therapeutic to be approved for use in cancers of any tissue type, so long as they express a specific genetic biomarker (i.e. high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) tumours). This is an important breakthrough, since up until this point FDA approvals, including earlier approvals for pembrolizumab, had always been restricted to certain tissue-specific cancers.
Ligand Activity Visualisation Charts
These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.✖
|No information available.|
|Summary of Clinical Use|
|The US FDA granted pembrolizumab priority review designation in June 2014 following very encouraging clinical trial results which were presented at the American Society of Clinical Oncology 50th Annual Meeting in Chicago, 2014. Lyle et al. (J Clin Oncol 32:5s, 2014 (suppl; abstr 9077)) reported complete remission of 52% of metastatic tumours in patients with advanced malignant melanoma, the remission rate was highest in lung metastases. In early September of the same year, the antibody was approved as a therapy for patients with advanced or unresectable melanoma who are no longer responding to other drugs.
Further clinical trials are still ongoing, testing the efficacy of this antibody, as either a monotherapy or in combination with other anti-neoplastics, across a range of more than 30 different cancer types. Click here to view these trials at ClinicalTrials.gov.
In October 2014, the US FDA granted Breakthrough Therapy Designation for pembrolizumab to be used to treat advanced non-small cell lung cancer (NSCLC), in particular for NSCLC which is epidermal growth factor receptor (EGFR) mutation negative, or anaplastic lymphoma kinase (ALK) rearrangement-negative and which has progressed during or following platinum-based chemotherapy. This was granted in response to data from the Phase 1b clinical trial NCT01295827 (KEYNOTE-001). Click here to link to ClinicalTrials.gov's list of active Phase 2 and III pembrolizumab/NSCLC trials.
In December 2015, FDA approval was granted for pembrolizumab use to include first-line therapy for unresectable or metastatic melanoma.
Results of a Phase 2 clinical trial (NCT02267603) suggest that pembrolizumab may be effective in the treatment of the rare skin cancer, Merkel cell carcinoma (MCC) .
In August 2016, the US FDA granted pembrolizumab injection accelerated approval for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. A multicenter, randomized trial is ongoing to ascertain pembrolizumab's superiority over standard therapy and to elucidate its clinical benefit. In October 2016 FDA approval was expanded to include first-line treatment of metastatic PD-L1-expressing NSCLC (as determined by an FDA-approved test).
In March 2017, the FDA expanded approval to include treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. FDA accelerated approval was granted in May 2017 for the treatment of previously untreated metastatic non-squamous NSCLC (in combination with pemetrexed and carboplatin). Further approval expansion in May 2017 covers the use of pembrolizumab to treat locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Later in May 2017, accelerated approval was granted for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors (notably in any tissue) that have progressed following prior treatment and who have no satisfactory alternative treatment options, or with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Accelerated approval for PD-L1 +ve recurrent locally advanced or metastatic gastric cancer or cancer of the gastroesophageal junction was granted by the FDA in September 2017.
June 2018 brought two more FDA approvals for pembrolizumab: as a treatment for relapsed (after two or more prior therapies) or refractory primary mediastinal large B-cell lymphoma (PMBCL)  (see KEYNOTE‑170 trial NCT02576990), and as the first anti-PD-1 therapy for advanced cervical cancer (in patients with recurrent or metastatic PD-1 +ve cervical cancer that progressed on or after chemotherapy; see KEYNOTE-158 trial NCT02628067). In August 2018 the FDA granted regular approval for the use of pembrolizumab (in combination with pemetrexed and platinum-containing chemotherapy) as a first-line treatment for metastatic, non-squamous NSCLCs that have no EGFR or ALK genomic alterations. October 2018 saw a further expansion in approval for a combination therapy containing pembrolizumab, carboplatin and paclitaxel or nab-paclitaxel as a first-line treatment for metastatic, non-squamous NSCLC (based on results from the KEYNOTE-407 trial NCT02775435) . FDA approval for use in patients with hepatocellular carcinoma, and previously treated with sorafenib was granted in November 2018.
April 2019 saw FDA approval for pembrolizumab plus axitinib as a first-line therapy for advanced renal cell carcinoma (RCC), based on results from the KEYNOTE‑426 trial (NCT02853331) [3,10]. Approval was further expanded in June 2019 as a first-line option for metastatic or unresectable recurrent head and neck squamous cell carcinoma, that can be used either as a single agent or in combination with a platinum-based chemotherapeutic and fluorouracil (see KEYNOTE-048 trial NCT02358031 ). Use as monotherapy to treat advanced esophageal squamous cell cancer was granted FDA approval in July 2019, based on results from the KEYNOTE-181 study (NCT02564263). Pembrolizumab is the first immunotherapy to be approved for this type of cancer.
|Mechanism Of Action and Pharmacodynamic Effects|
|Like nivolumab, pembrolizumab binds to the programmed cell death 1 (PD-1, PDCD1) receptor on activated T cells  and prevents receptor activation by endogenous ligands PD-L1 and PD-L2. PD-L1 has an immuno-inhibitory effect on T cells, whereby activation of PD-1 by PD-L1 results in T cell death or quiescence. Many cancer cells express PD-L1 [4,6,12], and this permits these malignant cells to 'evade' destruction by the immune system. By preventing binding of the cancer cell-derived PD-L1, pembrolizumab restores local immune detection/destruction by T cells.|
|Clinical Trial ID||Title||Type||Source||Comment||References|
|NCT01295827||Study of Pembrolizumab (MK-3475) in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (P07990/MK-3475-001/KEYNOTE-001)||Phase 1 Interventional||Merck Sharp & Dohme Corp.|
|NCT02267603||Pembrolizumab in Treating Patients With Advanced Merkel Cell Cancer||Phase 2 Interventional||National Cancer Institute (NCI)|
|NCT02358031||A Study of Pembrolizumab (MK-3475) for First Line Treatment of Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck (MK-3475-048/KEYNOTE-048)||Phase 3 Interventional||Merck Sharp & Dohme Corp.|
|NCT02564263||Study of Pembrolizumab (MK-3475) Versus Investigator's Choice Standard Therapy for Participants With Advanced Esophageal/Esophagogastric Junction Carcinoma That Progressed After First-Line Therapy (MK-3475-181/KEYNOTE-181)||Phase 3 Interventional||Merck Sharp & Dohme Corp.|
|NCT02576990||Study of Pembrolizumab (MK-3475) in Participants With Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma or Relapsed or Refractory Richter Syndrome (MK-3475-170/KEYNOTE-170)||Phase 2 Interventional||Merck Sharp & Dohme Corp.|
|NCT02628067||Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158)||Phase 2 Interventional||Merck Sharp & Dohme Corp.|
|NCT02775435||A Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With First Line Metastatic Squamous Non-small Cell Lung Cancer (MK-3475-407/KEYNOTE-407)||Phase 3 Interventional||Merck Sharp & Dohme Corp.|
|NCT02853331||Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426)||Phase 3 Interventional||Merck Sharp & Dohme Corp.|
|NCT04003636||Pembrolizumab (MK-3475) Plus Gemcitabine/Cisplatin Versus Placebo Plus Gemcitabine/Cisplatin for First-Line Advanced and/or Unresectable Biliary Tract Carcinoma (BTC) (MK-3475-966/KEYNOTE-966)||Phase 3 Interventional||Merck Sharp & Dohme LLC||The KEYNOTE-966 study: results published in April 2023. Pembrolizumab in addition to gemcitabine and cisplatin treatment for previously untreated metastatic or unresectable biliary tract cancer improved overall survival compared with gemcitabine and cisplatin. Adding pembrolizumab was not associated with any new safety signals.||7|
For extended ADME data see the following:
Electronic Medicines Compendium (eMC)
European Medicines Agency (EMA)