pembrolizumab pembrolizumab pembrolizumab, sold under the brand name keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. it is given by slow injection into a vein. pembrolizumabfrom pdb entry 5dk3monoclonal antibodytypewhole antibodysourcehumanized (from mouse)targetpd-1clinical datatrade nameskeytrudaother namesmk-3475, lambrolizumabahfs/drugs.commonographmedlineplusa614048license data eu ema: by inn us dailymed: pembrolizumab pregnancycategory au: d not for pregnant women routes ofadministrationintravenousdrug classantineoplastic agentsatc codel01ff02 (who) legal statuslegal status au: s4 (prescription only) uk: pom (prescription only) us: ℞-only eu: rx-only in general: ℞ (prescription only) identifierscas number1374853-91-4drugbankdb09037chemspidernoneuniidpt0o3t46pkeggd10574 ychemblchembl3137343echa infocard100.234.370 chemical and physical dataformulac6534h10004n1716o2036s46molar mass146648.64 g·mol−1 common side effects include fatigue, musculoskeletal pain, decreased appetite, itchy skin (pruritus), diarrhea, nausea, rash, fever (pyrexia), cough, difficulty breathing (dyspnea), constipation, pain, and abdominal pain. it is an igg4 isotype antibody that blocks a protective mechanism of cancer cells and thereby, allows the immune system to destroy them. it targets the programmed cell death protein 1 (pd-1) receptor of lymphocytes. pembrolizumab was approved for medical use in the united states in 2014. in 2017, the us food and drug administration (fda) approved it for any unresectable or metastatic solid tumor with certain genetic anomalies (mismatch repair deficiency or microsatellite instability). it is on the world health organization's list of essential medicines. medical uses micrograph showing a pd-l1 positive non-small cell lung carcinoma. pd-l1 immunostain as of 2019, pembrolizumab is used via intravenous infusion to treat inoperable or metastatic melanoma, metastatic non-small cell lung cancer (nsclc) in certain situations, as a first-line treatment for metastatic bladder cancer in patients who cannot receive cisplatin-based chemotherapy and have high levels of pd-l1, as a second-line treatment for head and neck squamous cell carcinoma (hnscc), after platinum-based chemotherapy, for the treatment of adult and pediatric patients with refractory classic hodgkin's lymphoma (chl), and recurrent locally advanced or metastatic esophageal squamous cell carcinoma. for nsclc, pembrolizumab is used in combination with chemotherapy (for all pd-l1, a pd-1 receptor ligand, levels) or by itself as a first-line treatment if the cancer expresses (≥1%) pd-l1 and the cancer has no mutations in egfr or in alk; if chemotherapy has already been administered, then pembrolizumab can be used as a second-line treatment, but if the cancer has egfr or alk mutations, agents targeting those mutations should be used first. assessment of pd-l1 expression must be conducted with a validated and approved companion diagnostic. pembrolizumab (pembro) use for treatment of lung cancer in the first line with or without chemotherapy (chemo). median overall survival in months (m). hazarad ration (hr). in 2017, the us food and drug administration (fda) approved pembrolizumab for any unresectable or metastatic solid tumor with certain genetic anomalies (mismatch repair deficiency or microsatellite instability). this was the first time the fda approved a cancer drug based on tumor genetics rather than tissue type or tumor site; therefore, pembrolizumab is a so-called tissue-agnostic drug. in the european union, pembrolizumab is indicated for: the treatment of advanced (unresectable or metastatic) melanoma in adults as monotherapy. the adjuvant treatment of adults with stage iii melanoma and lymph node involvement who have undergone complete resection as monotherapy. the first-line treatment of metastatic non-small cell lung carcinoma (nsclc) in adults whose tumors express pd-l1 with a ≥ 50% tumor proportion score (tps) with no egfr or alk positive tumor mutations as monotherapy. the first-line treatment of metastatic non-squamous nsclc in adults whose tumors have no egfr or alk positive mutations in combination with pemetrexed and platinum chemotherapy. the first-line treatment of metastatic squamous nsclc in adults in combination with carboplatin and either paclitaxel or nab-paclitaxel. the treatment of locally advanced or metastatic nsclc in adults whose tumors express pd-l1 with a ≥ 1% tps and who have received at least one prior chemotherapy regimen. people with egfr or alk positive tumor mutations should also have received targeted therapy before receiving keytruda as monotherapy. the treatment of adults with relapsed or refractory classical hodgkin lymphoma (chl) who have failed autologous stem cell transplant (asct) and brentuximab vedotin (bv), or who are transplant-ineligible and have failed bv as monotherapy. the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy as monotherapy. the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumors express pd l1 with a combined positive score (cps) ≥ 10 as monotherapy. the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (hnscc) in adults whose tumors express pd-l1 with a cps ≥ 1 as monotherapy or in combination with platinum and 5-fluorouracil (5-fu) chemotherapy. the treatment of recurrent or metastatic hnscc in adults whose tumors express pd-l1 with a ≥ 50% tps and progressing on or after platinum-containing chemotherapy as monotherapy. the first-line treatment of advanced renal cell carcinoma (rcc) in adults in combination with axitinib. in june 2020, the us fda approved a new indication for pembrolizumab as the first-line treatment for people with unresectable or metastatic microsatellite instability-high (msi‑h) or mismatch repair deficient (dmmr) colorectal cancer. the approval marks the first immunotherapy approved for that population in the us as a first-line treatment and which is administered to people without also giving chemotherapy. in march 2021, the us fda approved pembrolizumab in combination with platinum and fluoropyrimidine-based chemotherapy to treat metastatic or locally advanced esophageal or gastroesophageal (gej) (tumors with epicenter 1 to 5 centimeters above the gastroesophageal junction) carcinoma in people who are not candidates for surgical resection or definitive chemoradiation. efficacy was evaluated in keynote-590 (nct03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 participants with metastatic or locally advanced esophageal or gastroesophageal junction carcinoma who were not candidates for surgical resection or definitive chemoradiation. in may 2021, the us fda approved pembrolizumab in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of people with locally advanced unresectable or metastatic her2 positive gastric or gastroesophageal junction (gej) adenocarcinoma. approval was based on the prespecified interim analysis of the first 264 participants of the ongoing keynote-811 (nct03615326) trial, a multicenter, randomized, double‑blind, placebo‑controlled trial in people with her2‑positive advanced gastric or gastroesophageal junction (gej) adenocarcinoma who had not previously received systemic therapy for metastatic disease. in july 2021, the us fda approved pembrolizumab for high-risk, early-stage, triple-negative breast cancer (tnbc) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. the fda also granted regular approval to pembrolizumab in combination with chemotherapy for people with locally recurrent unresectable or metastatic tnbc whose tumors express pd-l1 (combined positive score ≥10) as determined by an fda approved test. in november 2021, the us fda approved pembrolizumab for the adjuvant treatment of people twelve years of age and older with stage iib or iic melanoma following complete resection. in march 2022, the us fda approved pembrolizumab for the treatment of advanced endometrial cancer. in january 2023, the us fda approved pembrolizumab for adjuvant treatment following resection and platinum-based chemotherapy for stage ib (t2a ≥4 cm), ii, or iiia non-small cell lung cancer. contraindications if a person is taking corticosteroids or immunosuppressants, those drugs should be stopped before starting pembrolizumab because they may interfere with pembrolizumab; they may be used after pembrolizumab is started to deal with immune-related adverse effects. women of child-bearing age should use contraception when taking pembrolizumab; it should not be administered to pregnant women because animal studies have shown that it can reduce tolerance to the fetus, increasing the risk of miscarriage. it is not known whether pembrolizumab is present in breast milk. as of 2017, the drug had not been tested in people with active infections (including any hiv, hepatitis b or hepatitis c infection), kidney or liver disease, active central nervous system (cns) metastases, active systemic autoimmune disease, interstitial lung disease, prior pneumonia, and people with a history of severe reaction to another monoclonal antibody. adverse effects people have had severe infusion-related reactions to pembrolizumab. there have also been severe immune-related adverse effects including lung inflammation (including fatal cases) and inflammation of endocrine organs that caused inflammation of the pituitary gland, of the thyroid (causing both hypothyroidism and hyperthyroidism in different people), and pancreatitis that caused type 1 diabetes and diabetic ketoacidosis; some people have had to go on lifelong hormone therapy as a result (e.g. insulin therapy or thyroid hormones). people have also had colon inflammation, liver inflammation, kidney inflammation due to the drug. the common adverse reactions have been fatigue (24%), rash (19%), itchiness (pruritus) (17%), diarrhea (12%), nausea (11%) and joint pain (arthralgia) (10%). other adverse effects occurring in between 1% and 10% of people taking pembrolizumab have included anemia, decreased appetite, headache, dizziness, distortion of the sense of taste, dry eye, high blood pressure, abdominal pain, constipation, dry mouth, severe skin reactions, vitiligo, various kinds of acne, dry skin, eczema, muscle pain, pain in a limb, arthritis, weakness, edema, fever, chills, myasthenia gravis, and flu-like symptoms. mechanism of action pembrolizumab is a therapeutic antibody that binds to and blocks pd-1 located on lymphocytes. this receptor is generally responsible for preventing the immune system from attacking the body's own tissues; it is a so-called immune checkpoint. normally, the pd-1 receptor on activated t-cells binds to the pd-l1 or pd-l2 ligands present on normal cells in the body, deactivating any potential cell-mediated immune response against these cells. many cancers make proteins such as pd-l1 that also bind to the pd-1 receptor, thus shutting down the ability of the body to kill the cancer. pembrolizumab works by inhibiting lymphocytes' pd-1 receptors, blocking the ligands that would deactivate it and prevent an immune response. this allows the immune system to target and destroy cancer cells, but also blocks a key mechanism preventing the immune system from attacking the body itself. this checkpoint inhibitor function of pembrolizumab thus has immune-dysfunction side effects as a result. tumors often have mutations that cause impaired dna mismatch repair. this in turn often results in microsatellite instability allowing the tumor to generate numerous mutant proteins that could serve as tumor antigens, triggering an immune response against the tumor. by preventing the self-checkpoint system from blocking the t-cells, pembrolizumab appears to facilitate clearance of any such tumor by the immune system. pharmacology since pembrolizumab is cleared from the circulation through non-specific catabolism, no metabolic drug interactions are expected and no studies were done on routes of elimination. the systemic clearance is about 0.2 l/day and the terminal half-life is about 25 days. chemistry and manufacturing pembrolizumab is an immunoglobulin g4, with a variable region against the human pd-1 receptor, a humanized mouse monoclonal γ4 heavy chain (134-218') disulfide and a humanized mouse monoclonal κ light chain dimer (226-226:229-229)-bisdisulfide. it is recombinantly manufactured in chinese hamster ovary (cho) cells. history pembrolizumab was invented by scientists at organon after which they worked with medical research council technology (which became lifearc) starting in 2006, to humanize the antibody; schering-plough acquired organon in 2007, and merck & co. acquired schering-plough two years later. inventors gregory carven, hans van eenennaam and gradus dulos were recognized as inventors of the year by the intellectual property owners education foundation in 2016. the development program for pembrolizumab was seen as high priority at organon, but low at schering and later merck. in early 2010, merck terminated development and began preparing to out-license it. later, in 2010, scientists from bristol myers squibb published a paper in the new england journal of medicine showing that their checkpoint inhibitor, ipilimumab (yervoy), had shown strong promise in treating metastatic melanoma and that a second bristol myers squibb checkpoint inhibitor, nivolumab (opdivo), was also promising. merck at that time had little commitment or expertise in either oncology or immunotherapy, but understood the opportunity and reacted strongly, reactivating the program and filing its ind by the end of 2010. as one example, martin huber was one of the few senior people at merck with strong experience in lung cancer drug development, but had been promoted to senior management and was no longer involved in product development. he stepped down from his role to lead clinical development of pembrolizumab for lung cancer. scientists at the company argued for developing a companion diagnostic and limiting testing of the drug