Pembrolizumab
Pembrolizumab Uses, Dosage, Side Effects, Food Interaction and all others data.
Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. Pembrolizumab for injection is a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5. Pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.
Pembrolizumab pharmacodynamic reports indicate that there are not effector functions by binding to C1q and CD64 not by cytokine release. On clinical trials, the objective response rate, defined as the proportion of patients with tumor size reduction of a predefined amount for a minimum time period, was assessed based on independent central review and a response duration. These studies performed for different classes of cancer showed a response either partial or complete in a range of 14.3-26% of the individuals. The response duration was estimated to be of 11 months and 45-91% of the patients had a response equal or greater than 6 months.
In other clinical trials, it was reported the progression-free survival, defined as the time during and after the treatment that the patient lives with the disease without worsening. The administration of pembrolizumab improved the progression-free survival when compared to patients assigned to regular chemotherapy. The increase reached 34% of the individuals while chemotherapy reports only 16%.
The results mentioned above have been so clear and consistent that in phase III clinical trials the trial was stopped early to allow patients to switch to the treatment with pembrolizumab.
| Trade Name | Pembrolizumab |
| Availability | Prescription only |
| Generic | Pembrolizumab |
| Pembrolizumab Other Names | Lambrolizumab, Pembrolizumab |
| Related Drugs | Opdivo, methotrexate, Keytruda, Arimidex, medroxyprogesterone, megestrol, hydroxyurea, carboplatin, capecitabine, fluorouracil |
| Weight | 50mg, 25mg/ml, |
| Type | Intravenous Powder For Injection, Intravenous Solution, Intravenous |
| Formula | C6504H10004N1716O2036S46 |
| Weight | 149000.0 Da |
| Protein binding | Pembrolizumab is not expected to bind to plasma proteins in a specific manner. |
| Groups | Approved |
| Therapeutic Class | Immunological Chemotherapy, Immunosuppressant |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Pembrolizumab is a programmed death receptor-1 (PD-1)-blocking antibody used:
Melanoma:
- for the treatment of patients with unresectable or metastatic melanoma.
- for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.
- in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations.
- in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC.
- as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.
- as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Pembrolizumab.
Head and Neck Squamous Cell Cancer (HNSCC):
- in combination with platinum and FU for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC.
- as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
- as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
Primary Mediastinal Large B-Cell Lymphoma (PMBCL): for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy.
Urothelial Carcinoma:
- for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
- for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
- for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
Gastric Cancer: for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.
Esophageal Cancer: for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.
Cervical Cancer: for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
Hepatocellular Carcinoma (HCC): for the treatment of patients with HCC who have been previously treated with sorafenib.
Merkel Cell Carcinoma (MCC): for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma.
Renal Cell Carcinoma (RCC): in combination with axitinib, for the first-line treatment of patients with advanced RCC.
Endometrial Carcinoma: in combination with lenvatinib, for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.
The safety and effectiveness of Pembrolizumab in pediatric patients have not been established. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
Pembrolizumab is also used to associated treatment for these conditions: Advanced Renal Cell Carcinoma, Cervical Cancers, Colorectal Cancers, Metastatic Melanoma, Metastatic Solid Tumors, Unresectable Melanoma, Urothelial carcinoma ureter metastatic, Locally advanced Urothelial Carcinoma, Locally advanced gastroesphageal juntion adenocarcinoma, Metastatic gastroesphageal juntion adenocarcinoma, Metastatic nonsquamous non-small cell lung cancer, Recurrent, metastatic Head and Neck Squamous Cell Carcinoma, Refractory, metastatic Non small cell lung cancer, Refractory, relapsed Hodgkin Lymphoma, Refractory, relapsed Mediastinal Large B-cell Lymphoma, Unresectable Solid Tumors
How Pembrolizumab works
Pembrolizumab, as an IgG4 subclass antibody, is preferred over other subclasses as it only induces weakly the complement and cell activation due to low affinity to C1q and Fc receptors. It binds with high affinity to the cell surface receptor programmed cell death protein 1 (PD-1) and it antagonizes its interaction with its known ligands PD-L1 and PD-L2. In normal circumstances, the binding of the ligands of PD-1 to the receptor inhibits the TCR-mediated T cell proliferation and cytokine production. This inhibitory signal seems to be essential for self-tolerance, collateral damage minimizing after immune response against a pathogen and maternal tolerance to fetal tissue. Therefore, the binding of pembrolizumab to PD-1 prevents the inhibitory pathway causing a physiological shift to immune reactivity and enhancing tumor immunosurveillance and anti-tumor immune response.
Dosage
Pembrolizumab dosage
- Melanoma: 200 mg every 3 weeks
- NSCLC: 200 mg every 3 weeks
- SCLC: 200 mg every 3 weeks
- HNSCC: 200 mg every 3 weeks
- cHL or PMBCL: 200 mg every 3 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics
- Urothelial Carcinoma: 200 mg every 3 weeks
- MSI-H Cancer: 200 mg every 3 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics
- Gastric Cancer: 200 mg every 3 weeks
- Esophageal Cancer: 200 mg every 3 weeks
- Cervical Cancer: 200 mg every 3 weeks
- HCC: 200 mg every 3 weeks
- MCC: 200 mg every 3 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics
- RCC: 200 mg every 3 weeks with axitinib 5 mg orally twice daily
- Endometrial Carcinoma: 200 mg every 3 weeks with lenvatinib 20 mg orally once daily for tumors that are not MSI-H or dMMR.
Side Effects
Most common adverse reactions (reported in ≥20% of patients) were:
Pembrolizumab as a single agent: fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
Pembrolizumab in combination with chemotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, and stomatitis.
Pembrolizumab in combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.
Pembrolizumab in combination with lenvatinib: fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.
Toxicity
Pembrolizumab seems to be very well tolerated for a cancer therapy and the rate of discontinuations is reported to be of 14%. The presence of side effects of grade 3-4 is 10-14%. Due to the mechanism of action, the immune response was highly managed with treatment interruption and corticosteroid treatment. even though fertility studies have not been performed, there are no notable effects in reproductive organs in not sexually mature animals.
Precaution
Immune-mediated pneumonitis: Withhold for moderate, and permanently discontinue for severe, life-threatening or recurrent moderate pneumonitis.
Immune-mediated colitis: Withhold for moderate or severe, and permanently discontinue for life-threatening colitis.
Immune-mediated hepatitis (Pembrolizumab) and hepatotoxicity (Pembrolizumab in combination with axitinib): Monitor for changes in hepatic function. Based on severity of liver enzyme elevations, withhold or discontinue Pembrolizumab, axitinib, or Pembrolizumab and axitinib. Consider corticosteroid therapy.
Immune-mediated endocrinopathies:
- Adrenal insufficiency: Withhold for moderate and withhold or permanently discontinue for severe or life-threatening adrenal insufficiency.
- Hypophysitis: Withhold for moderate and withhold or permanently discontinue for severe or life-threatening hypophysitis.
- Thyroid disorders: Monitor for changes in thyroid function. Withhold or permanently discontinue for severe or life-threatening hyperthyroidism.
- Type 1 diabetes mellitus: Monitor for hyperglycemia. Withhold Pembrolizumab in cases of severe hyperglycemia.
Immune-mediated skin adverse reactions including, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN): Withhold for severe and permanently discontinue for life-threatening skin reactions.
Other immune-mediated adverse reactions: In organ transplant recipients, consider the benefit of treatment with Pembrolizumab versus the risk of possible organ rejection.
Infusion-related reactions: Stop infusion and permanently discontinue Pembrolizumab for severe or life-threatening infusion reactions.
Complications of allogeneic HSCT: Allogeneic HSCT after treatment with Pembrolizumab: Monitor for hepatic veno-occlusive disease, grade 3-4 acute GVHD including hyperacute GVHD, steroid-requiring febrile syndrome, and other immune-mediated adverse reactions. Transplant-related mortality has occurred. Allogeneic HSCT prior to treatment with Pembrolizumab: In patients with a history of allogeneic HSCT, consider the benefit of treatment with Pembrolizumab versus the risk of GVHD.
Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective method of contraception.
Food Interaction
No interactions found.Pembrolizumab Hypertension interaction
[Major] The use of monoclonal antibodies administered via IV infusion may cause serious infusion reactions, including bronchospasm, hypoxia, dyspnea, fluctuations in blood pressure, laryngeal edema and pulmonary edema.
Caution should be taken in patients with a history of cardiopulmonary disease as they may require additional post-infusion medications to manage respiratory complications.
It is recommended to administer required intravenous hydration and premedication with antihistamines, analgesics, and antipyretics before administration.
Monitor closely for signs and symptoms of infusion reactions during and for at least 4 hours following completion of each infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.
Immediately interrupt or permanently discontinue treatment and institute supportive management for severe or prolonged infusion reactions as appropriate.
Pembrolizumab Disease Interaction
Major: infections, infusion reactions, tumor lysis syndromeModerate: myasthenia gravis, colitis, diabetes, hepatic impairment, multiple myeloma, pneumonitis, renal dysfunction, thyroid disease
Volume of Distribution
The volume of distribution at steady state of pembrolizumab is 7.5 L which indicated a limited extravascular distribution.
Elimination Route
When administered intravenously, pembrolizumab is completely bioavailable. When administered in repeated doses every 3 weeks, the systemic accumulation accounts for a 2.2 fold increase. the reported time to reach steady-state is of 18 weeks. The absorption profile of pembrolizumab is proportionally increased with increases in the dosage.
Half Life
The terminal half-life of pembrolizumab is 26 days.
Clearance
Clearance is increased proportionally with the body weight and the mean clearance is registered to be 0.22 L/day. The renal clearance of pembrolizumab is not clinically modified in a significant manner by the presence of mild to moderate renal impairment.
Pregnancy & Breastfeeding use
Based on its mechanism of action, Pembrolizumab can cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. There are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Pembrolizumab and for 4 months after the final dose.
Contraindication
None.
Storage Condition
Store vials under refrigeration at 2°C to 8°C.
Innovators Monograph
You find simplified version here Pembrolizumab
Pembrolizumab contains Pembrolizumab see full prescribing information from innovator Pembrolizumab Monograph, Pembrolizumab MSDS, Pembrolizumab FDA label
