Pembrolizumab – Uses, Dosage, Side Effects, Interaction

Pembrolizumab is a monoclonal antibody used to treat certain types of cancer. It works by blocking a certain protein in the body that helps cancer cells grow and spread. This protein is called programmed cell death 1 (PD-1). Pembrolizumab is used to treat advanced or metastatic melanoma, non-small cell lung cancer, and head and neck squamous cell cancer. It may also be used to treat other types of cancer as determined by your healthcare provider.

Pembrolizumab is a PD-1 blocking antibody used to treat various types of cancer, including metastatic melanoma, non-small-cell lung cancer, cervical cancer, head and neck cancer, and Hodgkin’s lymphoma. Pembrolizumab is a medication used in the management and treatment of various oncologic conditions. It is in the cancer immunotherapy class of drugs.

Pembrolizumab is a highly selective IgG4-kappa humanized monoclonal antibody against PD-1 receptors. It was generated by grafting the variable sequences of a very high-affinity mouse antihuman PD-1 antibody onto a human IgG4-kappa isotype containing a stabilizing S228P Fc mutation.[rx] It contains 32 cysteine residues and the complete folded molecule includes 4 disulfide linkages as interchain bonds and 23 interchain bonds.[rx] It was developed by Merck & Co and first approved for the treatment of metastatic malignant melanoma by the FDA on September 4, 2014,[rx] becoming the first approved therapy against PD-1.[rx] In the time since its initial approval, pembrolizumab has been granted approval in the treatment of a wide variety of cancers.[rx,rx]

Mechanism of action

Pembrolizumab binds with high affinity to the cell surface receptor programmed cell death protein 1 (PD-1) and antagonizes its interaction with its known ligands PD-L1 and PD-L2.[rx] Under 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 appears to play a role in self-tolerance and collateral damage minimization after immune responses against a pathogen and maternal tolerance to fetal tissue.

The binding of pembrolizumab to PD-1 prevents this inhibitory pathway, causing a physiological shift towards immune reactivity and enhancing tumor immunosurveillance and anti-tumor immune response.[rx]

Pembrolizumab exerts its pharmacologic effects by releasing PD-1 pathway-mediated inhibition of the immune response, which in turn improves the anti-tumor immune response.[rx] Due to its relatively broad mechanism of action, it is useful in the treatment of a wide variety of cancers.

Pembrolizumab can cause immune-mediated adverse reactions – including hepatitis, nephritis, and pneumonitis – in any organ system or tissue. Careful monitoring of the patient (including laboratory evaluation of liver, kidney, and thyroid function) should occur at baseline and periodically throughout therapy to monitor for emerging immune-mediated reactions.[rx]

Indications

Pembrolizumab is indicated for the following conditions:

  • Melanoma – for the treatment of patients with unresectable or metastatic melanoma (adult patients in the US8 and patients ≥12 years old in the EU)[rx]for the adjuvant treatment of adult and pediatric patients 12 years of age and older with Stage IIB, IIC, or III melanoma following complete resection.
  • Non-Small Cell Lung Cancer (NSCLC) – in combination with pemetrexed and platinum-based chemotherapy as a first-line treatment for patients with metastatic nonsquamous NSCLC with no EGFR or ALK mutations in combination with carboplatin and paclitaxel as a first-line treatment for patients with metastatic squamous NSCLC as a monotherapy for the first-line treatment of NSCLC expressing PD-L1 with no EGFR or ALK mutations in patients with metastatic disease or stage III disease who are not candidates for surgery or chemoradiation as a monotherapy for the treatment of NSCLC expressing PD-L1 with disease progression on or after platinum-based chemotherapy – this includes patients with EGFR or ALK mutations, providing they have experienced disease progression on prior FDA-approved therapy for these aberrations
  • Head and Neck Squamous Cell Cancer (HNSCC) – in combination with fluorouracil and platinum-based chemotherapy as a first-line treatment for patients with metastatic or recurrent, unresectable HNSCC as a monotherapy for the first-line treatment of patients with metastatic or recurrent, unresectable HNSCC expressing PD-L1 as a monotherapy for the treatment of patients with metastatic or recurrent HNSCC with disease progression on or after platinum-based chemotherapy
  • Classical Hodgkin Lymphoma (cHL) – for the treatment of adult patients with relapsed or refractory cHL for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed following ≥2 lines of therapy
  • Primary Mediastinal Large B-cell Lymphoma (PMBCL) – for the treatment of adult and pediatric patients with refractory PMBCL, or PMBCL that has relapsed following ≥2 lines of therapy
  • Urothelial Carcinoma – for the treatment of locally advanced or metastatic urothelial carcinoma in patients ineligible for platinum-based chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-based chemotherapy or within 12 months of adjuvant/neoadjuvant platinum-based chemotherapy for the treatment of BCG vaccine-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ, with or without papillary tumors, who are are not candidates for cystectomy
  • Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient Cancer (dMMR) – as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer
  • Gastric Cancer – in combination with trastuzumab, with fluoropyrimidine- and platinum-containing chemotherapy, as a first-line treatment for patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma
  • Esophageal Cancer in combination with fluoropyrimidine – and platinum-based chemotherapy for the treatment of patients with locally advanced or metastatic esophageal or GEJ carcinoma who are not candidates for surgery or definitive chemoradiation as a monotherapy for the treatment of locally advanced or metastatic esophageal or GEJ carcinoma expressing PD-L1 in patients who are not candidates for surgery or definitive chemoradiation.
  • Cervical Cancer – in combination with other chemotherapies, with or without bevacizumab, for the treatment of persistent, recurrent, or metastatic cervical cancer expressing PD-L1 as a monotherapy for the treatment of recurrent or metastatic cervical cancer expressing PD-L1 in patients who have experienced disease progression on or after previous chemotherapy
  • Hepatocellular Carcinoma (HCC) – as a monotherapy for the treatment of HCC in patients 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 MCC
  • Renal Cell Carcinoma (RCC) – in combination with either axitinib or lenvatinib as a first-line treatment for adult patients with advanced RCC for the adjuvant treatment of patients with RCC who are at an intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions
  • Endometrial Carcinoma – in combination with lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR who experience disease progression following prior systemic therapy and who are not candidates for surgery or radiation therapy as a monotherapy for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation
  • Tumor Mutational Burden-High (TMB-H) Cancer – as a last-line therapy for the treatment of adult and pediatric patients with unresectable or metastatic TMB-H solid tumors that have progressed following prior treatment
  • Cutaneous Squamous Cell Carcinoma (cSCC) – for the treatment of patients with recurrent or metastatic sCC, or locally advanced sCC that is not curable with surgery or radiation therapy
  • Triple-Negative Breast Cancer (TNBC) – for the treatment of patients with high-risk early-stage TNBC, in combination with chemotherapy as a neoadjuvant treatment followed by continued use as a single adjuvant agent following surgery in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic TNBC expressing PD-L1. For all approved adult indications, pembrolizumab may be used for an additional 6 weeks at 400mg weekly.[rx]
  • Advanced Endometrial Cancer
  • Advanced Renal Cell Carcinoma
  • Hepatocellular Carcinoma
  • Locally Advanced Cutaneous Squamous Cell Carcinoma
  • Metastatic Cervical Cancer
  • Metastatic Esophageal Carcinoma
  • Metastatic Melanoma
  • Metastatic Non-Small Cell Lung Cancer
  • Metastatic Renal Cell Carcinoma ( mRCC)
  • Metastatic Squamous Cell Carcinoma of the Head and Neck (HNSCC)
  • Metastatic Triple-negative Breast Cancer
  • Metastatic Ureter Urothelial Carcinoma
  • Metastatic cutaneous squamous cell carcinoma
  • Metastic Renal Cell Carcinoma
  • Persistent Cervical Cancer
  • Recurrent Cervical Cancer
  • Refractory Primary Mediastinal Large B-Cell Cell Lymphoma
  • Renal Cell Carcinoma
  • Stage IIB Melanoma
  • Stage IIC Melanoma
  • Stage III Melanoma
  • Unresectable Melanoma
  • Advanced Microsatellite Instability High Endometrial Carcinoma
  • Advanced Mismatch Repair-deficient (dMMR) Endometrial Carcinoma
  • High risk, early Triple Negative Breast Cancer
  • High risk, in situ Non-Muscle Invasive Bladder Cancer (NMIBC) Refractory to BCG
  • Locally advanced Adenocarcinomas of the Gastroesophageal Junction
  • Locally advanced Esophageal Carcinoma
  • Locally advanced Urothelial Carcinoma
  • Metastatic Adenocarcinomas of the Gastroesophageal Junction
  • Metastatic HER2-positive Adenocarcinoma of the Stomach
  • Metastatic HER2-positive Adenocarcinomas of the Gastroesophageal Junction
  • Metastatic High Tumor Mutation Burden Solid Tumors
  • Metastatic Merkel Cell Carcinoma (MCC)
  • Metastatic Microsatellite Instability High Colorectal Cancer
  • Metastatic Microsatellite Instability-High (MSI-H) Solid Tumors
  • Metastatic Mismatch Repair Deficient Colorectal Cancer
  • Metastatic Mismatch repair deficient (dMMR) solid tumors
  • Recurrent Cutaneous Squamous Cell Carcinoma
  • Recurrent Squamous Cell Carcinoma of the Head and Neck (SCCHN)
  • Recurrent, locally advanced Adenocarcinomas of the Gastroesophageal Junction
  • Recurrent, locally advanced Merkel Cell Carcinoma
  • Refractory Classical Hodgkin’s Lymphoma
  • Relapsed Classical Hodgkin’s Lymphoma
  • Stage 3 Non-Small Cell Lung Carcinoma (NSCLC)
  • Unresectable High Tumor Mutation Burden Solid Tumors
  • Unresectable Microsatellite Instability High Colorectal Cancer
  • Unresectable Microsatellite Instability-High (MSI-H) Solid Tumors
  • Unresectable Mismatch Repair Deficient Colorectal Cancer
  • Unresectable Mismatch repair deficient (dMMR) solid tumors
  • Unresectable, locally advanced HER2-positive Adenocarcinoma of the Stomach
  • Unresectable, locally advanced HER2-positive Adenocarcinomas of the Gastroesophageal Junction
  • Unresectable, locally recurrent Triple Negative Breast Cancer
  • Unresectable, recurrent Squamous Cell Carcinoma of the Head and Neck (SCCHN)

FDA-approved indications (with clinical trial summaries)

Melanoma

  • Unresectable or metastatic melanoma

    • In an advanced melanoma population naive to ipilimumab therapy, median overall survival was not reached in two different pembrolizumab doses (every two weeks, every three weeks dosing) as compared to ipilimumab alone at 16.0 months (hazard ratio = 0.68, p<0.001) at a median follow-up of 22.9 months.
    • In previously treated, ipilimumab refractory, advanced melanoma, treatment with pembrolizumab resulted in overall survival of 13.4 months (2 mg/kg dose) and 14.7 months (10 mg/kg dose) as compared to investigator choice chemotherapy at 11.0 months (results were not statistically significant) at a median follow-up of 28 months.

  • Adjuvant therapy following complete resection of lymph node involved melanoma.

    • In patients with completely resected stage III melanoma, pembrolizumab showed a recurrence-free survival of 75.4% vs. placebo of 61.0% (hazard ratio=0.57, p<0.001) at a median follow-up of 15 months.

Non-Small Cell Lung Cancer (NSCLC)

  • First-line metastatic non-squamous NSCLC without EGFR/ALK tumor abnormality in combination with platinum chemotherapy and pemetrexed.

    • In patients with metastatic non-squamous NSCLC, first-line treatment of pembrolizumab plus chemotherapy (pemetrexed and carboplatin or cisplatin) showed a median progression-free survival of 8.8 months as compared to 4.9 months from chemotherapy alone (p<0.001) with a median follow up of 10.5 months.

  • First-line metastatic squamous NSCLC with paclitaxel (or paclitaxel protein-bound) and carboplatin

    • In patients with metastatic squamous NSCLC, first-line treatment of pembrolizumab plus chemotherapy (carboplatin plus paclitaxel or nanoparticle albumin-bound paclitaxel) showed a median overall survival of 15.9 months as compared to 11.3 months for chemotherapy alone (p<0.001) with a median follow up of 7.8 months.

  • First-line single-agent use for nonresectable or metastatic NSCLC without EGFR/ALK tumor abnormality with tumor PD-L1 expression greater than 1%.

    • In patients with previously untreated advanced NSCLC with a PD-1 score greater than 50%, first-line treatment of single-agent pembrolizumab showed a median overall survival of 30.0 months as compared to chemotherapy (investigator’s choice platinum-based regimen) control arm of 14.2 months(hazard ratio = 0.63), with a median follow up of 25.2 months.

  • Single-agent use for metastatic NSCLC with tumor PD-L1 expression greater than 1% who have progressed after platinum-based chemotherapy. (EGFR/ALK tumor abnormality patients with progression after targeted therapy for their respective tumor abnormality).

    • In patients with previously treated, advanced NSCLC with a PD-1 score greater than 50%, subsequent treatment with pembrolizumab (10mg/kg) showed a median survival of 17.3 months as compared to the docetaxel arm of 8.2 months (p<0.0001).

Head and Neck Squamous Cell Carcinoma (HNSCC)

  • First-line metastatic or unresectable/recurrent HNSCC in combination with FU and platinum.

    • In patients previously untreated for locally incurable recurrent or metastatic head and neck cancer, treatment with pembrolizumab plus chemotherapy (cisplatin or carboplatin/5-FU) resulted in median overall survival of 13.0 months as compared to cetuximab plus chemotherapy(cisplatin or carboplatin/5-FU) of 10.7 months.
  • First-line single-agent use in metastatic or unresectable/recurrent HNSCC with tumor PD-L1 expression greater than 1%.

  • Single-agent recurrent or metastatic HNSCC with progression after platinum-based chemotherapy

    • In patients with previously treated advanced head and neck squamous cell carcinoma, a single-arm study showed that treatment with pembrolizumab resulted in an 18% objective response rate; overall survival was 38% at 12 months (after a median follow up of 9 months).

Renal Cell Carcinoma (RCC)

  • First-line advanced RCC in combination with axitinib

    • In patients previously untreated for advanced clear-cell renal cell carcinoma, treatment with pembrolizumab plus axitinib resulted in a 12-month survival rate of 89.9% compared to treatment with sunitinib at 78.3% (p<0.0001) at a median follow-up of 12.8 months.

Urothelial Carcinoma

  • Locally advanced or metastatic urothelial carcinoma who have progressed on platinum-based chemotherapy

  • Locally advanced or metastatic urothelial carcinoma within 12 months of neoadjuvant/adjuvant platinum-based chemotherapy.

    • In patients with previously treated advanced urothelial cancer, treatment with pembrolizumab resulted in a median one-year survival rate of 44.2% compared to 29.8% for chemotherapy (paclitaxel or docetaxel or vinflunine) alone. The median two-year survival rate was 26.9% for pembrolizumab compared to 11.0% for chemotherapy alone (at a median follow-up of 27.7 months).

FDA-approved indications under accelerated approval (with clinical trial summaries):

Classical Hodgkin Lymphoma (cHL)

  • Refractory cHL for pediatric and adult patients who have relapsed after three or more treatments

    • In patients with relapsed/refractory classical Hodgkin lymphoma, pembrolizumab monotherapy resulted in a 69.9% objective response rate and a complete response rate of 22.5% at a median follow-up of 13 treatment cycles.

Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

  • Refractory PMBCL for pediatric and adults who have relapsed after two or more treatments

    • In patients with relapsed/refractory Primary Mediastinal Large B-cell lymphoma, pembrolizumab treatment resulted in a 41% objective response rate and a 12-month overall survival rate of 62% after a median follow-up of 6.6 months.

 Urothelial Carcinoma

  • Locally advanced or metastatic urothelial carcinoma with tumor expression PD-L1 of greater than 10%, ineligible for cisplatin-containing chemotherapy.

    • In patients with advanced urothelial carcinoma who were ineligible for cisplatin, treatment with pembrolizumab resulted in a 29% objective response rate and a median follow-up of 7.8 months.
  • Locally advanced or metastatic urothelial carcinoma not eligible for any platinum-based chemotherapy

Microsatellite Instability-High (MSI-H) Cancer

  • Previously treated adult and pediatric unresectable or metastatic MSI-H solid tumors with no remaining alternative treatments.

  • Adult and pediatric unresectable or metastatic MSI-H colorectal cancer following treatment with irinotecan, oxaliplatin, and fluoropyrimidine

    • In patients with previously treated microsatellite instability-high colorectal cancer, treatment with pembrolizumab resulted in a 32% objective response rate, a 4.1 month PFS and a 76% 12-month overall survival rate after a median follow-up of 12.6 months.

Gastric Cancer

  • Locally advanced, metastatic gastric or gastroesophageal junction adenocarcinoma with tumor PD-L1 expression greater than 1% with disease progression after at least two lines of therapy, including platinum or fluoropyrimidine chemotherapy (and HER2/neu targeted therapy, if appropriate)

    • In patients with previously treated gastric and gastroesophageal junction cancer, treatment with pembrolizumab resulted in an 11.6% objective response rate at a median follow-up of 5.8 months.

Cervical Cancer

  • Metastatic or recurrent cervical cancer, following chemotherapy, with tumor expression of PD-L1 greater than 1%.

    • In patients previously treated for advanced cervical cancer, treatment with pembrolizumab resulted in an objective response rate of 12.2% at a median follow-up of 10.2 months.

Hepatocellular Carcinoma (HCC)

  • HCC patients previously treated with sorafenib

    • In patients with previously treated hepatocellular carcinoma, treatment with pembrolizumab resulted in an objective response rate of 18% at a data cutoff of February 2018.

Merkel Cell Carcinoma (MCC)

  • Pediatric and adult recurrent or locally advanced MCC.

    • In patients naive to systemic treatment for advanced Merkel cell carcinoma, treatment with pembrolizumab resulted in an objective response rate of 56% and 24-month overall survival of 68.7% at a median follow-up of 14.9 months.

Small Cell Lung Cancer (SCLC)

  • Metastatic SCLC following platinum-based chemotherapy and at least one other therapy

    • In patients with previously treated advanced small cell lung cancer, treatment with pembrolizumab resulted in an 18.7% objective response rate and a median overall survival of 9.1months.

Non-FDA approved indications in later-stage clinical trials

  • Nasopharyngeal cancer
  • Mesothelioma
  • Liver cancer
  • Esophageal cancer
  • Cutaneous squamous cell carcinoma
  • Colorectal cancer
  • Breast cancer
  • Prostate cancer
  • Ovarian cancer

Use in Cancer

Pembrolizumab is approved to treat:

  • Breast cancer that is triple negative. Pembrolizumab is used:
    • With chemotherapy in patients whose cancer has the PD-L1 protein and has come back and cannot be removed by surgery or has spread.
    • With chemotherapy before surgery and then alone after surgery in patients with early-stage cancer that has a high risk of coming back.
  • Cervical cancer. Pembrolizumab is used:
    • Alone in patients whose cancer has come back or has spread to other parts of the body, has the PD-L1 protein, and got worse during or after chemotherapy.
    • With chemotherapy, with or without bevacizumab, in patients whose cancer has the PD-L1 protein and has come back or has spread to other parts of the body or did not respond to treatment.
  • Classic Hodgkin lymphoma. Pembrolizumab is used:
    • In adults whose cancer does not respond to treatment or has relapsed.
    • In children whose cancer is refractory or has relapsed after at least two other types of treatment.
  • Cutaneous squamous cell carcinoma (a type of skin cancer) that has spread or come back. Pembrolizumab is used in patients whose cancer cannot be cured with surgery or radiation therapy.
  • Endometrial carcinoma cannot be cured with surgery or radiation therapy and that got worse after other systemic therapies. Pembrolizumab is used:
    • With lenvatinib in patients whose cancer is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
    • Alone in patients whose cancer is MSI-H or dMMR.
  • Esophageal or gastroesophageal junction cancer has spread and cannot be cured with surgery or a combination of chemotherapy and radiation therapy. Pembrolizumab is used:
    • With platinum chemotherapy and fluoropyrimidine.
    • Alone in patients with squamous cell cancer that has the PD-L1 protein and has been treated with systemic therapy.
  • Gastric (stomach) cancer or gastroesophageal junction adenocarcinoma. Pembrolizumab is used with trastuzumab and fluoropyrimidine and platinum chemotherapy as the first treatment in patients whose cancer is HER2 positive and has spread or cannot be treated with surgery.¹
  • Hepatocellular carcinoma (a type of liver cancer) in patients who have been treated with sorafenib.¹
  • Melanoma. Pembrolizumab is used in:
    • Patients whose cancer cannot be removed by surgery or has spread to other parts of the body.
    • Adults and children aged 12 years and older with stage IIB, stage IIC, or stage III melanoma. It is used to prevent melanoma from coming back after it has been removed by surgery.
  • Merkel cell carcinoma in adults and children. Pembrolizumab is used in patients whose cancer has come back or spread.¹
  • Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer that is has spread to other parts of the body or cannot be removed by surgery. Pembrolizumab is used to treat:
    • Solid tumors in adults and children that got worse after other treatment and cannot be treated with other therapies.¹
    • Colorectal cancer.

    MSI-H and dMMR cancers have certain genetic mutations and may not respond to some types of treatment.

  • Non-small cell lung cancer. Pembrolizumab is used:
    • Pemetrexed and platinum chemotherapy is the first treatment in patients with nonsquamous cancer that has spread to other parts of the body and does not have a mutation in the EGFR gene or ALK gene.
    • Carboplatin and either paclitaxel or paclitaxel albumin-stabilized nanoparticle formulation is the first treatment for squamous cancer that has spread to other parts of the body.
    • Alone is the first treatment in patients whose cancer has the PD-L1 protein and does not have a mutation in the EGFR gene or ALK gene. Pembrolizumab is used in patients with stage III cancer that cannot be treated with surgery, chemotherapy, or radiation therapy. It is also used in patients whose cancer has spread to other parts of the body.
    • Alone in patients whose cancer has spread to other parts of the body, has the PD-L1 protein, and has gotten worse during or after treatment with platinum chemotherapy. Patients whose cancer has EGFR or ALK gene mutations should receive pembrolizumab only if their disease got worse after treatment with an FDA-approved therapy for these mutations.
  • Primary mediastinal large B-cell lymphoma. Pembrolizumab is used in adults and children whose cancer does not respond to treatment or has returned after at least two other therapies.
  • Renal cell carcinoma (a type of kidney cancer). It is used:
    • Axitinib or lenvatinib as the first treatment in patients whose cancer has spread or cannot be removed by surgery.
    • As adjuvant therapy in patients whose cancer has a high risk of coming back after surgery to remove the kidney or surgery to remove the kidney and metastatic cancer.
  • Solid tumors are tumor mutational burden-high (TMB-H) and have spread to other parts of the body or cannot be removed by surgery. Pembrolizumab is used in adults and children whose cancer got worse after treatment and who are not able to receive other therapies.¹
  • Squamous cell carcinoma of the head and neck that has come back or has spread to other parts of the body. Pembrolizumab is used:
    • Platinum chemotherapy and fluorouracil as the first treatment in patients whose cancer cannot be removed by surgery.
    • Alone is the first treatment in patients whose cancer cannot be removed by surgery and whose tumors have the PD-L1 protein.
    • Alone in patients whose cancer got worse during or after treatment with platinum chemotherapy.
  • Urothelial carcinoma (a type of bladder cancer). Pembrolizumab is used in:
    • Patients whose cancer has spread and cannot be treated with platinum chemotherapy or has gotten worse during or after treatment with platinum chemotherapy.
    • Patients with carcinoma in situ that is a high risk, do not respond to treatment with bacillus Calmette-Guérin (BCG), and has not spread to the bladder muscle. Pembrolizumab is used in patients whose disease cannot be treated with surgery or who have decided not to have surgery.

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that pembrolizumab provides a clinical benefit in these patients.

Pembrolizumab is also being studied in the treatment of other types of cancer.

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).[rx][rx] 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.[rx]

In the European Union, pembrolizumab is indicated for:

  • the treatment of advanced (unresectable or metastatic) melanoma in adults as monotherapy.[rx]
  • the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection as monotherapy.[rx]
  • 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.[rx]
  • 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.[rx]
  • the first-line treatment of metastatic squamous NSCLC in adults in combination with carboplatin and either paclitaxel or nab-paclitaxel.[rx]
  • 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.[rx]
  • 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.[rx]
  • the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy as monotherapy.[rx]
  • 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.[rx]
  • 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.[rx]
  • 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.[rx]
  • the first-line treatment of advanced renal cell carcinoma (RCC) in adults in combination with axitinib.[rx]

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.[rx] 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.[rx]

Contraindications

The contraindications for pembrolizumab are

  • Pembrolizumab is not recommended in PMBCL (primary mediastinal large B-cell lymphoma) patients who require urgent cytoreductive therapy.
  • Pembrolizumab’s safety and effectiveness in MSI-H central nervous system pediatric cancer have not been established as this population met the exclusion criteria from clinical trials.
  • overactive thyroid gland
  • a condition with low thyroid hormone levels
  • myasthenia gravis, a skeletal muscle disorder
  • a type of inflammation of the lung called interstitial pneumonitis
  • inflammation of the large intestine
  • inflammation of the liver called hepatitis
  • kidney inflammation
  • high blood sugar
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • inflammation of the pituitary gland

Dosage

Strengths: 25 mg/mL; 50 mg

Malignant Melanoma

  • Monotherapy for unresectable or metastatic melanoma: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression or unacceptable toxicity
  • Adjuvant treatment of melanoma: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 12 months
  • Treatment of patients with unresectable or metastatic melanoma
  • Adjuvant treatment of patients with melanoma with Stage IIB, IIC, or III melanoma following complete resection.

Melanoma – Metastatic

  • Monotherapy for unresectable or metastatic melanoma: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression or unacceptable toxicity
  • Adjuvant treatment of melanoma: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 12 months
  • Treatment of patients with unresectable or metastatic melanoma
  • Adjuvant treatment of patients with melanoma with Stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • COMBINATION THERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Administer this drug prior to chemotherapy when given on the same day
  • As a single agent for the first-line treatment of patients with non-small cell lung cancer (NSCLC) expressing PD-L1 (Tumor Proportion Score [TPS] 1% or greater) 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% or greater) 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 this drug
  • In combination with pemetrexed and platinum chemotherapy for first-line treatment of metastatic NSCLC with no EGFR or ALK genomic tumor aberrations.
  • In combination with carboplatin and either paclitaxel or paclitaxel protein-bound for first-line treatment of patients with metastatic squamous NSCLC.

Head and Neck Cancer

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • COMBINATION THERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Administer this drug prior to chemotherapy when given on the same day
  • As a single agent for first line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell cancer (HNSCC) whose tumors express PD-L1 (Combined Positive Score [CPS] greater than or equal to 1) as determined by an FDA-approved test
  • As a single agent for treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
  • In combination with platinum and fluorouracil for first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC.

Hodgkin’s Disease

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • For the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL)

Lymphoma

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • For the treatment of patients with refractory primary mediastinal large B-cell lymphoma (PMBCL) or who have relapsed after 2 or more prior lines of therapy (not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy)

Urothelial Carcinoma

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • This drug is indicated 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.
  • For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy
  • 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.

Bladder Cancer

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until persistent or recurrent high-risk non-muscle invasive bladder cancer (NMIBC), disease progression, unacceptable toxicity, or up to 24 months
  • For the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, NMIBC with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy

Colorectal Cancer

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • For treatment of patients with unresectable or metastatic microsatellite instability-high MSI-H or mismatch repair deficient dMMR colorectal cancer (CRC).

Gastric Cancer

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • COMBINATION THERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Administer this drug prior to trastuzumab and chemotherapy when given on the same day
  • These indications are approved under accelerated approval based on tumor response rate and durability of response; continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • In combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma
  • As a single agent for patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 Positive Score (CPS) 1 or greater 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

Cervical Cancer

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • COMBINATION THERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Administer this drug prior to chemotherapy with or without bevacizumab when given on the same day
  • For the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1 or greater) as determined by an FDA-approved test
  • In combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1 or greater) as determined by an FDA-approved test

Hepatocellular Carcinoma

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • This indication is approved under accelerated approval based on tumor response rate and durability of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • For the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

Merkel Cell Carcinoma

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • This indication is approved under accelerated approval based on tumor response rate and durability of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • For the treatment of patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC)

Renal Cell Carcinoma

  • Adjuvant treatment of renal cell carcinoma (RCC): 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 12 months
  • COMBINATION THERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Administer this drug in combination with axitinib 5 mg orally twice a day OR lenvatinib 20 mg orally once a day
  • When axitinib is used in combination with this drug, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer.
  • In combination with axitinib for the first-line treatment of advanced RCC.
  • In combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC.
  • For the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Esophageal Carcinoma

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • COMBINATION THERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Administer this drug prior to chemotherapy when given on the same day

Uses: For the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 cm above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

  • In combination with platinum- and fluoropyrimidine-based chemotherapy, OR
  • As a single agent after 1 or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS 10 or greater) as determined by an FDA-approved test

Endometrial Carcinoma

  • COMBINATION THERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Administer this drug with lenvatinib 20 mg orally once a day
  • Patients should be selected for combination treatment with lenvatinib based on MSI or MMR status in tumor specimens.
  • 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 in any setting and are not candidates for curative surgery or radiation

Squamous Cell Carcinoma

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • For the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation

Breast Cancer

For treatment of patients with 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:

  • COMBINATION THERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes; administer this drug prior to chemotherapy when given on the same day
  • Neoadjuvant treatment in combination with chemotherapy for 24 weeks (8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks) or until disease progression or unacceptable toxicity
  • Follow with adjuvant treatment as a single agent for up to 27 weeks (9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks) or until disease recurrence or unacceptable toxicity

For the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10 or greater) as determined by an FDA-approved test:

  • COMBINATION THERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Administer this drug prior to chemotherapy when given on the same day
  • Patients who experience disease progression or unacceptable toxicity related to this drug with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent therapy with this drug.

Solid Tumors

  • MONOTHERAPY: 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks
  • Administer as IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Because the effect of prior chemotherapy on test results for tumor mutation burden (TMB-H), MSI-H, or dMMR in patients with high-grade gliomas is unclear, it is recommended to test for these markers in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas.
  • This indication is approved under accelerated approval based on tumor response rate and durability of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • For the treatment of patients with unresectable or metastatic TMB-H (10 mutations/megabase or greater) solid tumors, as determined by an FDA-approved test that have progressed following prior treatment and who have no satisfactory alternative treatment options.
  • For the treatment of patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

Hodgkin’s Disease

  • MONOTHERAPY: 2 mg/kg IV every 3 weeks; Maximum dose: 200 mg
  • Administer as an IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • For the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy

Pediatric Dose

Lymphoma

  • MONOTHERAPY: 2 mg/kg IV every 3 weeks; Maximum dose: 200 mg
  • Administer as an IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • For the treatment of pediatric patients 6 months or older with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy (this drug is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy)

Merkel Cell Carcinoma

  • MONOTHERAPY: 2 mg/kg IV every 3 weeks; Maximum dose: 200 mg
  • Administer as an IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • This indication is approved under accelerated approval based on tumor response rate and durability of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • For the treatment of pediatric patients 6 months or older with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC)

Solid Tumors

  • MONOTHERAPY: 2 mg/kg IV every 3 weeks; Maximum dose: 200 mg
  • Administer as an IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months
  • Because the effect of prior chemotherapy on test results for tumor mutation burden (TMB-H), MSI-H, or dMMR in patients with high-grade gliomas is unclear, it is recommended to test for these markers in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas.
  • The safety and effectiveness in pediatric patients with MSI-H central nervous system cancers have not been established.
  • This indication is approved under accelerated approval based on tumor response rate and durability of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • For the treatment of patients with unresectable or metastatic TMB-H (10 mutations/megabase or greater) solid tumors, as determined by an FDA-approved test that have progressed following prior treatment and who have no satisfactory alternative treatment options.
  • For the treatment of patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

Malignant Melanoma

12 years or older:

  • Adjuvant treatment of melanoma: 2 mg/kg IV every 3 weeks; Maximum dose: 200 mg
  • Administer as an IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 12 months
  • Adjuvant treatment of pediatric patients 12 years or older with Stage IIB, IIC, or III melanoma following complete resection

Melanoma – Metastatic

12 years or older:

  • Adjuvant treatment of melanoma: 2 mg/kg IV every 3 weeks; Maximum dose: 200 mg
  • Administer as an IV infusion over 30 minutes until disease progression, unacceptable toxicity, or up to 12 months
  • Adjuvant treatment of pediatric patients 12 years or older with Stage IIB, IIC, or III melanoma following complete resection.

Dose Adjustments

Dose reductions are generally not recommended for this drug; therapy may be held or discontinued to manage adverse reactions:

  • For severe (Grade 3) immune-mediated adverse reactions, therapy may be interrupted and resumed in patients with complete or partial resolution
  • For patients with life-threatening (Grade 4) immune-mediated adverse reactions or recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg/day or less of prednisone (or equivalent) within 12 weeks of initiating steroids, therapy should be discontinued

Dose modifications for adverse reactions that require management different from general guidelines are summarized below:
PNEUMONITIS:

  • Grade 2: Withhold therapy; resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or less (or equivalent) within 12 weeks of initiating steroids.
  • Grade 3 or 4: Permanently discontinue therapy.

COLITIS:

  • Grade 2 or 3: Withhold therapy; resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or less (or equivalent) within 12 weeks of initiating steroids.

Grade 4: Permanently discontinue therapy.
HEPATITIS WITH NO TUMOR INVOLVEMENT OF THE LIVER:

  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increases to more than 3 and up to 8 times upper limit of normal (ULN) OR total bilirubin increases to more than 3 x ULN: Withhold therapy; resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or less (or equivalent) within 12 weeks of initiating steroids
  • AST or ALT increases to more than 8 x ULN OR total bilirubin increases to more than 3 x ULN:

Permanently discontinue therapy.
HEPATITIS WITH TUMOR INVOLVEMENT OF THE LIVER:

  • If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue therapy based on recommendations for hepatitis with no liver involvement
  • If baseline AST or ALT is more than 1 and up to 3 x ULN and increases to more than 5 and up to 10 x ULN OR baseline AST or ALT is more than 3 and up 5 x ULN and increases to more than 8 and up to 10 times ULN: Withhold therapy; resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or less (or equivalent) within 12 weeks of initiating steroids.
  • If AST or ALT increases to more than 10 x ULN OR total bilirubin increases to more than 3 x ULN: Permanently discontinue therapy.

ENDOCRINOPATHIES:

  • Grade 3 or 4: Withhold therapy until stable or permanently discontinue therapy depending on severity.

NEPHRITIS WITH RENAL DYSFUNCTION:

  • Grade 2 or 3 increased blood creatinine: Withhold therapy; resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or less (or equivalent) within 12 weeks of initiating steroids.
  • Grade 4 increased blood creatinine: Permanently discontinue therapy.

EXFOLIATIVE DERMATOLOGIC CONDITIONS:

  • Suspected Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS): Withhold therapy; resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or less (or equivalent) within 12 weeks of initiating steroids.
  • Confirmed SJS, TEN, or DRESS: Permanently discontinue therapy.

MYOCARDITIS:

  • Grade 2, 3, or 4: Permanently discontinue therapy.

NEUROLOGICAL TOXICITIES:

  • Grade 2: Withhold therapy; resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue therapy if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or less (or equivalent) within 12 weeks of initiating steroids.
  • Grade 3 or 4: Permanently discontinue therapy.

HEMATOLOGIC TOXICITY IN PATIENTS WITH cHL OR PMBCL:

  • Grade 4: Withhold until resolution to Grade 0 or 1.

INFUSION-RELATED REACTIONS:

  • Grade 1 or 2 Interrupt or slow the rate of infusion.
  • Grade 3 or 4: Permanently discontinue therapy.

DOSE MODIFICATIONS FOR ADVERSE REACTIONS IN COMBINATION WITH AXITINIB:
Liver enzyme elevations (consider corticosteroid therapy):

  • ALT or AST increases to at least 3 but less than 10 x ULN without concurrent total bilirubin at least 2 x ULN: Withhold both pembrolizumab and axitinib until resolution to Grade 0 or 1; consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery; if rechallenging with axitinib, consider dose reduction as per the axitinib Prescribing Information.
  • ALT or AST increases to more than 3 x ULN with concurrent total bilirubin at least 2 x ULN OR ALT or AST 10 x ULN or greater: Permanently discontinue both pembrolizumab and axitinib.

DOSE MODIFICATIONS FOR ADVERSE REACTIONS IN COMBINATION WITH LENVATINIB:

  • May need to modify 1 or both drugs; withhold or discontinue pembrolizumab as above; refer to lenvatinib prescribing information for additional dose modification information.

Administration advice:

  • Administer as IV infusion over 30 minutes through an IV line containing low-protein binding 0.2 micron to 5 micron in-line or add-on filter
  • Dilute prior to administration; dilute in 0.9% sodium chloride or 5% dextrose; mix diluted solution by gentle inversion; do not shake
  • Final concentration should be between 1 mg/mL and 10 mg/mL
  • IV compatibility: Do not administer other drugs through the same infusion line
  • An additional Dosing Regimen of 400 mg Every 6 Weeks is approved for use for all approved adult indications. This dosing regimen is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety; continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials.
  • Information on FDA-approved tests used for patient selection is available at: http://www.fda.gov/CompanionDiagnostics .
  • Additional information on patient selection for single-agent and combination therapy may be found in the manufacturer’s product information.

Side Effects

The Most Common

  • muscle, joint, or bone pain
  • changes in skin color
  • extreme tiredness or lack of energy
  • nausea
  • vomiting
  • constipation
  • blisters or peeling skin; skin redness; rash; or itching
  • painful sores or ulcers in mouth, nose, throat, or genital area
  • fever or flu-like symptoms
  • shortness of breath
  • swollen glands
  • chest pain
  • new or worsening cough
  • diarrhea
  • stools that are black, tarry, sticky, or contain blood or mucus
  • severe abdominal pain
  • severe nausea and vomiting
  • increased or decreased appetite
  • increased thirst
  • pain in upper right part of the stomach
  • yellowing of the skin or eyes
  • easy bleeding or bruising
  • fast heartbeat
  • changes in weight (gain or loss)
  • hair loss
  • increased sweating
  • feeling cold
  • deepening of voice or hoarseness
  • changes in mood or behavior
  • decreased sex drive
  • swelling in front of the neck (goiter)
  • tingling and weakness in the feet, legs, hands, and arms
  • stiff neck
  • severe or persistent headache
  • severe muscle weakness or pain
  • dizziness or lightheadedness
  • fainting
  • change in amount or color of urine
  • pain or a burning sensation while urinating
  • blood in urine
  • swelling of feet, ankles, or lower legs
  • changes in vision, including sensitivity to light, eye pain
  • feeling confused

More common

  • Black, tarry stools
  • bladder pain
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • bloody or cloudy urine
  • blurred vision
  • body aches or pain
  • burning, numbness, tingling, or painful sensations
  • Nervous system (headache)
  • Musculoskeletal (back pain, arthralgia)
  • Skin (vitiligo, rash, pruritus)
  • Metabolism (decreased appetite, weight loss, hyponatremia)
  • Respiratory (cough, dyspnea)
  • General (fatigue, pyrexia, asthenia, influenza-like illness, peripheral edema
  • Gastrointestinal (diarrhea, constipation, abdominal pain, nausea, vomiting)
  • Endocrine (hypothyroidism, hyperthyroidism)
  • Infections (pneumonia, urinary tract infection, upper respiratory tract infection)
  • Cardiac (arrhythmias)
  • Blood/lymphatic (anemia)
  • Hepatobiliary (hepatoxicity, elevated liver function tests)
  • Renal and urinary (hematuria, increase blood creatinine)
  • clay-colored stools
  • confusion
  • constipation
  • cough
  • dark urine
  • decreased appetite
  • depressed mood
  • difficult, burning, or painful urination
  • difficulty with breathing
  • difficulty with moving
  • dizziness
  • dry mouth
  • dry skin and hair
  • ear congestion
  • feeling cold
  • fever
  • flushing
  • frequent urge to urinate
  • fruit-like breath odor
  • hair loss
  • headache
  • hoarseness or husky voice
  • increased hunger
  • increased thirst
  • increased urination
  • itching, skin rash
  • joint or bone pain
  • loss of voice
  • lower back or side pain
  • mood or mental changes
  • muscle cramps, pain, and stiffness
  • nausea
  • neck pain
  • nervousness
  • numbness and tingling around the mouth, fingertips, or feet
  • painful or difficult urination
  • pale skin
  • pounding in the ears
  • rapid weight gain
  • redness, swelling, or pain of the skin
  • runny or stuffy nose
  • scaling of the skin on the hands and feet
  • slow or fast heartbeat
  • sneezing
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • stomach cramps, pain or tenderness
  • swelling of the face, ankles, or hands
  • tingling of the hands or feet
  • ulceration of the skin
  • unsteadiness or awkwardness
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • vomiting
  • weakness in the arms, hands, legs, or feet
  • yellow eyes or skin

Rare

  • Blue lips, fingernails, or skin
  • chest pain or discomfort
  • decrease in urine output or decrease in urine-concentrating ability
  • difficulty with chewing, swallowing, or talking
  • double vision
  • drooping eyelids
  • general feeling of discomfort or illness
  • inability to speak
  • irregular, fast or slow, or shallow breathing
  • muscle weakness
  • pain and swelling in the genitals or anal area
  • seizures
  • sensitivity to heat
  • severe or sudden headache
  • slurred speech
  • sweating
  • temporary blindness
  • tenderness
  • thickening of bronchial secretions
  • trouble sleeping
  • watery or bloody diarrhea
  • weakness in the arm or leg on one side of the body, sudden and severe
  • Back or leg pain
  • bleeding gums
  • blistering, peeling, or loosening of the skin
  • cracks in the skin
  • drowsiness
  • eye pain
  • general body swelling
  • indigestion
  • joint redness or swelling
  • joint or muscle pain
  • light-colored stools
  • loss of heat from the body
  • nosebleeds
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • pale skin
  • red, swollen skin
  • red irritated eyes
  • red skin lesions, often with a purple center
  • redness of the eye
  • scaly skin
  • sensitivity of the eye to light
  • swollen glands
  • tearing
  • upper right abdominal or stomach pain

Drug Interaction

Pregnancy and Lactation

Pregnancy

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue (see Data). Human IgG4 (immunoglobulins) are known to cross
the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

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 KEYTRUDA and for 4 months after the final dose.

Why is this medication prescribed?

Pembrolizumab injection is used alone or in combination with other chemotherapy medications to treat certain types of melanoma (a type of skin cancer), Merkel cell carcinoma (MCC; a type of skin cancer), and cutaneous squamous cell carcinoma (CSCC; skin cancer). It is also used to prevent the return of melanoma after surgery. Pembrolizumab injection is also used alone and/or in combination with other chemotherapy medications to treat certain types of lung cancer (non-small-cell lung cancer; NSCLC), head and neck cancer, Hodgkin’s lymphoma (Hodgkin’s disease), primary mediastinal B-cell lymphoma (PMBCL; non-Hodgkin lymphoma), urothelial cancer (cancer of the lining of the bladder and other parts of the urinary tract), bladder cancer, colorectal cancer (cancer that begins in the large intestine), gastric cancer (cancer of the stomach), esophageal cancer (cancer of the tube that connects your throat to your stomach), cervical cancer (cancer that begins in the opening of the uterus [womb]), cancer of the endometrium (lining of the uterus), hepatocellular carcinoma (HCC; a type of liver cancer), renal cell carcinoma (RCC, a type of cancer that begins in the kidneys), breast cancer, and certain other solid tumors. Pembrolizumab injection is in a class of medications called monoclonal antibodies. It works by helping your immune system to slow or stop the growth of cancer cells.

Your doctor will review your specific type of cancer and past treatment history and other available treatments to determine if pembrolizumab is right for you.

How should this medicine be used?

Pembrolizumab injection comes as a powder to be mixed with liquid and injected intravenously (into a vein) over 30 minutes by a doctor or nurse in a hospital or medical facility. It is usually injected once every 3 or 6 weeks for as long as your doctor recommends that you receive treatment.

Pembrolizumab injection may cause serious reactions during, or shortly after the infusion of the medication. If you experience any of the following symptoms, tell your doctor immediately: flushing, fever, chills, shaking, dizziness, feeling faint, shortness of breath, difficulty breathing, back pain, itching, rash, or hives.

Your doctor may delay or stop your treatment with pembrolizumab injection, or treat you with additional medications, depending on your response to the medication and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with pembrolizumab injection and each time you receive a dose. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer’s website to obtain the Medication Guide.

What special precautions should I follow?

Before receiving pembrolizumab injection,

  • tell your doctor and pharmacist if you are allergic to pembrolizumab, any other medications, or any of the ingredients in pembrolizumab injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take while you are receiving pembrolizumab injection. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have ever had an organ or bone marrow transplant and if you have or have ever had radiation therapy to your chest area; an autoimmune disease (condition in which the immune system attacks a healthy part of the body) such as Crohn’s disease (condition in which the immune system attacks the lining of the digestive tract causing pain, diarrhea, weight loss, and fever), ulcerative colitis (condition which causes swelling and sores in the lining of the colon [large intestine] and rectum), or lupus (condition in which the immune system attacks many tissues and organs including the skin, joints, blood, and kidneys); diabetes; thyroid problems; any type of lung disease or breathing problems; any condition that affects your nervous system such as myasthenia gravis (a disorder of the nervous system that causes muscle weakness) or Guillain-Barré syndrome (weakness, tingling, and possible paralysis due to sudden nerve damage); or kidney or liver disease.
  • tell your doctor if you are pregnant or plan to become pregnant. You will have to take a pregnancy test before starting treatment. You should not become pregnant while you are receiving pembrolizumab injection and for 4 months after your final dose. Talk to your doctor about birth control methods that will work for you. If you become pregnant while receiving pembrolizumab injection, call your doctor immediately. Pembrolizumab injection may harm the fetus.
  • tell your doctor if you are breastfeeding or plan to breastfeed. Your doctor may tell you not to breastfeed while receiving pembrolizumab injection, and for 4 months after your final dose.