Pembrolizumab

• Pembrolizumab (Keytruda) is an immunotherapy used to treat cancers, including types of non-small cell lung cancer (NSCLC), breast cancer, melanoma, head and neck cancer, and many more.
• Pembrolizumab works by blocking the PD-1, a protein on immune cells, which allows T-cells to stay active and better recognize and attack cancer cells. Pembrolizumab is a programmed death receptor-1 (PD-1)-blocking antibody.
• Pembrolizumab is administered as an intravenous infusion, usually given every 3 weeks or 6 weeks, depending on the cancer type being treated and your dosage.

Pembrolizumab is often given when the cancer has spread to other parts of the body, or cannot be treated with surgery or radiation, or when other cancer treatments have not worked or have stopped working.

For some types of cancer, pembrolizumab is given only if your tumor tests positive for "PD-L1", or if the tumor has been tested for a specific genetic marker (including "EGFR," "ALK,” or "TMB").

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.

• Drug class: Immune checkpoint inhibitor
• Type: Monoclonal antibody
• Category: Biologic therapy
• Mechanism: PD-1 receptor blocker
• First FDA Approval: September 4, 2014

Pembrolizumab is a PD-1 inhibitor and immune checkpoint inhibitor that works differently from traditional chemotherapy by enhancing your immune system's natural cancer-fighting abilities.

Cancer cells sometimes avoid the immune system by producing proteins called PD-L1 and PD-L2, which bind to PD-1 receptors on T-cells. When these proteins connect with PD-1, they act like a brake, shutting down the T-cells’ ability to recognize and attack cancer.

Pembrolizumab works by attaching to the PD-1 receptors first, blocking PD-L1 and PD-L2 from binding. With this brake removed, your immune system can:

• Recognize cancer cells more easily
• Launch a stronger attack against tumors
• Slow or stop cancer growth

Pembrolizumab is FDA-approved for the following cancers. Relevant KEYNOTE or other clinical trials are listed beside each cancer approval.

Non-Small Cell Lung Cancer (NSCLC)

• In combination with pemetrexed and platinum chemotherapy as first-line treatment of adults with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations. (KEYNOTE-189)
• In combination with carboplatin and either paclitaxel or paclitaxel protein-bound as first-line treatment of adults with metastatic squamous NSCLC. (KEYNOTE-407)
• 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-authorized 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. (KEYNOTE-024, KEYNOTE-042)
• As a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%), 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 before receiving pembrolizumab. (KEYNOTE-010)
• In combination with platinum-containing chemotherapy as neoadjuvant treatment, then continued as a single agent as adjuvant treatment after surgery, for adults with resectable (tumors ≥4 cm or node positive) NSCLC. (KEYNOTE-671)
• As a single agent for adjuvant treatment following resection and platinum-based chemotherapy for adults with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. (KEYNOTE-091)

Melanoma

• Unresectable or metastatic melanoma. (KEYNOTE-006, KEYNOTE-002)
• As adjuvant treatment for Stage IIB, IIC, or III melanoma following complete resection in adults and pediatrics aged 12 years and older. (KEYNOTE-716, KEYNOTE-054)

Triple-Negative Breast Cancer (TNBC)

• High-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, then continued as a single agent as adjuvant treatment after surgery. (KEYNOTE-522)
• In combination with sacituzumab govitecan-hziy, for the first-line treatment of unresectable locallyadvanced or metastatic TNBC in adults whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. (KEYNOTE-D19)
• In combination with chemotherapy, for locally recurrent, unresectable or metastatic TNBC in adults whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-authorized test. (KEYNOTE-355)

Urothelial Cancer (UC)

• In combination with enfortumab vedotin for adults with locally advanced or metastatic UC. (EV-302/KEYNOTE-A39)
• As a single agent for adults with locally advanced or metastatic UC who: Are not eligible for platinum-containing chemotherapy, or (KEYNOTE-052) Have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (KEYNOTE-045)
• In combination with enfortumab vedotin as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment of adults with muscle-invasive bladder cancer (MIBC). (KEYNOTE-905/EV-303, KEYNOTE-B15)
• As a single agent for adults 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. (KEYNOTE-057)

Renal Cell Carcinoma (RCC)

• In combination with axitinib for the first-line treatment of adults with advanced RCC. (KEYNOTE-426)
• In combination with lenvatinib for the first-line treatment of adults with advanced RCC. (KEYNOTE-581/Study 307)
• As adjuvant treatment for patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. (KEYNOTE-564)
• In combination with belzutifan for the adjuvant treatment of adults with RCC with a clear cell component (ccRCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. (LITESPARK-022)

Head and Neck Squamous Cell Cancer (HNSCC)

• Adults with resectable locally advanced HNSCC whose tumors express PD-L1 (CPS ≥1) as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy with or without cisplatin, and then as a single agent. (KEYNOTE-689)
• In combination with platinum and FU for the first-line treatment of patients with metastatic or unresectable, recurrent HNSCC. (KEYNOTE-048)
• As a single agent for the first-line treatment of patients with metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS ≥1). (KEYNOTE-048)
• As a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. (KEYNOTE-040)

Cervical Cancer

• In combination with chemoradiotherapy to treat patients with locally advanced cervical cancer involving the lower third of the vagina, with or without extension to the pelvic sidewall, or hydronephrosis/non-functioning kidney, or spread to adjacent pelvic organs (FIGO 2014 Stage III-IVA). (KEYNOTE-A18)
• In combination with chemotherapy, with or without bevacizumab, to treat patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1). (KEYNOTE-826)
• As a single agent to treat patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (CPS ≥1). (KEYNOTE-158)

Endometrial Carcinoma

• In combination with carboplatin and paclitaxel, followed by pembrolizumab as a single agent, for adults with primary advanced or recurrent endometrial carcinoma. (KEYNOTE-868)
• In combination with lenvatinib for the treatment of adults with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (KEYNOTE-775/Study 309)
• As a single agent for the treatment of adults with advanced endometrial carcinoma that is MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (KEYNOTE-158)

Gastric Cancer

• In combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1). (KEYNOTE-811)
• In combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥1). (KEYNOTE-859)

Esophageal Cancer

Patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) carcinoma (tumors with epicenter 1 to 5 centimeters above the GEJ) that is not amenable to surgical resection or definitive chemoradiation, either:

• In combination with platinum- and fluoropyrimidine-based chemotherapy for patients whose tumors express PD-L1 (CPS ≥1). (KEYNOTE-590)
• As a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10). (KEYNOTE-181)

Microsatellite Instability-High (MSI-H) or Mismatch Repair-Deficient (dMMR) Colorectal Cancer (CRC)

• Patients with unresectable or metastatic MSI-H or dMMR CRC. (KEYNOTE-177)

Classical Hodgkin Lymphoma (cHL)

• Adults with relapsed or refractory cHL. (KEYNOTE-204, KEYNOTE-087)
• Pediatrics with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. (KEYNOTE-087, KEYNOTE-051)

Hepatocellular Carcinoma (HCC)

• HCC secondary to hepatitis B in patients who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. (KEYNOTE-394).

Biliary Tract Cancer (BTC)

• In combination with gemcitabine and cisplatin to treat patients with locally advanced unresectable or metastatic BTC. (KEYNOTE-966)

Malignant Pleural Mesothelioma (MPM)

• In combination with pemetrexed and a platinum chemotherapy as first-line treatment of adults with unresectable advanced or metastatic MPM. (KEYNOTE-483)

Ovarian Cancer

• Platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma in adults whose tumors express PD-L1 (CPS ≥1) and who have received 1 or 2 prior systemic treatment regimens. Used in combination with paclitaxel, with or without bevacizumab. (KEYNOTE-B96).

Cutaneous Squamous Cell Carcinoma (cSCC)

• Recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. (KEYNOTE-629)

Merkel Cell Carcinoma (MCC)

• Adults and pediatrics with recurrent locally advanced or metastatic MCC. (KEYNOTE-017, KEYNOTE-913)

Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

• Adults and pediatrics with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy. (KEYNOTE-170)

Pembrolizumab is not recommended for patients with PMBCL who require urgent cytoreductive therapy.

Microsatellite Instability-High (MSI-H) or Mismatch Repair-Deficient (dMMR) Cancer

• Adults and pediatrics with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. (KEYNOTE-158, KEYNOTE-164, KEYNOTE-051)

Tumor Mutational Burden-High (TMB-H) Cancer

• Adults and pediatrics with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. (KEYNOTE-158). Accelerated approval designation.

It is not known if pembrolizumab is safe and effective in children with TMB-H central nervous system cancers.

Biomarker-Based Approvals

• MSI-H or dMMR Solid Tumors: For any advanced or metastatic cancer with these biomarkers after prior treatment, when no other good treatment options exist
• TMB-H Cancer: For advanced or metastatic solid tumors with high tumor mutational burden (≥10 mutations/megabase) after prior treatment, when no other good treatment options exist

Important: Specific biomarker testing, PD-L1 expression levels, and prior treatment requirements apply to many indications. Patients should consult the full prescribing information for detailed eligibility criteria and dosing schedules.

• Immune-Mediated Adverse Reactions
• Hypersensitivity and Administration-Related Reactions: Interrupt injection and resume upon symptom resolution, or permanently discontinue KEYTRUDA QLEX based on the severity of reaction.
• Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody.
• 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

Pembrolizumab can change the way your immune system works, which may cause certain side effects that can lead to serious medical problems.

Pembrolizumab can cause serious or life-threatening side effects. Some side effects may need to be treated with other medicine, and your cancer treatments may be delayed. You will need frequent medical tests to help your doctor determine if it is safe for you to keep receivingthis medicine.

Call your doctor at once if you have: skin problems, vision problems, fever, swollen glands, neck stiffness, chest pain, cough, shortness of breath, muscle or joint pain, pale skin, weakness, diarrhea, severe stomach pain, blood in your stools, bruising or bleeding, dark urine, yellowing of the skin or eyes, a hormonal disorder (frequent headaches, feeling light-headed, rapid heartbeats, a deeper voice, increased thirst or urination, feeling cold, weight gain or loss), or a change in the amount or color of your urine.

To make sure pembrolizumab is safe for you, tell your doctor if you have ever had:

• an autoimmune disorder such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, lupus, or psoriasis;
• received or plan to receive a stem cell transplant that uses donor stem cells;
• an organ transplant;
• radiation to your chest; or
• a nerve-muscle disorder such as myasthenia gravis or Guillain-Barré syndrome.

Pembrolizumab may harm an unborn baby. You may need a pregnancy test to make sure you are not pregnant. Use effective birth control while using pembrolizumab and for at least 4 months after your last dose. Tell your doctor if you become pregnant.

Do not breastfeed while using pembrolizumab, and for at least 4 months after your last dose.

Common pembrolizumab side effects

• nausea, vomiting, stomach pain, loss of appetite, diarrhea, constipation, weight loss;
• low blood sodium levels, abnormal thyroid, liver and kidney function tests;
• low blood cell counts;
• tingling or numbness in your hands or feet, loss of movement in the arms and legs;
• bleeding;
• pain and burning when you urinate;
• fever, headache, feeling weak or tired, dizziness, trouble sleeping;
• cough, hoarse voice, feeling short of breath;
• changes in your sense of taste, dry skin and dry eyes;
• itching, hair loss, rash or blisters on your hands or feet;
• increased blood pressure;
• pain in your muscles, bones, or joints; or
• mouth sores or swelling around your mouth, nose, eyes, throat, intestines or vagina.

Serious pembrolizumab side effects

Get emergency medical help if you have signs of an allergic reaction to pembrolizumab (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).

Seek medical treatment if you have a serious drug reaction that can affect many parts of your body. Symptoms may include skin rash, fever, swollen glands, muscle aches, severe weakness, unusual bruising, or yellowing of your skin or eyes.

Some side effects may occur during the injection. Tell your medical caregiver if you feel dizzy, nauseated, light-headed, itchy, sweaty, or have a headache, chest tightness, back pain, trouble breathing, or swelling in your face.

Pembrolizumab causes your immune system to attack tumor cells, but it could also attack healthy organs and tissues in your body. This could lead to serious or life-threatening side effects on your lungs, liver, pancreas, kidneys, intestines, thyroid, or adrenal glands.

Call your doctor at once if you have:

• new or worsening cough, chest pain, shortness of breath;
• pale skin, easy bruising or bleeding;
• severe muscle pain, cramps, weakness, neck stiffness;
• double or blurry vision;
• confusion, sleep or memory problems, changes in mood or behavior, balance problems;
• numbness, tingling, burning pain, redness, rash, or blisters on your hands or feet;
• fever or flu-like symptoms, swollen glands, sores in your mouth, throat, nose, or on your genital area;
• diarrhea, severe stomach pain or tenderness, bloody or tarry stools;
• feeling sick or uneasy, with pain or swelling near your transplanted organ;
• high blood sugar = increased thirst, increased urination, dry mouth, fruity breath odor;
• kidney problems = swelling, blood in your urine, urinating less, loss of appetite, feeling tired or short of breath;
• liver problems = swelling around your midsection, right-sided upper stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• hormonal problems = unusual headaches, sensitivity to light, eye problems, rapid heartbeats, increased sweating, extreme tiredness, weight gain or weight loss, increased hunger or thirst, increased urination, hair loss, feeling cold, constipation, hoarse or deepened voice, dizziness, fainting, decreased sex drive; or
• low red blood cells (anemia) = pale skin, tiredness, feeling light-headed or short of breath, cold hands and feet.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Pembrolizumab is given as an infusion into a vein, usually once every 3 to 6 weeks. A healthcare provider will give you this injection.

This medicine must be given slowly over 30 minutes.

You will need frequent medical tests to help your doctor determine if it is safe for you to keep receiving pembrolizumab. Do not miss any follow-up visits.

Call your doctor for instructions if you miss an appointment for your pembrolizumab injection.

In a medical setting an overdose would be treated quickly.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Tell your doctor about all other cancer treatments you are receiving.

Other drugs may interact with pembrolizumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all other medicines you use.

KeytrudaActive ingredient: pembrolizumabInactive ingredients: L-histidine, polysorbate 80, sucrose, and water for injection

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