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KEYTRUDA QLEX is a brand name for Pembrolizumab. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE KEYTRUDA QLEX is a combination of pembrolizumab, a programmed death receptor-1 (PD-1)-blocking antibody, and berahyaluronidase alfa, an endoglycosidase, indicated: Melanoma for the treatment of adult patients with unresectable or metastatic melanoma. ( 1.1 ) for the adjuvant treatment of adult…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION KEYTRUDA QLEX has different recommended dosage and administration than intravenous pembrolizumab. 2 ) KEYTRUDA QLEX is for subcutaneous use in the thigh or abdomen only. 2 ) Do not administer KEYTRUDA QLEX intravenously.
2 ) KEYTRUDA QLEX must be administered by a healthcare provider. 4 mL subcutaneously in the abdomen or thigh over 1 minute. 8 mL subcutaneously in the abdomen or thigh over 2 minutes. 3 ) For RCC, administer KEYTRUDA QLEX as a single agent in the adjuvant setting, or in the advanced setting with either: axitinib 5 mg orally twice daily or lenvatinib 20 mg orally once daily.
3 ) For Endometrial Carcinoma, administer KEYTRUDA QLEX: in combination with carboplatin and paclitaxel regardless of MMR or MSI status, or in combination with lenvatinib 20 mg orally once daily for pMMR or not MSI-H tumors, or as a single agent for MSI-H or dMMR tumors.
3 ) See Full Prescribing Information for dosage modifications for adverse reactions and preparation and administration instructions. 1 Patient Selection See information on FDA-authorized tests for intravenous pembrolizumab. gov/CompanionDiagnostics .
4) ] . 4) ]. 6) ] . 11) ] . 12) ] . 9) ]. 18) ]. Because subclonal dMMR mutations and microsatellite instability may arise in high-grade gliomas during temozolomide therapy, it is recommended to test for TMB-H, MSI-H, and dMMR in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas.
Additional Patient Selection Information for MSI-H or dMMR in Patients with non-CRC Solid Tumors Due to discordance between local tests and FDA-authorized tests, confirmation of MSI-H or dMMR status is recommended by an FDA-authorized test in patients with MSI-H or dMMR solid tumors, if feasible.
8) ] . 6) ] . 11) ]. 12) ]. 17) ] . 20) ] . 21) ] . 2 Important Dosage and Administration Information KEYTRUDA QLEX has different recommended dosage and administration instructions than intravenous pembrolizumab. To reduce the risk of medication errors, check the vial labels to ensure that the drug being prepared and administered is KEYTRUDA QLEX for subcutaneous use and not intravenous pembrolizumab.
Do not substitute KEYTRUDA QLEX with intravenous pembrolizumab because they have different recommended dosages and routes of administration. Patients receiving intravenous pembrolizumab can switch to subcutaneous KEYTRUDA QLEX at their next scheduled dose.
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. 1) ] . 2) ]. The most common adverse reactions (≥20%) in patients treated with KEYTRUDA QLEX in combination with chemotherapy were nausea, fatigue, and musculoskeletal pain.
1 ) The safety of KEYTRUDA QLEX for the approved indications is also based on the safety of intravenous pembrolizumab given as a single agent or in combination with other antitumor medicines. The most common adverse reactions (reported in ≥20% of patients) with intravenous pembrolizumab were: As a single agent: fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism.
1 ) In combination with chemotherapy or chemoradiotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, hypothyroidism, radiation skin injury, dysphagia, dry mouth and musculoskeletal pain.
1 ) In combination with chemotherapy and bevacizumab: peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, decreased appetite, pyrexia, epistaxis, decreased white blood cell count, and stomatitis.
1 ) In combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.
1 ) In combination with lenvatinib: hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury.
1 ) Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection.
Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Withhold or permanently discontinue based on severity and type of reaction.
Hypersensitivity and Administration-Related Reactions:
Interrupt injection and resume upon symptom resolution, or permanently discontinue KEYTRUDA QLEX based on the severity of reaction. 2 ) Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody.
3 ) 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. 4 ) 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. 1 Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA QLEX is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions.
Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously.
4 CONTRAINDICATIONS KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients. KEYTRUDA QLEX is contraindicated in patients with known hypersensitivity to berahyaluronidase alfa, hyaluronidase or to any of its excipients.
( 4 )
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Patients receiving subcutaneous KEYTRUDA QLEX can switch to intravenous pembrolizumab at their next scheduled dose. Administer KEYTRUDA QLEX as a subcutaneous injection into the thigh or abdomen, avoiding the 5 cm area around the navel.
4 mL subcutaneously over 1 minute. Treatment duration is provided in Recommended Dosage (Table 1). 8 mL subcutaneously over 2 minutes. Treatment duration is provided in Recommended Dosage (Table 1). Inject into healthy skin and never into areas where the skin is red, bruised, tender, or hard.
5 cm from the previous injection site. During treatment with KEYTRUDA QLEX, do not administer other medications for subcutaneous use at the same site as KEYTRUDA QLEX. Do not administer KEYTRUDA QLEX intravenously. KEYTRUDA QLEX must be administered by a healthcare provider.
3 Recommended Dosage The recommended dosages of KEYTRUDA QLEX are presented in Table 1. 4 mL subcutaneously over 1 minute. 8 mL subcutaneously over 2 minutes. 4) ] . (12 years and older who weigh greater than 40 kg) with MSI-H or dMMR Cancer, MCC, or TMB- H Cancer 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Until disease progression, unacceptable toxicity, or up to 24 months Pediatric patients (12 years and older who weigh greater than 40 kg) for adjuvant treatment of melanoma 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Until disease recurrence, unacceptable toxicity, or up to 12 months Combination Therapy Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA QLEX for recommended dosing information, as appropriate.
Adult patients with resectable NSCLC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day. Neoadjuvant treatment in combination with chemotherapy for 12 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA QLEX as a single agent after surgery for 39 weeks or until disease recurrence or unacceptable toxicity Adult patients with NSCLC, MPM, HNSCC, HER2-negative Gastric Cancer, Esophageal Cancer, or BTC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day.
Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with locally advanced or metastatic urothelial cancer 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX after enfortumab vedotin when given on the same day.
Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with locally advanced HNSCC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to cisplatin when given on the same day.
Neoadjuvant:
Administer KEYTRUDA QLEX for 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity.
Adjuvant:
Administer KEYTRUDA QLEX in combination with RT with or without cisplatin. Continue KEYTRUDA QLEX as a single agent. Continue KEYTRUDA QLEX until disease recurrence or unacceptable toxicity or up to one year Adult patients with MIBC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX after enfortumab vedotin when given on the same day.
Neoadjuvant:
Administer KEYTRUDA QLEX 395 mg/4,800 units every 3 weeks for 3 doses in combination with enfortumab vedotin or until disease progression that precludes curative-intent cystectomy or unacceptable toxicity.
Adjuvant:
Administer KEYTRUDA QLEX 395 mg/4,800 units every 3 weeks for 14 doses or 790 mg/9,600 units every 6 weeks for 7 doses in combination with enfortumab vedotin or until disease recurrence or unacceptable toxicity Adult patients with HER2-positive Gastric Cancer 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to trastuzumab and chemotherapy when given on the same day.
Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with Cervical Cancer 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemoradiotherapy or prior to chemotherapy with or without bevacizumab when given on the same day.
Until disease progression, unacceptable toxicity, or for KEYTRUDA QLEX, up to 24 months Adult patients with RCC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX in combination with axitinib 5 mg orally twice daily When axitinib is used in combination with KEYTRUDA QLEX, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer.
or Administer KEYTRUDA QLEX in combination with lenvatinib 20 mg orally once daily. Until disease progression, unacceptable toxicity, or for KEYTRUDA QLEX, up to 24 months Adult patients with Endometrial Carcinoma 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to carboplatin and paclitaxel when given on the same day.
or Administer KEYTRUDA QLEX in combination with lenvatinib 20 mg orally once daily. Until disease progression, unacceptable toxicity, or for KEYTRUDA QLEX, up to 24 months Adult patients with high-risk early-stage TNBC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day.
Neoadjuvant treatment in combination with chemotherapy for 24 weeks (8 doses of 395 mg/4,800 units every 3 weeks or 4 doses of 790 mg/9,600 units every 6 weeks) or until disease progression or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA QLEX as a single agent for up to 27 weeks (9 doses of 395 mg/4,800 units every 3 weeks or 5 doses of 790 mg/9,600 units every 6 weeks) or until disease recurrence or unacceptable toxicity Patients who experience disease progression or unacceptable toxicity related to KEYTRUDA QLEX with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA QLEX.
Adult patients with locally recurrent unresectable or metastatic TNBC 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with Ovarian Cancer 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks Administer KEYTRUDA QLEX prior to paclitaxel with or without bevacizumab when given on the same day.
4 Dosage Modifications No dose reduction for KEYTRUDA QLEX is recommended. In general, withhold KEYTRUDA QLEX for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA QLEX for Life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.
Dosage modifications for KEYTRUDA QLEX for adverse reactions that require management different from these general guidelines are summarized in Table 2. 1) ] Pneumonitis Grade 2 Withhold Resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper.
Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids. 5 and up to 3 times ULN Withhold For liver enzyme elevations in patients treated with combination therapy with axitinib, see Table 3 .
AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA QLEX based on recommendations for hepatitis with no liver involvement.
2) ] Grade 1 or 2 Interrupt injection (if not already fully administered). If symptoms resolve, resume injection Grade 3 or 4 Permanently discontinue The following table represents dosage modifications that are different from those described above for KEYTRUDA QLEX or in the Full Prescribing Information for the drug administered in combination.
0. 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 times ULN with concurrent total bilirubin at least 2 times ULN or ALT or AST ≥10 times ULN Permanently discontinue both KEYTRUDA QLEX and axitinib Recommended Dose Modifications for Adverse Reactions for KEYTRUDA QLEX in Combination with Lenvatinib When administering KEYTRUDA QLEX in combination with lenvatinib, modify the dosage of one or both drugs.
Withhold or discontinue KEYTRUDA QLEX as shown in Table 2. Refer to lenvatinib prescribing information for additional dose modification information. 5 Preparation KEYTRUDA QLEX is a ready-to-use solution. Do not dilute KEYTRUDA QLEX. Do not shake.
Preparation of the Syringe Remove KEYTRUDA QLEX vial from refrigerated storage [2°C to 8°C (36°F to 46°F)] and allow it to equilibrate to room temperature [20°C to 25°C (68°F to 77°F)] for at least 30 minutes. Prior to preparation for administration, if needed, the unpunctured vial may be stored at room temperature for up to 24 hours.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution is clear to slightly opalescent, colorless to slightly yellow.
Discard the vial if visible particles are observed. Use a sterile, polypropylene or polycarbonate syringe and a stainless steel transfer needle (18 to 21 gauge) to withdraw KEYTRUDA QLEX from the vial. 4 mL into the syringe. 8 mL into the syringe.
To avoid needle clogging, change the needle to a 25 to 30 gauge, ½-inch, stainless steel hypodermic injection needle immediately prior to subcutaneous injection. Discard any unused portion left in the vial. Storage of Prepared Syringe The product does not contain a preservative and should be used immediately after withdrawing from the vial.
If not used immediately, store the syringe containing KEYTRUDA QLEX with the transfer needle and cap in place: At room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours, or In the refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours.
The 24-hour period may include up to 8 hours at room temperature. Discard if storage time exceeds these limits. If refrigerated, allow the filled syringe to come to room temperature for at least 30 minutes prior to administration. Do not freeze.
1 ) In combination with enfortumab vedotin: rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, nausea, constipation, dysgeusia, and urinary tract infection. gov/medwatch . 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in the WARNINGS AND PRECAUTIONS reflect exposure to intravenous pembrolizumab as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC.
In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA QLEX in combination with platinum doublet chemotherapy in a randomized, open-label, active-controlled trial (Study MK-3475A-D77), which enrolled 251 patients with NSCLC; intravenous pembrolizumab as a single agent in a randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC; a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE-040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in a randomized, open-label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE-426), which enrolled 429 patients with RCC; and in post-marketing use.
Across all trials, patients were administered either KEYTRUDA QLEX 790 mg/9,600 units every 6 weeks or intravenous pembrolizumab at doses of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks.
Among the 2799 patients who received intravenous pembrolizumab, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more. The most common adverse reactions (≥20%) in patients who received KEYTRUDA QLEX in combination with chemotherapy were nausea (25%), fatigue (25%), and musculoskeletal pain (21%).
The safety of KEYTRUDA QLEX for the approved indications is also based on the safety of intravenous pembrolizumab given as a single agent or in combination with other antitumor medicines. The most common adverse reactions (≥20%) in patients who received intravenous pembrolizumab were: as a single agent : fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism.
in combination with chemotherapy or chemoradiotherapy : fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, hypothyroidism, radiation skin injury, dysphagia, dry mouth, and musculoskeletal pain.
in combination with chemotherapy and bevacizumab : peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, decreased appetite, pyrexia, epistaxis, decreased white blood cell count, and stomatitis.
in combination with axitinib : diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.
in combination with lenvatinib : hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury.
in combination with enfortumab vedotin : rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, nausea, constipation, dysgeusia, and urinary tract infection. 1) ]. A total of 377 patients received either KEYTRUDA QLEX 790 mg/9,600 units every 6 weeks in combination with platinum doublet chemotherapy (n=251) or intravenous pembrolizumab 400 mg every 6 weeks in combination with platinum doublet chemotherapy (n=126).
2% were exposed for greater than one year. 8% Alaska Native or American Indian; and 29% were of Hispanic or Latino ethnicity. Serious adverse reactions occurred in 39% of patients who received KEYTRUDA QLEX in combination with chemotherapy.
2%). 4%). Permanent discontinuation of KEYTRUDA QLEX due to an adverse reaction occurred in 16% of patients. Adverse reactions which resulted in permanent discontinuation of KEYTRUDA QLEX in ≥2% of patients included pneumonia and pneumonitis.
Dosage interruptions of KEYTRUDA QLEX due to an adverse reaction occurred in 45% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included neutropenia, anemia, thrombocytopenia, pneumonia, rash, and increased aspartate aminotransferase.
Tables 4 and 5 summarize the adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA QLEX in Study MK-3475A-D77. 8 Diarrhea Includes diarrhea, colitis, and enterocolitis. 6 General Fatigue Includes fatigue, asthenia.
2 Musculoskeletal and Connective Tissue Musculoskeletal pain Includes musculoskeletal pain, arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, non-cardiac chest pain, and pain in extremity.
4 Skin and Subcutaneous Tissue Rash Includes rash, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative, eczema, erythema multiforme, immune-mediated dermatitis, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and skin exfoliation.
8 Endocrine Hypothyroidism 14 0 12 0 Infections Pneumonia Includes pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung abscess, pneumocystis jirovecii pneumonia, pneumonia bacterial, and pneumonia mycoplasmal. 17 10 16 7 Nervous System Peripheral neuropathy Includes neuropathy peripheral, hypoaesthesia, neuralgia, paraesthesia, and peripheral sensory neuropathy.
8 Respiratory, Thoracic and Mediastinal Cough Includes cough, productive cough, and upper-airway cough syndrome. 4%).
Table 5:
Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with Metastatic NSCLC Receiving KEYTRUDA QLEX in Study MK-3475A-D77 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA QLEX plus platinum doublet chemotherapy (range: 240 to 246 patients) and intravenous pembrolizumab plus platinum doublet chemotherapy (range: 124 to 125 patients).
4 34 0 Hypokalemia 21 5 24 6 Adverse Reactions in Adult and Pediatric Patients Treated with Intravenous Pembrolizumab The safety of KEYTRUDA QLEX for its approved indications [see Indications and Usage (1) ] has been established in adequate and well-controlled studies of KEYTRUDA QLEX in combination with platinum doublet chemotherapy (Study MK-3475A-D77) and intravenous pembrolizumab, as a single agent or in combination therapy, across tumor types.
Below is a description of adverse reactions of intravenous pembrolizumab in these adequate and well-controlled studies. Melanoma Ipilimumab-Naive Melanoma The safety of intravenous pembrolizumab for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006.
3) ] . Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.
0 months) for intravenous pembrolizumab and similar in both treatment arms. Fifty-one and 46% of patients received intravenous pembrolizumab 10 mg/kg every 2 or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year.
The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had an elevated lactate dehydrogenase (LDH) value at baseline; 65% had M1c stage disease; 9% with history of brain metastasis; and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).
In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both intravenous pembrolizumab arms. Adverse reactions leading to permanent discontinuation of intravenous pembrolizumab occurred in 9% of patients.
4%). 5%). Tables 6 and 7 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-006. 1 Skin and Subcutaneous Tissue Rash Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash.
8 Other clinically important adverse reactions occurring in ≥10% of patients receiving intravenous pembrolizumab were diarrhea (26%), nausea (21%), and pruritus (17%).
Table 7:
Selected Laboratory abnormalities occurring at same or higher incidence than in ipilimumab arm Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-006 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: intravenous pembrolizumab n=429 and ipilimumab n=183; hypercholesterolemia: intravenous pembrolizumab n=484 and ipilimumab n=205.
1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4). Ipilimumab-Refractory Melanoma The safety of intravenous pembrolizumab in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002.
3) ] . Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.
8 months). In the intravenous pembrolizumab 2 mg/kg arm, 36% of patients were exposed to intravenous pembrolizumab for ≥6 months and 4% were exposed for ≥12 months. In the 10 mg/kg arm, 41% of patients were exposed to intravenous pembrolizumab for ≥6 months and 6% of patients were exposed to intravenous pembrolizumab for ≥12 months.
The study population characteristics were: median age of 62 years (range: 15 to 89); 61% male; 98% White; 41% had an elevated LDH value at baseline; 83% had M1c stage disease; 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis.
In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both intravenous pembrolizumab arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving intravenous pembrolizumab; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%).
Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-002.
7%).
Table 9:
Selected Laboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-002 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: intravenous pembrolizumab n=247 and chemotherapy n=116; decreased bicarbonate: intravenous pembrolizumab n=263 and chemotherapy n=123.
6 Other laboratory abnormalities occurring in ≥20% of patients receiving intravenous pembrolizumab were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4). 4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible.
Adverse reactions occurring in patients with Stage IIB or IIC melanoma were similar to those occurring in 1011 patients with Stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent.
3) ] . Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received intravenous pembrolizumab for 6 months or longer.
The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had Stage IIIA, 46% had Stage IIIB, 18% had Stage IIIC (1-3 positive lymph nodes), and 20% had Stage IIIC (≥4 positive lymph nodes).
Two patients treated with intravenous pembrolizumab died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving intravenous pembrolizumab.
2%), and diarrhea (1%). 4%), dyspnea (1%), and fatigue (1%). Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-054. 2 8 0 Influenza like illness 11 0 8 0 Investigations Weight loss 11 0 8 0 Table 11: Selected Laboratory abnormalities occurring at same or higher incidence than placebo.
Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-054 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 502 to 505 patients) and placebo (range: 491 to 497 patients).
4) ] . A total of 607 patients received intravenous pembrolizumab 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by intravenous pembrolizumab and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202).
Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.
1 months). Sixty percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab for ≥6 months. Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; and 18% with history of brain metastases at baseline.
Intravenous pembrolizumab was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were pneumonitis (3%) and acute kidney injury (2%).
Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%).
Tables 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-189. 5 Skin and Subcutaneous Tissue Rash Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.
7 26 5 Table 13: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab /pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients).
4) ] . Safety data are available for the first 203 patients who received intravenous pembrolizumab and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.
The median duration of exposure to intravenous pembrolizumab was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab for ≥6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin.
The study population characteristics were: median age of 65 years (range: 40 to 83), 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases. Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority.
Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 43% of patients; the most common (≥2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).
The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the intravenous pembrolizumab and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.
4) ]. Patients received intravenous pembrolizumab 200 mg every 3 weeks (n=636) or investigator's choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks.
Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.
3 months). Forty-eight percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab 200 mg for ≥6 months. The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black.
Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (Stage IV), 13% had Stage III disease (2% Stage IIIA and 11% Stage IIIB), and 5% had treated brain metastases at baseline. Intravenous pembrolizumab was discontinued for adverse reactions in 19% of patients.
4%). 0%). 2%). Tables 14 and 15 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with intravenous pembrolizumab in KEYNOTE-042. 3 Skin and Subcutaneous Tissue Rash Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.
2 Table 15: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 598 to 610 patients) and chemotherapy (range: 585 to 598 patients); increased prothrombin INR: intravenous pembrolizumab n=203 and chemotherapy n=173.
4) ] . A total of 991 patients received intravenous pembrolizumab 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m 2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.
8 months). The data described below reflect exposure to intravenous pembrolizumab 2 mg/kg in 31% of patients exposed to intravenous pembrolizumab for ≥6 months. In the intravenous pembrolizumab 10 mg/kg arm, 34% of patients were exposed to intravenous pembrolizumab for ≥6 months.
The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; and 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases.
Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease. In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682).
Treatment was discontinued for adverse reactions in 8% of patients receiving intravenous pembrolizumab. 8%). 3%), and pneumonitis (1%). Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-010.
3 Other clinically important adverse reactions occurring in patients receiving intravenous pembrolizumab were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).
Table 17:
Selected Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm. Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving Intravenous Pembrolizumab in KEYNOTE-010 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 631 to 638 patients) and docetaxel (range: 271 to 277 patients).
7% Grades 3-4). 4) ]. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. 6 months). The study population characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older, 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino.
Adverse reactions occurring in patients with resectable NSCLC receiving intravenous pembrolizumab in combination with platinum containing chemotherapy, given as neoadjuvant treatment and continued as single agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving intravenous pembrolizumab in combination with chemotherapy.
Neoadjuvant Phase of KEYNOTE-671 A total of 396 patients received at least 1 dose of intravenous pembrolizumab in combination with platinum-containing chemotherapy as neoadjuvant treatment and 399 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment.
3%), and anemia (2%). 3%). 3%). 3% (n=17), respectively, did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reactions that led to cancellation of surgery in the intravenous pembrolizumab arm was interstitial lung disease (1%).
1% (n=10) experienced delay of surgery (surgery more than 8 weeks from last neoadjuvant treatment if patient received less than 4 cycles of neoadjuvant therapy or more than 20 weeks after first dose of neoadjuvant treatment if patient received 4 cycles of neoadjuvant therapy) due to adverse reactions.
5% (n=8) experienced delay of surgery due to adverse reactions. Of the 325 intravenous pembrolizumab-treated patients who received surgery, 7% (n=22) did not receive adjuvant treatment due to adverse reactions. 2% (n=10) did not receive adjuvant treatment due to adverse reactions.
Adjuvant Phase of KEYNOTE-671 A total of 290 patients in the intravenous pembrolizumab arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment. 4%). One fatal adverse reaction of pulmonary hemorrhage occurred.
4%), AST increased (1%), and musculoskeletal pain (1%). 4) ] . A total of 1161 patients received intravenous pembrolizumab 200 mg (n=580) or placebo (n=581) every 3 weeks. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis.
9 months). Sixty-eight percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab for ≥6 months. The adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving intravenous pembrolizumab as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%).
Two fatal adverse reactions of myocarditis occurred. 5) ] . A total of 473 patients received intravenous pembrolizumab 200 mg, pemetrexed, and platinum every 3 weeks for up to 6 cycles followed by intravenous pembrolizumab (n=241), or pemetrexed and platinum chemotherapy every 3 weeks for up to 6 cycles (n=232).
Patients with autoimmune disease that required systemic therapy within 3 years of treatment or a medical condition that required immunosuppression were ineligible. 2 months). Sixty-one percent of patients in the intravenous pembrolizumab arm were exposed to intravenous pembrolizumab for ≥6 months.
Adverse reactions occurring in patients with MPM were generally similar to those in other patients receiving intravenous pembrolizumab in combination with pemetrexed and platinum chemotherapy. 6) ]. Intravenous pembrolizumab was administered as single-agent neoadjuvant therapy before definitive surgery, during adjuvant radiotherapy (RT) with or without concurrent cisplatin, and then as single agent adjuvant therapy.
Concurrent cisplatin was added to intravenous pembrolizumab and adjuvant RT for high-risk disease pathology. A total of 361 patients received treatment on the intravenous pembrolizumab arm and 315 patients received treatment on the SOC therapy arm.
9 weeks). The median duration of exposure to intravenous pembrolizumab in the adjuvant phase was 42 weeks (range: 1 day to 82 weeks). 7% unknown race; and 15% Hispanic or Latino. The most common adverse reactions (≥ 20%) on the intravenous pembrolizumab arm were stomatitis (48%), radiation skin injury (40%), weight loss (36%), fatigue (33%), dysphagia (29%), constipation (27%), hypothyroidism (26%), nausea (24%), rash (22%), dry mouth (22%), diarrhea (22%), and musculoskeletal pain (22%).
Table 18 and Table 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-689. 3 Neoadjuvant Phase of KEYNOTE-689 Of the 361 patients who received at least one dose of single agent intravenous pembrolizumab as neoadjuvant treatment, 11% of patients experienced serious adverse reactions.
6%). 1% of patients who received neoadjuvant intravenous pembrolizumab including respiratory failure, clostridium infection, septic shock, and myocardial infarction (one patient each). 8% of patients who received intravenous pembrolizumab as neoadjuvant treatment.
6%). Of the 361 patients who received intravenous pembrolizumab as neoadjuvant treatment, 11% (n=38) did not receive surgery. 3% (n=1). Of the 351 patients randomized to SOC, 12% (n=43) did not receive surgery. 4% (n=5). 2% (n=4) experienced delay of surgery (defined as on-study surgery occurring ≥ 9 weeks after initiation of neoadjuvant intravenous pembrolizumab) due to adverse reactions.
3% (n=1) experienced delay of surgery (defined as surgery occurring ≥ 6 weeks after randomization) due to adverse reactions. 8% (n=9) did not receive adjuvant treatment due to adverse reactions. 6% (n=11) did not receive adjuvant RT or chemoradiation due to adverse reactions.
Adjuvant Phase of KEYNOTE-689 A total of 275 patients in the intravenous pembrolizumab arm and 275 patients in the SOC arm started the adjuvant phase of treatment. On the intravenous pembrolizumab arm, 100 patients received intravenous pembrolizumab and cisplatin with concurrent RT, 154 patients received intravenous pembrolizumab alone with concurrent RT, 7 patients received cisplatin alone with concurrent RT, and 13 patients received RT alone.
One patient received intravenous pembrolizumab alone. On the SOC arm, 139 patients received cisplatin with concurrent RT while 136 patients received RT alone. For the intravenous pembrolizumab arm, a total of 222 patients received single-agent intravenous pembrolizumab following RT.
Of the 255 patients who received at least one dose of intravenous pembrolizumab in the adjuvant phase, 38% experienced serious adverse reactions. 2%). 4%). Permanent discontinuation of adjuvant intravenous pembrolizumab due to an adverse reaction occurred in 17% of patients.
The most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant intravenous pembrolizumab were pneumonitis, colitis, immune-mediated hepatitis and death not otherwise specified. Of the 275 patients who received SOC in the adjuvant phase, 23% experienced serious adverse reactions.
3%). 9%). 6) ] . Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received intravenous pembrolizumab 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by intravenous pembrolizumab, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab.
2 months) in the combination arm. Seventeen percent of patients in the intravenous pembrolizumab single agent arm and 18% of patients in the combination arm were exposed to intravenous pembrolizumab for ≥12 months. Fifty-seven percent of patients receiving intravenous pembrolizumab in combination with chemotherapy started treatment with carboplatin.
Intravenous pembrolizumab was discontinued for adverse reactions in 12% of patients in the intravenous pembrolizumab single agent arm. 3%). 3%), and hyponatremia (2%). Intravenous pembrolizumab was discontinued for adverse reactions in 16% of patients in the combination arm.
4%). 9%). Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-048. 7 10 0 8 0 Table 21: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-048 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab/chemotherapy (range: 240 to 267 patients), intravenous pembrolizumab (range: 245 to 292 patients), cetuximab/chemotherapy (range: 249 to 282 patients).
9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012. The study population characteristics were: median age of 60 years (range: 20 to 84), 35% age 65 or older; 83% male; and 77% White, 15% Asian, and 5% Black.
Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease. Intravenous pembrolizumab was discontinued due to adverse reactions in 17% of patients.
Serious adverse reactions occurred in 45% of patients receiving intravenous pembrolizumab. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure.
The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea.
1) ] . 7) ]. 25 mg/kg on Days 1 and 8 of each 21-day cycle compared to 433 patients who received gemcitabine on Days 1 and 8 and investigator’s choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. 5 months). 2%). Serious adverse reactions occurred in 50% of patients receiving intravenous pembrolizumab in combination with enfortumab vedotin.
3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of intravenous pembrolizumab occurred in 27% of patients. 4%). Dose interruptions of intravenous pembrolizumab occurred in 61% of patients. 5%), pneumonia (2%), and pruritus (2%).
Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with enfortumab vedotin in KEYNOTE-A39. 5%). 7) ] . 25 mg/kg on days 1 and 8 of each 21-day cycle.
6 months). 8%). Serious adverse reactions occurred in 50% of patients receiving intravenous pembrolizumab and enfortumab vedotin. 5%). Permanent discontinuation of intravenous pembrolizumab occurred in 32% of patients. 5%). Dose interruptions of intravenous pembrolizumab occurred in 69% of patients.
5%). Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with enfortumab vedotin in KEYNOTE-869. 8%). 2 Hematology Anemia 69 15 Lymphopenia 64 17 Neutropenia 32 12 Platinum-Ineligible Patients with Urothelial Carcinoma The safety of intravenous pembrolizumab was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities.
7) ] . Patients received intravenous pembrolizumab 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression. 8 months). Intravenous pembrolizumab was discontinued due to adverse reactions in 11% of patients.
Eighteen patients (5%) died from causes other than disease progression. 8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia.
Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ≥40 mg oral prednisone equivalent.
Table 26 summarizes adverse reactions in patients on intravenous pembrolizumab in KEYNOTE-052. 0 Previously Treated Urothelial Carcinoma The safety of intravenous pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045.
7) ] . Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. 5 months (range: 1 day to 14 months) in patients who received chemotherapy.
Intravenous pembrolizumab was discontinued due to adverse reactions in 8% of patients. 9%). 1%). Serious adverse reactions occurred in 39% of intravenous pembrolizumab-treated patients. The most frequent serious adverse reactions (≥2%) in intravenous pembrolizumab-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis.
Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-045. 6 Table 28: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Urothelial Carcinoma Patients Receiving Intravenous Pembrolizumab in KEYNOTE-045 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: intravenous pembrolizumab n=232 and chemotherapy n=222.
1 Neoadjuvant and Adjuvant Treatment of Cisplatin-Ineligible Patients with MIBC in Combination with Enfortumab Vedotin The safety of intravenous pembrolizumab in combination with enfortumab vedotin as neoadjuvant treatment and continued after radical cystectomy (RC) as adjuvant treatment was investigated in KEYNOTE-905, an open-label, multicenter, randomized, active-controlled trial in patients with previously untreated MIBC who were ineligible for or declined cisplatin-based chemotherapy.
7) ] . 7 months) and the median number of cycles of intravenous pembrolizumab was 3 (range: 1 to 3) out of the planned 3 cycles in the neoadjuvant phase. 9 months) and the median number of cycles of intravenous pembrolizumab was 12 (range: 1 to 14) out of the planned 14 cycles in the adjuvant phase.
Across the combined neoadjuvant and adjuvant phases (n=167), the median number of cycles of intravenous pembrolizumab was 5 (range: 1 to 17) out of the planned 17 cycles. Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with enfortumab vedotin in KEYNOTE-905.
Table 29:
Adverse Reactions ≥20% (All Grades) in Patients Treated with Intravenous Pembrolizumab in Combination with Enfortumab Vedotin in KEYNOTE-905 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks in combination with enfortumab vedotin before and after RC with PLND n=167 RC with PLND alone n=159 All Grades % Grade 3-4 % All Grades % Grade 3-4 % Skin and subcutaneous tissue disorders Rash Includes multiple terms.
, Includes rash, rash maculo-papular, conjunctivitis, erythema, eczema, skin exfoliation, palmar-plantar erythrodysesthesia syndrome, blister, dermatitis, dermatitis exfoliative generalized, exfoliative rash, rash papular, rash pruritic, dermatitis bullous, drug eruption, pemphigoid, rash vesicular, and dermatitis contact.
6% each).
Table 30:
Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Treated with Intravenous Pembrolizumab in Combination with Enfortumab Vedotin in KEYNOTE-905 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Intravenous pembrolizumab in combination with enfortumab vedotin (167 patients), and RC and PLND alone (range: 110 to 121 patients).
03 % Grades 3-4 % All Grades % Grades 3-4 % ALT = alanine aminotransferase; AST = aspartate aminotransferase. 7 Neoadjuvant Phase of KEYNOTE-905 A total of 167 patients received at least 1 dose of intravenous pembrolizumab in combination with enfortumab vedotin as neoadjuvant treatment before receiving RC.
In the neoadjuvant phase, serious adverse reactions occurred in 27% of patients receiving intravenous pembrolizumab in combination with enfortumab vedotin. 4%). 6% each). 4% each). Permanent discontinuation of intravenous pembrolizumab due to an adverse reaction occurred in 15% of patients.
2% each). Adverse reactions leading to dose interruption of intravenous pembrolizumab in the neoadjuvant phase occurred in 20% of patients. 4%). 2%) patients did not receive surgery due to adverse reactions. 6% each). 1%) patients experienced delay of surgery (defined as time from last neoadjuvant treatment to surgery exceeding 8 weeks) due to adverse reactions.
Adjuvant Phase of KEYNOTE-905 Patients who did not proceed to surgery were ineligible for adjuvant therapy. Of the 149 patients who underwent surgery, 100 patients received adjuvant treatment with intravenous pembrolizumab in combination with enfortumab vedotin.
Of the 49 patients who did not receive adjuvant treatment, discontinuation of treatment prior to the adjuvant phase was due to an adverse event in 21 patients. In the adjuvant phase, serious adverse reactions occurred in 43% of patients; the most frequent (≥2%) serious adverse reactions were urinary tract infection (8%), acute kidney injury and pyelonephritis (5% each), urosepsis (4%), and hypokalemia, intestinal obstruction, and sepsis (2% each).
Fatal adverse reactions occurred in 7% of patients, including urosepsis, intracranial hemorrhage, death, myocardial infarction, multiple organ dysfunction syndrome, and pseudomonal pneumonia (1% each). Permanent discontinuation of intravenous pembrolizumab due to an adverse reaction occurred in 28% of patients.
The most frequent (>1%) adverse reactions resulting in permanent discontinuation of intravenous pembrolizumab were diarrhea (5%), and peripheral neuropathy, acute kidney injury, and pneumonitis (2% each). Adverse reactions leading to dose interruption of intravenous pembrolizumab in the adjuvant phase occurred in 38% of patients.
The most common adverse reactions (≥2%) leading to dose interruption of intravenous pembrolizumab were rash (7%), urinary tract infection (6%), diarrhea (4%), and abdominal pain, COVID-19, fatigue, pruritus, and pyelonephritis (2% each).
BCG-unresponsive High-risk NMIBC The safety of intravenous pembrolizumab was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors.
Patients received intravenous pembrolizumab 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. 6 months). Intravenous pembrolizumab was discontinued due to adverse reactions in 11% of patients.
4%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 22% of patients; the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of intravenous pembrolizumab-treated patients.
The most frequent serious adverse reactions (≥2%) in intravenous pembrolizumab-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-057.
8) ]. 5 months). Adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received intravenous pembrolizumab as a single agent. 6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.
Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent. 10) ] . 6 months). Fatal adverse reactions occurred in 3 patients who received intravenous pembrolizumab in combination with trastuzumab and CAPOX or FP and included pneumonitis in 2 patients and hepatitis in 1 patient.
Intravenous pembrolizumab was discontinued due to adverse reactions in 13% of patients. 1%). 3%), increased blood creatinine (2%), and colitis (2%). In the intravenous pembrolizumab arm versus placebo, there was a difference of ≥5% incidence between patients treated with intravenous pembrolizumab versus standard of care for diarrhea (53% vs.
47%), rash (35% vs. 28%), hypothyroidism (11% vs. 5%), and pneumonia (11% vs. 5%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. There was a difference of ≥5% incidence between patients treated with intravenous pembrolizumab versus standard of care for decreased leukocytes (60% vs.
54%), decreased calcium (56% vs. 46%), decreased lymphocytes (59% vs. 51%), decreased potassium (41% vs. 36%), increased bilirubin (33% vs. 25%), increased creatinine (28% vs. 18%), and decreased glucose (17% vs. 11%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.
10) ] . 7 months). Serious adverse reactions occurred in 45% of patients receiving intravenous pembrolizumab. 4%). 3%). Permanent discontinuation of intravenous pembrolizumab due to adverse reactions occurred in 15% of patients. 0%). Dosage interruptions of intravenous pembrolizumab due to an adverse reaction occurred in 65% of patients.
2%), nausea (2%), palmar-plantar erythrodysesthesia syndrome (2%), and vomiting (2%). Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-859. 11) ] .
A total of 740 patients received either intravenous pembrolizumab 200 mg (n=370) or placebo (n=370) every 3 weeks for up to 35 cycles, both in combination with up to 6 cycles of cisplatin and up to 35 cycles of FU. 1 months (range: 3 days to 27 months) in the chemotherapy arm.
Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. 1%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 67% of patients. 2%). Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-590.
03 (%) Grades 3-4 One fatal event of diarrhea was reported in each arm. 4 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent.
12) ] . Two hundred ninety-four patients received intravenous pembrolizumab in combination with chemoradiotherapy and 303 patients received placebo in combination with chemoradiotherapy. The median duration of exposure to intravenous pembrolizumab was 20 months (range: 1 day to 32 months).
3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 34% of patients receiving intravenous pembrolizumab in combination with chemoradiotherapy. 4%), and sepsis (1%). Intravenous pembrolizumab was discontinued for adverse reactions in 9% of patients.
The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). 7%). Table 37 and Table 38 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-A18.
12) ] . A total of 616 patients, regardless of tumor PD-L1 expression, received intravenous pembrolizumab 200 mg and chemotherapy with or without bevacizumab (n=307) every 3 weeks or placebo and chemotherapy with or without bevacizumab (n=309) every 3 weeks.
9 months (range: 1 day to 26 months). 6% of patients receiving intravenous pembrolizumab in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection.
Serious adverse reactions occurred in 50% of patients receiving intravenous pembrolizumab in combination with chemotherapy with or without bevacizumab. 3%). Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients.
The most common adverse reaction resulting in permanent discontinuation of intravenous pembrolizumab (≥1%) was colitis (1%). 3%), decreased appetite (2%), and cough (2%). For patients treated with intravenous pembrolizumab, chemotherapy, and bevacizumab (n=196), the most common (≥20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).
Table 39 and Table 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-826. 1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.
Intravenous pembrolizumab was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving intravenous pembrolizumab. 1%). Tables 41 and 42 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-158.
3% Grades 3-4). HCC Previously Treated HCC The safety of intravenous pembrolizumab was investigated in KEYNOTE-394, a multicenter, double-blind, randomized, placebo-controlled trial that enrolled patients with previously treated HCC.
13) ] . 5 months) in the placebo arm. Intravenous pembrolizumab was discontinued due to adverse reactions in 13% of patients. 3%). Adverse reactions leading to interruption of intravenous pembrolizumab occurred in 26% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of intravenous pembrolizumab (≥2%) were increased blood bilirubin (9%), increased AST (5%), and increased ALT (2%).
Tables 43 and 44 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-394. 7 14 0 Skin and Subcutaneous Tissue Rash Includes dermatitis, dermatitis allergic, dermatitis bullous, rash, rash erythematous, rash maculo-papular, rash pustular, and blister.
7 Respiratory, Thoracic, and Mediastinal Cough 11 0 9 0 Endocrine Hypothyroidism 10 0 7 0 Table 44: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with HCC Receiving Intravenous Pembrolizumab in KEYNOTE-394 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 223 to 297 patients) and placebo (range: 144 to 151 patients).
14) ] . A total of 1063 patients received either intravenous pembrolizumab 200 mg plus gemcitabine and cisplatin chemotherapy (n=529) or placebo plus gemcitabine and cisplatin chemotherapy (n=534) every 3 weeks. The median duration of exposure to intravenous pembrolizumab was 6 months (range: 1 day to 28 months).
Intravenous pembrolizumab was discontinued for adverse reactions in 15% of patients. 3%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 55% of patients. 3%). In the intravenous pembrolizumab plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥5% incidence in adverse reactions between patients treated with intravenous pembrolizumab versus placebo for pyrexia (26% vs 20%), rash (21% vs 13%), pruritus (15% vs 10%), and hypothyroidism (9% vs.
6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. There was a difference of ≥5% incidence in laboratory abnormalities between patients treated with intravenous pembrolizumab plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs 61%).
There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. 3 months (range 1 day to 28 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.
Adverse reactions occurring in patients with MCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included increased lipase (17%).
16) ] . Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren's syndrome, and hypothyroidism stable on hormone replacement were ineligible.
Patients received intravenous pembrolizumab 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. 2 months). The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90-100 and 20% KPS of 70-80.
3% of patients receiving intravenous pembrolizumab in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier's gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.
Serious adverse reactions occurred in 40% of patients receiving intravenous pembrolizumab in combination with axitinib. 3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction of either intravenous pembrolizumab or axitinib occurred in 31% of patients; 13% intravenous pembrolizumab only, 13% axitinib only, and 8% both drugs.
2%). Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of intravenous pembrolizumab infusions due to infusion-related reactions, occurred in 76% of patients receiving intravenous pembrolizumab in combination with axitinib.
This includes interruption of intravenous pembrolizumab in 50% of patients. Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of intravenous pembrolizumab were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%).
The most common adverse reactions (≥20%) in patients receiving intravenous pembrolizumab and axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.
Twenty-seven percent (27%) of patients treated with intravenous pembrolizumab in combination with axitinib received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 45 and 46 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with intravenous pembrolizumab and axitinib in KEYNOTE-426.
5 Table 46: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab with Axitinib in KEYNOTE-426 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 421 patients).
9 Activated partial thromboplastin time prolonged Two patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity. 16) ]. Patients received intravenous pembrolizumab 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily (n=352), or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340).
1 to 39). 3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage.
Serious adverse reactions occurred in 51% of patients receiving intravenous pembrolizumab and lenvatinib. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).
Permanent discontinuation of either of intravenous pembrolizumab, lenvatinib or both due to an adverse reaction occurred in 37% of patients receiving intravenous pembrolizumab in combination with lenvatinib; 29% intravenous pembrolizumab only, 26% lenvatinib only, and 13% both.
The most common adverse reactions (≥2%) resulting in permanent discontinuation of intravenous pembrolizumab, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).
Dose interruptions of intravenous pembrolizumab, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving intravenous pembrolizumab in combination with lenvatinib. Intravenous pembrolizumab was interrupted in 55% of patients and both drugs were interrupted in 39% of patients.
The most common adverse reactions (≥3%) resulting in interruption of intravenous pembrolizumab were diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%), musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%).
Fifteen percent (15%) of patients treated with intravenous pembrolizumab in combination with lenvatinib received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 47 and 48 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with intravenous pembrolizumab and lenvatinib in KEYNOTE-581.
Table 47:
Adverse Reactions Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab with Lenvatinib in KEYNOTE-581 Adverse Reaction Intravenous Pembrolizumab 200 mg every 3 weeks with Lenvatinib N=352 Sunitinib 50 mg N=340 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue Includes asthenia, fatigue, lethargy, malaise 63 9 56 8 Gastrointestinal Diarrhea Includes diarrhea, gastroenteritis 62 10 50 6 Stomatitis Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, stomatitis 43 2 43 2 Nausea 36 3 33 1 Abdominal pain Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, upper abdominal pain 27 2 18 1 Vomiting 26 3 20 1 Constipation 25 1 19 0 Musculoskeletal and Connective Tissue Musculoskeletal disorders Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw 58 4 41 3 Endocrine Hypothyroidism Includes hypothyroidism, increased blood thyroid stimulating hormone, secondary hypothyroidism 57 1 32 0 Vascular Hypertension Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, labile blood pressure 56 29 43 20 Hemorrhagic events Includes all hemorrhage terms.
3 Respiratory, Thoracic and Mediastinal Dysphonia 30 0 4 0 Renal and Urinary Proteinuria Includes hemoglobinuria, nephrotic syndrome, proteinuria 30 8 13 3 Acute kidney injury Includes acute kidney injury, azotemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxic 21 5 16 2 Hepatobiliary Hepatotoxicity Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, gamma-glutamyltransferase increased 25 9 21 5 Nervous System Headache 23 1 16 1 Clinically relevant adverse reactions (<20%) that occurred in patients receiving intravenous pembrolizumab with lenvatinib were myocardial infarction (3%) and angina pectoris (1%).
Table 48:
Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) of Patients Receiving Intravenous Pembrolizumab with Lenvatinib in KEYNOTE-581 Laboratory Test With at least one Grade increase from baseline Intravenous Pembrolizumab 200 mg every 3 weeks with Lenvatinib Sunitinib 50 mg All Grades % Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: intravenous pembrolizumab with lenvatinib (range: 343 to 349 patients) and sunitinib (range: 329 to 335 patients).
3 22 0 Increased alkaline phosphatase 32 4 32 1 Hypocalcemia 30 2 22 1 Hypophosphatemia 29 7 50 8 Hypomagnesemia 25 2 15 3 Increased creatine phosphokinase 24 6 36 5 Hypermagnesemia 23 2 22 3 Hypercalcemia 21 1 11 1 Hematology Lymphopenia 54 9 66 15 Thrombocytopenia 39 2 73 13 Anemia 38 3 66 8 Leukopenia 34 1 77 8 Neutropenia 31 4 72 16 Grade 3 and 4 increased ALT or AST was seen in 9% of patients.
Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed on rechallenge in 10 patients receiving both intravenous pembrolizumab and lenvatinib (n=38) and was not observed on rechallenge with intravenous pembrolizumab alone (n=3).
16) ] . 3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Serious adverse reactions occurred in 20% of these patients receiving intravenous pembrolizumab. Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each).
2% of those treated with intravenous pembrolizumab, including one case of pneumonia. 6%), colitis (1%), and adrenal insufficiency (1%). 4%), rash, decreased appetite, and vomiting (1% each). Tables 49 and 50 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in KEYNOTE-564.
2 Table 50: Selected Laboratory abnormalities occurring at same or higher incidence than placebo Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-564 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab (range: 440 to 449 patients) and placebo (range: 461 to 469 patients); increased INR: intravenous pembrolizumab n=199 and placebo n=224.
17) ] . A total of 759 patients received intravenous pembrolizumab 200 mg every 3 weeks and chemotherapy for 6 cycles followed by intravenous pembrolizumab 400 mg every 6 weeks for up to 14 cycles (n=382) or placebo and chemotherapy for 6 cycles followed by placebo for up to 14 cycles (n=377).
0 months). Serious adverse reactions occurred in 35% of patients receiving intravenous pembrolizumab in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy. 3%). Intravenous pembrolizumab was discontinued for an adverse reaction in 14% of patients.
Chemotherapy dose reduction was required in 29% of patients receiving intravenous pembrolizumab in combination with chemotherapy, compared to 23% of patients receiving placebo in combination with chemotherapy. There were no clinically meaningful differences in chemotherapy discontinuations or interruptions between arms.
9% Grades 3-4). In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H. 17) ]. Patients with endometrial carcinoma that is pMMR or not MSI-H received intravenous pembrolizumab 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325) .
8 months). 7% of those treated with intravenous pembrolizumab and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.
Serious adverse reactions occurred in 50% of these patients receiving intravenous pembrolizumab and lenvatinib. 2%). Discontinuation of intravenous pembrolizumab due to an adverse reaction occurred in 15% of these patients. 2%). Dose interruptions of intravenous pembrolizumab due to an adverse reaction occurred in 48% of these patients.
5%). Tables 51 and 52 summarize adverse reactions and laboratory abnormalities, respectively, in patients on intravenous pembrolizumab in combination with lenvatinib in KEYNOTE-775. 9 0 Table 52: Laboratory Abnormalities Worsened from Baseline With at least one grade increase from baseline Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-775 Endometrial Carcinoma (pMMR or not MSI-H) Laboratory Test Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: intravenous pembrolizumab and lenvatinib (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients).
9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent. 18) ]. 2 months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received intravenous pembrolizumab as a single agent.
9 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with intravenous pembrolizumab as a single agent.
Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%). TNBC Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC The safety of intravenous pembrolizumab in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with intravenous pembrolizumab as a single agent was investigated in KEYNOTE-522, a randomized (2:1), multicenter, double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC .
20) ]. 9 months). 9% of patients receiving intravenous pembrolizumab, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction.
Serious adverse reactions occurred in 44% of patients receiving intravenous pembrolizumab. 2%). Intravenous pembrolizumab was discontinued for adverse reactions in 20% of patients. 5%), and rash (1%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 57% of patients.
1%). Tables 53 and 54 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with intravenous pembrolizumab in KEYNOTE-522. 5 19 0 Table 54: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab in KEYNOTE-522 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab in combination with chemotherapy followed by intravenous pembrolizumab as a single agent (range: 762 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 381 to 389 patients).
20) ] . A total of 596 patients (including 34 patients from a safety run-in) received intravenous pembrolizumab 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. 0 months).
3%). Serious adverse reactions occurred in 30% of patients receiving intravenous pembrolizumab in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. 2%), and thrombocytopenia (2%). Intravenous pembrolizumab was discontinued for adverse reactions in 11% of patients.
2%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 50% of patients. 9%), and diarrhea (2%). Tables 55 and 56 summarize the adverse reactions and laboratory abnormalities in patients on intravenous pembrolizumab in KEYNOTE-355.
7 Table 56: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Intravenous Pembrolizumab with Chemotherapy in KEYNOTE-355 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous pembrolizumab + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients).
21) ]. 9 months). Serious adverse reactions occurred in 54% of patients receiving intravenous pembrolizumab and paclitaxel with or without bevacizumab. 1%). 4%). Intravenous pembrolizumab was permanently discontinued for adverse reactions in 16% of patients.
3%). Adverse reactions leading to the interruption of intravenous pembrolizumab occurred in 44% of patients. 1%). The most common (≥20%) adverse reactions for patients treated with intravenous pembrolizumab in combination with paclitaxel with or without bevacizumab were: diarrhea (45%), fatigue (43%), nausea (41%), alopecia (38%), peripheral neuropathy (38%), epistaxis (31%), urinary tract infection (27%), constipation (25%), abdominal pain (24%), decreased appetite (24%), vomiting (24%), hypothyroidism (21%), cough (20%), hypertension (20%), and rash (20%).
The most common (≥20%) laboratory abnormalities worsening from baseline were: anemia (85%), leukopenia (82%), decreased neutrophil count (71%), lymphopenia (60%), hypoalbuminemia (50%), hyponatremia (53%), hypomagnesemia (45%), increased aspartate aminotransferase (43%), increased alanine aminotransferase (40%), hypocalcemia(40%), increased alkaline phosphatase (31%), increased creatinine (29%), hypokalemia (27%) and neutropenia (21%).
For patients treated with intravenous pembrolizumab in combination with paclitaxel and bevacizumab (N=169), decreased white blood cell count (27%), stomatitis (22%) and pyrexia (21%) were also reported as adverse reactions. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of intravenous pembrolizumab.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal:
Exocrine pancreatic insufficiency Hepatobiliary: sclerosing cholangitis
Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions.
Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA QLEX in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated.
In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. 4) ] .
In general, if KEYTRUDA QLEX requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.
Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. , endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis KEYTRUDA QLEX can cause immune-mediated pneumonitis.
The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. 2%) adverse reactions. 3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. 9% (26) of patients.
All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients. 3%), and Grade 3 (1%) adverse reactions. 3 months).
5%) of patients. Of the patients who developed pneumonitis, 54% interrupted intravenous pembrolizumab, 63% discontinued intravenous pembrolizumab, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA QLEX can cause immune-mediated colitis, which may present with diarrhea.
Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
4%) adverse reactions. 4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. 2% of patients. 5% (13) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 23% had recurrence of colitis.
Colitis resolved in 85% of the 48 patients. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA QLEX can cause immune-mediated hepatitis. 4%) adverse reactions. 1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis.
Eleven percent of these patients required additional immunosuppressant therapy. 3% (9) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, none had recurrence of hepatitis.
Hepatitis resolved in 79% of the 19 patients. In Combination with Axitinib KEYTRUDA QLEX in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA QLEX alone.
Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. 4) ] . Intravenous Pembrolizumab in Combination with Axitinib With the combination of intravenous pembrolizumab and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen.
Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either intravenous pembrolizumab (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving intravenous pembrolizumab, 16 patients receiving axitinib, and 24 patients receiving both intravenous pembrolizumab and axitinib.
All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA QLEX can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated.
4) ]. 8%) adverse reactions. 3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. 3% (8) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement.
Hypophysitis KEYTRUDA QLEX can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism.
Initiate hormone replacement as indicated. 4) ] . 2%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. 3% (7) of patients.
All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. Thyroid Disorders KEYTRUDA QLEX can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism.
Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. 4) ]. 4%). 2%). Hypothyroidism occurred in 14% (35/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy, including Grade 2 (11%).
3%). No patients discontinued intravenous pembrolizumab due to thyroiditis. 1% (1) of patients. 8%). 3% (7) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. 2%) hyperthyroidism.
2%). 5% (14) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. 3%) hypothyroidism. 3%) hypothyroidism.
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. 4) ] . 4% (1/251) of patients receiving KEYTRUDA QLEX in combination with chemotherapy.
2% (6/2799) of patients receiving intravenous pembrolizumab. 1% (1) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy.
Immune-Mediated Nephritis with Renal Dysfunction KEYTRUDA QLEX can cause immune-mediated nephritis. 1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. 1% (3) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, none had recurrence of nephritis.
Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA QLEX can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies.
Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. 4) ] . 8%) adverse reactions. 1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions.
6% (16) of patients. All patients who were withheld reinitiated intravenous pembrolizumab after symptom improvement; of these, 6% had recurrence of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients.
Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA QLEX, intravenous pembrolizumab, or were reported with the use of other PD-1/PD-L1 blocking antibodies.
Severe or fatal cases have been reported for some of these adverse reactions.
Cardiac/Vascular:
Myocarditis, pericarditis, vasculitis Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur.
Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
5%), polymyalgia rheumatica Endocrine: Hypoparathyroidism Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reporting as the co-occurrence of either two or all three adverse reactions.
2 Hypersensitivity and Administration-Related Reactions KEYTRUDA QLEX can cause severe or life-threatening administration-related reactions, including hypersensitivity and anaphylaxis. 8%). Monitor patients for signs and symptoms of administration-related systemic reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever.
Interrupt injection (if not already fully administered) and resume if symptoms resolve for mild or moderate hypersensitivity and administration-related systemic reactions. 4) ] . 3 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.
Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause).
These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.
4 Increased Mortality in Patients with Multiple Myeloma when Pembrolizumab is Added to a Thalidomide Analogue and Dexamethasone In two randomized trials in patients with multiple myeloma, the addition of intravenous pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality.
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 trials. 5 Embryo-Fetal Toxicity Based on its mechanism of action, KEYTRUDA QLEX can cause fetal harm when administered to a pregnant woman.
Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
3) ].