Pembrolizumab (Keytruda)

General information

Class/mechanism: PD-1 antibody. Pembrolizumab is a humanized monoclonal antibody which binds to the PD-1 receptor on T-cells. In some cancers, the PD-1 ligands are upregulated, which results in inhibition of T-cell immune surveillance of tumors. By blocking the interaction between the PD-1 receptor and its ligands PD-L1 and PD-L2, pembrolizumab decreases this immune system inhibition and facilitates anti-tumor immune response.
Route: IV
Extravasation: no information

For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as Micromedex, Lexicomp, UpToDate (courtesy of Lexicomp), or the prescribing information.

Toxicity management

• Immunotherapy toxicity management

Diseases for which it is established (work in progress)

• Colorectal cancer, MSI-H or dMMR
• Hepatocellular carcinoma
• Merkel cell carcinoma
• MSI-H or dMMR solid tumors (tissue-agnostic)
• Primary mediastinal B-cell lymphoma
• Renal cell carcinoma
  • Clear cell renal cell carcinoma

Diseases for which it is used

• Anal cancer
• Bladder cancer
• Cervical cancer
• Cholangiocarcinoma
• Cutaneous squamous cell carcinoma
• Endometrial cancer
• Esophageal cancer
  • Esophageal squamous cell carcinoma
• Gastric cancer
• Head and neck squamous cell carcinoma
• Classical Hodgkin lymphoma
• Melanoma
  • Uveal melanoma
• Non-small cell lung cancer
  • Non-small cell lung cancer, nonsquamous
  • Non-small cell lung cancer, squamous
• TMB-H solid tumors (tissue-agnostic)
• Triple-negative breast cancer (TNBC)

Diseases for which it was used

• Small cell lung cancer

Patient drug information

• Pembrolizumab (Keytruda) package insert
• Pembrolizumab (Keytruda) patient drug information (Chemocare)
• Keytruda wallet card about side effects
• Pembrolizumab (Keytruda) patient drug information (UpToDate)

Management checklist

• CBC, comprehensive metabolic panel, Mg, Phos, LDH, TSH. Consider baseline EKG and troponin.

History of changes in FDA dosing recommendations

• 2020-04-28: FDA accelerated approval to a new dosage of 400 mg every 6 weeks for all approved adult indications.

History of changes in FDA indication

Bladder cancer

• 2017-05-18: Regular approval for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (New disease indication; based on KEYNOTE-045)
• 2017-05-18: Accelerated approval for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. (New disease indication; based on KEYNOTE-052)
  • 2021-08-31: Converted to regular approval. (Based on KEYNOTE-361)
• 2018-06-19: Label revised for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing therapy and whose tumors express PD-L1 (Combined Positive Score at least 10). (Biomarker restriction; based on KEYNOTE-361)
• 2018-06-19: Label revised for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. (Based on KEYNOTE-361)
• 2020-01-08: Approved for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. (Based on KEYNOTE-057)

Cervical cancer

• 2018-06-12: Accelerated approval for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS at least 1) as determined by an FDA-approved test. (New disease indication; based on KEYNOTE-158)
  • 2021-10-13: Full approval in combination with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS at least 1) (Based on KEYNOTE-826)

Classical Hodgkin lymphoma (cHL)

• 2017-03-14: Accelerated approval for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL). (New disease indication; based on KEYNOTE-087)
  • 2020-04-30: Converted to regular approval. (No supporting studies are cited)
• 2017-03-14: Accelerated approval for the treatment of adult and pediatric patients with classical Hodgkin lymphoma (cHL) that has relapsed after three or more prior lines of therapy. (New disease indication; based on KEYNOTE-087)
  • 2020-04-30: Converted to regular approval. (No supporting studies are cited)
• 2020-10-15: Approved for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). (Prior treatment criteria relaxed; based on KEYNOTE-204)
• 2020-10-15: Approved for the treatment of pediatric patients with refractory classical Hodgkin lymphoma (cHL). (Prior treatment criteria relaxed; based on KEYNOTE-204)
• 2020-10-15: Approved for the treatment of pediatric patients with classical Hodgkin lymphoma (cHL) that has relapsed after 2 or more lines of therapy. (Approval extended to third-line pediatric setting; based on KEYNOTE-204)

Colorectal cancer, MSI-H or dMMR

• 2017-05-23: Granted FDA accelerated approval for adult and pediatric patients with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. (New disease indication; based on KEYNOTE-164)
  • 2023-03-28: Converted to regular approval.
• 2020-06-29: Approved for the first-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. (Expanded to first-line setting; based on KEYNOTE-177)

Cutaneous squamous cell carcinoma

• 2020-06-24: Approved for patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation. (New disease indication; based on KEYNOTE-629)

Endometrial cancer

• 2019-09-17: Accelerated approval in combination with Lenvatinib (Lenvima) for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. (New disease indication; based on KEYNOTE-146)
  • 2021-07-21: Full approval in combination with Lenvatinib (Lenvima) for patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (Based on KEYNOTE-775)
• 2022-03-21: Approved as a single agent for patients with advanced endometrial carcinoma that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation. (Based on KEYNOTE-158)

Esophageal cancer

• 2019-07-30: Approved for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] at least 10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy. (New disease indication; based on KEYNOTE-180 and KEYNOTE-181)
• 2021-03-22: Approved in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal (GEJ) (tumors with epicenter 1 to 5 centimeters above the gastroesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation. (Histology-specific restriction removed; protein expression requirement removed; prior therapy requirement removed; surgery and radiation eligibility restriction added; drug combination requirement added; based on KEYNOTE-590)

Gastric or gastroesophageal junction adenocarcinoma - PARTIALLY WITHDRAWN

• 2017-09-22: Accelerated approval for patients with recurrent locally advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test. Patients must have had disease progression on or after two or more prior systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy. (New disease indication; based on KEYNOTE-059)
  • 2022: Indication withdrawn by manufacturer.
• 2021-05-05: Granted accelerated approval in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. (Based on KEYNOTE-811)

Head and neck squamous cell carcinoma

• 2016-08-05: Accelerated approval for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. (New disease indication; based on KEYNOTE-012)
• 2019-06-10: Converted to regular approval and approved for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in combination with platinum and fluorouracil (FU) for all patients. (Approval extended to first-line setting; based on KEYNOTE-048)
• 2019-06-10: Converted to regular approval and approved for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) as a single agent for patients whose tumors express PD-L1 (Combined Positive Score [CPS] at least 1) (Approval extended to first-line setting; based on KEYNOTE-048)

Hepatocellular carcinoma

• 2018-11-09: Accelerated approval for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. (New disease indication; based on KEYNOTE-224)

Melanoma

• 2014-09-04: Initial accelerated approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab, and if BRAF V600 mutation positive, a BRAF inhibitor. (Based on KEYNOTE-002)
  • 2015-12-18: Converted to regular approval for the treatment of patients with unresectable or metastatic melanoma. (Converted to regular approval; requirement for progression removed; based on KEYNOTE-006)
• 2019-02-15: Approved for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection. (Indication expanded to adjuvant setting; based on KEYNOTE-054)
• 2021-12-03: Approved for the adjuvant treatment of adult and pediatric (12 years of age or older) patients with stage IIB or IIC melanoma following complete resection. (Based on KEYNOTE-716)

Merkel cell carcinoma

• 2018-19-19: Accelerated approval for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). (New disease indication; based on KEYNOTE-017)

MSI-H or dMMR tumors (tissue-agnostic)

• 2017-05-23: Granted FDA accelerated approval for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. (New disease-agnostic indication; based on KEYNOTE-016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, and KEYNOTE-158)
  • 2023-03-28: Converted to regular approval.

Non-small cell lung cancer

• 2015-10-02: Accelerated approval for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed death ligand 1 (PD-L1) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab. (New disease indication; based on KEYNOTE-010)
• 2016-10-24: Full approval for patients with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC. (First-line indication with biomarker requirement; based on KEYNOTE-024)
• 2016-10-24: Full approval for patients with metastatic NSCLC whose tumors express PD-L1 (TPS greater than or equal to 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab. (Indication with biomarker requirement; based on KEYNOTE-042)
• 2017-05-10: Accelerated approval in combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC). (First-line indication with histology requirement; based on KEYNOTE-189)
  • 2018-08-20: Granted regular approval in combination with pemetrexed and platinum as first-line treatment of patients with metastatic, non-squamous non-small cell lung cancer (NSqNSCLC), with no EGFR or ALK genomic tumor aberrations. (Conversion to regular approval; based on KEYNOTE-189)
• 2018-10-30: Approval expanded in combination with carboplatin and either paclitaxel or nab-paclitaxel as first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC). (First-line indication with histology requirement; based on KEYNOTE-407)
• 2019-04-11: Approval expanded for the first-line treatment of patients with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC. Patients’ tumors must have no EGFR or ALK genomic aberrations and express PD-L1 (Tumor Proportion Score [TPS] greater than or equal to 1%) (Approval expanded to the non-metastatic setting; based on KEYNOTE-042)
• 2023-01-26: Approved for adjuvant treatment following resection and platinum-based chemotherapy for stage IB (T2a at least 4 cm), II, or IIIA non-small cell lung cancer (NSCLC). (Approval expanded to the maintenance setting; Based on PEARLS)

Primary mediastinal B-cell lymphoma

• 2018-06-13: Accelerated approval for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL). (New disease indication; based on KEYNOTE-170)
• 2018-06-13: Accelerated approval for the treatment of adult and pediatric patients with primary mediastinal large B-cell lymphoma (PMBCL) who have relapsed after two or more prior lines of therapy. (New disease indication; based on KEYNOTE-170)
• 2020-10-14: Converted to regular approval. (No supporting studies are cited)

Renal cell carcinoma

• 2019-04-19: Approved to be used together with Axitinib (Inlyta) for the first-line treatment of patients with advanced renal cell carcinoma (RCC). (New disease indication; based on KEYNOTE-426)
• 2021-08-10: Approved in combination with Lenvatinib (Lenvima) for first-line treatment of adult patients with advanced renal cell carcinoma (RCC). (Based on CLEAR)
• 2021-11-17: Approved for the adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. (Based on KEYNOTE-564)

Small cell lung cancer - WITHDRAWN

• 2019-06-17: Accelerated approval for patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. (New disease indication; based on KEYNOTE-028)
  • 2021-03-30: Approval withdrawn. (Based on KEYNOTE-604)

TMB-H (tissue agnostic)

• 2020-06-16: Accelerated approval for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB H) [at least 10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. (New disease-agnostic indication; based on KEYNOTE-158)

Triple-negative breast cancer (TNBC)

• 2020-11-13: Accelerated approval in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS at least 10) as determined by an FDA approved test. (New disease indication; based on KEYNOTE-355)
• 2021-07-26: Regular approval for high-risk, early-stage, triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. (Based on KEYNOTE-522)
• 2021-07-26: Regular approval in combination with chemotherapy for patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (Combined Positive Score [CPS] at least 10) as determined by an FDA approved test. (Based on KEYNOTE-522)

History of changes in EMA indication

• 2015-07-17: Initial marketing authorization as Keytruda.

History of changes in Health Canada indication

Bladder cancer

• 2019-04-11: Notice of compliance with conditions for the treatment of patients with locally advanced unresectable or metastatic urothelial carcinoma, as monotherapy, in adults who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) at least 10] as determined by a validated test.
• 2019-04-11: Notice of compliance with conditions for the treatment of patients with locally advanced unresectable or metastatic urothelial carcinoma, as monotherapy, in adults who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

Classical Hodgkin lymphoma

• 2021-02-03: Indication as a monotherapy, for the treatment for adult patients with refractory or relapsed classical Hodgkin Lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV) or who are not ASCT candidates and have failed BV withdrawn.
• 2021-02-05: Notice of compliance with conditions for the treatment of adult and pediatric patients with refractory or relapsed classical Hodgkin Lymphoma (cHL) who have failed autologous stem cell transplant (ASCT).
• 2021-02-05: Notice of compliance with conditions for the treatment of adult and pediatric patients with refractory or relapsed classical Hodgkin Lymphoma (cHL) who are not candidates for multi-agent salvage chemotherapy and ASCT.

Colorectal cancer

• 2019-04-18: Notice of compliance with conditions for the treatment of adults with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Endometrial cancer

• 2019-04-18: Notice of compliance with conditions for the treatment of adults with MSI-H or dMMR endometrial cancer that has progressed following prior therapy and who have no satisfactory alternative treatment options.
• 2019-09-20: Notice of compliance with conditions for the treatment of adults patients, in combination with lenvatinib, with advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior platinum-based systemic therapy and are not candidates for curative surgery or radiation.

Primary mediastinal B-cell lymphoma

• 2018-09-21: Notice of compliance with conditions for adult and pediatric patients with relapsed or refractory Primary Mediastinal B-cell Lymphoma (rrPMBCL).

History of changes in PMDA indication

Bladder cancer

• 2017-12-25: New additional indication for the treatment of unresectable urothelial cancer which progressed after cancer chemotherapy.

Breast cancer

• 2021-08-25: New indication and a new dosage for the treatment of PD-L1-positive, hormone receptor-negative and HER2-negative inoperable or recurrent breast cancer.
• 2022-09-26: New indication and a new dosage for the preoperative and postoperative adjuvant treatment of hormone receptor (HR)-negative and human epidermal growth factor receptor 2 (HER2)negative breast cancer with a high risk of recurrence.

Cervical cancer

• 2022-09-26: New indication for the treatment of advanced or recurrent cervical cancer.

Classical Hodgkin lymphoma

• 2017-11-30: New additional indication for the treatment of relapsed or refractory classical Hodgkin's lymphoma.

Colorectal cancer

• 2021-08-25: New indication for the treatment of unresectable advanced or recurrent microsatellite instability-high (MSI-High) colorectal cancer.

Endometrial cancer

• 2021-12-24: New indication and a new dosage for the treatment of unresectable advanced or recurrent endometrial carcinoma that has progressed after cancer chemotherapy.

Esophageal cancer

• 2020-08-21: New indication and a new dosage for the treatment of unresectable advanced or recurrent PD-L1-positive esophageal squamous cell carcinoma that has progressed after cancer chemotherapy.
• 2021-11-25: New indication and a new dosage for the treatment of unresectable advanced or recurrent esophageal cancer.

Head and neck cancer

• 2019-12-20: New indication for the treatment of recurrent or metastatic head and neck cancer.

Melanoma

• 2016-09-28: New approval for the treatment of unresectable melanoma.
• 2018-12-21: New indication for melanoma.

MSI-H or dMMR tumors (tissue-agnostic)

• 2018-12-21: Conditional new indication for advanced or recurrent microsatellite instability-high (MSI-High) solid tumors that have progressed after cancer chemotherapy (for use only if refractory or intolerant to standard therapies)

Non-small cell lung cancer

• 2016-12-19: New additional indication and a new dosage for the treatment of patients with PD-L1-positive, unresectable, recurrent or advanced non-small cell lung cancer.
• 2018-12-21: New indication for unresectable advanced or recurrent non-small cell lung cancer.

Renal cell carcinoma

• 2019-12-20: New indication and a new dosage for the treatment of unresectable or metastatic renal cell carcinoma.
• 2022-08-24: New indication and a new dosage for postoperative adjuvant treatment for renal cell carcinoma.

TMB-H (tissue agnostic)

• 2022-02-25: New indication for the treatment of advanced or recurrent solid tumors with tumor mutation burden-high (TMB-high) that have progressed after cancer chemotherapy (for use only if refractory or intolerant to standard therapies).

Also known as

• Code names: MK-3475, SCH 900475
• Generic names: lambrolizumab
• Brand name: Keytruda