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.

Diseases for which it is used

• Bladder cancer
• Cervical cancer
• Colon cancer
• Cutaneous squamous cell carcinoma
• Endometrial cancer
• Esophageal cancer
  • Esophageal squamous cell carcinoma
• Gastric cancer
• Head and neck squamous cell carcinoma
• Hepatocellular carcinoma
• Hodgkin lymphoma
• Melanoma
• Merkel cell carcinoma
• MSI-H or dMMR solid tumors (tissue-agnostic)
• Non-small cell lung cancer
• Primary mediastinal B-cell lymphoma
• Renal cell carcinoma
• 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 indication

Dosing

• 4/28/2020: FDA accelerated approval to a new "dosage of 400 mg every 6 weeks for all approved adult indications."

Bladder cancer

• 5/18/2017: 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)
• 5/18/2017: 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)
  • 8/31/2021: Converted to regular approval.
• 6/19/2018: 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 ≥ 10). (Biomarker restriction; based on KEYNOTE-361)
• 6/19/2018: 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)
• 1/8/2020: 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

• 6/12/2018: Accelerated approval for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. (New disease indication; based on KEYNOTE-158)
• 10/13/2021: Approved in combination with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) (Based on KEYNOTE-826)

Classical Hodgkin lymphoma (cHL)

• 3/14/2017: Accelerated approval for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or those who have relapsed after three or more prior lines of therapy. (New disease indication; based on KEYNOTE-087)
  • 4/30/2020: Converted to regular approval.
• 10/15/2020: FDA extended approval for the treatment of: "adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) and pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy." (Approval extended to third-line setting; based on KEYNOTE-204)

Colorectal cancer

• 5/23/2017: 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)
• 6/29/2020: Approved for the first-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. (Converted to regular approval; expanded to first-line setting; based on KEYNOTE-177)

Cutaneous squamous cell carcinoma

• 6/24/2020: 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

• 9/17/2019: 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)
• 7/21/2021: 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)

Esophageal cancer

• 7/30/2019: 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] ≥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)
• 3/22/2021: 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

• 9/22/2017: 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.
• 5/5/2021: 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

• 8/5/2016: 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)
• 6/10/2019: 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 and as a single agent for patients whose tumors express PD‑L1 (Combined Positive Score [CPS] ≥1) (Approval extended to first-line setting; based on KEYNOTE-048)

Hepatocellular carcinoma

• 11/9/2018: Accelerated approval for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. (New disease indication; based on KEYNOTE-224)

Melanoma

• 9/4/2014: Initial accelerated approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Based on KEYNOTE-002)
  • If BRAF V600 mutation positive, a BRAF inhibitor.
• 12/18/2015: Label expanded for the treatment of patients with unresectable or metastatic melanoma. (Requirement for progression removed; based on KEYNOTE-006)
• 2/15/2019: 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)
• 12/3/2021: Approved for the adjuvant treatment of adult and pediatric (≥12 years of age) patients with stage IIB or IIC melanoma following complete resection. (Based on KEYNOTE-716)

Merkel cell carcinoma

• 12/19/2018: 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)

• 5/23/2017: 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)
• 6/16/2020: FDA accelerated approval "for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥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." (based on KEYNOTE-158)

Non-small cell lung cancer

• 10/2/2015: 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. (New disease indication; based on KEYNOTE-010)
  • Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.
• 10/24/2016: Label expanded 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)
• 10/24/2016: Label expanded 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. (Indication with biomarker requirement; based on KEYNOTE-042)
  • Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.
• 5/10/2017: 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)
• 8/20/2018: 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)
• 10/30/2018: 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)
• 4/11/2019: 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)

Primary mediastinal B-cell lymphoma

• 6/13/2018: Accelerated approval for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after two or more prior lines of therapy. (New disease indication; based on KEYNOTE-170)
  • 10/14/2020: Converted to regular approval.

Renal cell carcinoma

• 4/19/2019: 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)
• 8/10/2021: Approved in combination with Lenvatinib (Lenvima) for first-line treatment of adult patients with advanced renal cell carcinoma (RCC). (Based on CLEAR)
• 11/17/2021: 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

• 6/17/2019: 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)
  • 3/30/2021: Approval withdrawn.

TMB-H (tissue agnostic)

• 6/16/2020: Accelerated approval for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB H) [≥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)

• 11/13/2020: 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 ≥10) as determined by an FDA approved test. (New disease indication; based on KEYNOTE-355)
• 7/26/2021: 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)
• 7/26/2021: Regular approval in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10) as determined by an FDA approved test. (Based on KEYNOTE-522)

History of changes in EMA indication

• 7/17/2015: Initial marketing authorization as Keytruda.

Also known as

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