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pembrolizumab (Keytruda)

FDA-approved Sept. 2014 Indications: - cutaneous melanoma - stage 3 cutaneous melanoma [8] - benefit regardless of PD-L1 status [8] - recurrence 46% PD-L1(+), 53% PD-L1(-) [8] - treatment of cutaneous melanoma BRAF V600 mutation positive with or without previous treatment with ipilimumab (NICE) [1] - treatment of metastatic non-small cell lung carcinoma (NSCLC) regardless of programmed death ligand 1 (PD-L1) expression on tumor cells [2] - treatment of metastatic head & neck squamous cell carcinoma (HNSCC) or recurrent HNSCC with with disease progression on or after platinum-containing chemotherapy [3] - advanced urothelial carcinoma that has failed platinum-based chemotherapy [3,7] - treatment of any unresectable or metastatic solid tumor with microsatellite instability or mismatch repair deficiency [4] - PD-L1 positive advanced esophageal cancer [6] - partial response in 30% of patients - triple-negative breast cancer (HER2-, ER-, PR-) in combination with niraparib [11] - niraparib + pembrolizumab may elicit a durable response in refractory (platinum-resistant) ovarian cancer [11] - cervical cancer, gastric cancer, hepatocellular carcinoma, - Hodgkin's lymphoma, diffuse large B-cell lymphoma [13] - Merkel cell carcinoma (FDA-approved) - recurrent or metastatic cutaneous squamous cell carcinoma (FDA-approved) [14] Contraindications: - not approved for treatment of multiple myeloma [5] Dosage: - 10 mg/kg every 2 or 3 weeks (cutaneous melanoma) [1] - 200 mg every 3 weeks (NSCLC) [2] - up to 1 year duration for adjuvant chemotherapy after surgical resection of stage 3 cutaneous melanoma [10] - 35 cycles every 3 weeks ~ 2 years (NSCLC) - q6weeks infusion frequency approved (NSCLC) Adverse effects: - pneumonitis, hypothyroidism, arthralgia, vitiligo common with PD-1 inhibitors [13] - immune-mediated colitis, autoimmune hepatitis Mechanism of action: - blocks ligand activation of programmed cell death-1 receptor (PD-1 receptor) on activated T cells (PD-L1 inhibitor) Notes: - cost ~ $150,000/year (2014)

Interactions

drug adverse effects of checkpoint inhibitor(s)

General

checkpoint inhibitor; immune checkpoint inhibitor; PD-1/PD-L1 inhibitor antineoplastic monoclonal antibody

References

  1. Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015 Apr 19; [e-pub] PMID: 25891173 http://www.nejm.org/doi/full/10.1056/NEJMoa1503093 - Postow MA et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015 Apr 20 PMID: 25891304 http://www.nejm.org/doi/full/10.1056/NEJMoa1414428
  2. Chustecka Z Earthquake in Lung Cancer: Immunotherapy First-Line. Medscape. Oct 14, 2016. http://www.medscape.com/viewarticle/870289 - Reck M, Rodriguez-Abreu D, Robinson AG et al Pembrolizumab versus Chemotherapy for PD-L1-positive non-Small-Cell Lung Cancer. N Engl J Med. Oct 9, 2016 PMID: 27718847 http://www.nejm.org/doi/full/10.1056/NEJMoa1606774 - Elia J, Fairchild DG, Di Francesco L FDA Approves Pembrolizumab for Non-Small-Cell Lung Cancer Physician's First Watch, Oct 26, 2016 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - US Food and Drug Administration. October 2, 2015. FDA approves Keytruda for advanced non-small cell lung cancer. First drug approved in lung cancer patients whose tumors express PD-L1. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm - Phull H 'Exciting But Very Real Possibility of Metastatic NSCLC Becoming a Chronic Illness' Impressive 5-year OS outcomes in this study certainly point to promising forecast. MedPage Today. ASCO Reading Room. August 6, 2021 https://www.medpagetoday.com/reading-room/asco/lung-cancer/93925 - Pal S Keytruda in Advanced NSCLC -- Still on Target for Upping Long-Term Survival. Clinically meaningful 5-year results from the KEYNOTE-024 trial. MedPage Today. ASCO Reading Room. August 6, 2021 https://www.medpagetoday.com/asco/lung-cancer/93926
  3. Bellmunt A, de Wit R, Vaughn DJ et al Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376:1015-1026. March 16, 2017 PMID: 28212060 Free full text http://www.nejm.org/doi/full/10.1056/NEJMoa1613683
  4. Bankhead C FDA Breaks New Ground with Expanded Keytruda Indication - Pembrolizumab for genetic defect, not tumor type. MedPage Today. May 23, 2017 https://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/65530 - FDA News Release. May 23, 2017 FDA approves first cancer treatment for any solid tumor with a specific genetic feature. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm560167.htm - Lemery S, Keegan P, Pazdur R First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication. N Engl J Med 2017; 377:1409-1412. October 12, 2017 PMID: 29020592 http://www.nejm.org/doi/full/10.1056/NEJMp1709968
  5. FDA Safety Alert. Aug 31, 2017 Keytruda (pembrolizumab) in Patients with Multiple Myeloma: FDA Statement - Two Clinical Trials on Hold. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm574347.htm
  6. George J, Pembrolizumab Promising in Advanced Esophageal Cancer. 30% of PD-L1-positive patients achieve partial response in small study. MedPage Today. January 07, 2018 https://www.medpagetoday.com/hematologyoncology/othercancers/70332
  7. Bankhead C Survival Bump in Bladder Cancer with Keytruda. But no outcome advantage for Tecentriq in metastatic urothelial cancer. MedPage Today. Feb 11, 2018 https://www.medpagetoday.com/meetingcoverage/mgucs/71089 - Bellmunt J et al Two-year follow-up from the phase III KEYNOTE 045 trial of pembrolizumab vs investigators choice in recurrent, advanced urothelial cancer. Genitourinary Cancers Symposium (GUCS) 2018; Abstract 410.
  8. Castellino AM Adjuvant Pembrolizumab for Melanoma -- Approval Imminent? Medscape - Apr 16, 2018. https://www.medscape.com/viewarticle/895204
  9. HIGHLIGHTS OF KEYTRUDA PRESCRIBING INFORMATION. Oct 2016 http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf
  10. Eggermont AMM et al Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med 2018; 378:1789-1801. May 10, 2018 PMID: 29658430 Free full text https://www.nejm.org/doi/full/10.1056/NEJMoa1802357
  11. Fuerst ML with expert critique by Sumrall AL Advanced TNBC: 'Durable Activity' for Niraparib + Pembrolizumab. Also benefit for platinum-resistant/refractory ovarian cancer. MedPage Today. ASCO Reading Room 06.21.2018 https://www.medpagetoday.com/reading-room/asco/immunotherapy/73611
  12. Kuznar W with critique by Hermel D Pembrolizumab Approved in Merkel Cell Carcinoma: Higher Response Rates, Less Toxicity Compared With Chemotherapy. Accelerated approval for both adults and children with recurrent locally advanced or metastatic disease. MedPage Today. ASCO Reading Room 01.26.2019 https://www.medpagetoday.com/reading-room/asco/skin-cancer/77620
  13. Marin-Acevedo JA, Chirila RM, Dronca RS. Immune Checkpoint Inhibitor Toxicities. Mayo Clinic Proc. July 2019. 94(7):1321-1329 PMID: 31272574
  14. Worcester S Latest FDA Pembrolizumab Approval Expands Label to Cutaneous SCCs. Medscape - Jul 13, 2021 https://www.medscape.com/viewarticle/954715