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Indian Journal of Medical and Paediatric Oncology
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DRUG REVIEW
Year : 2020  |  Volume : 41  |  Issue : 3  |  Page : 393-396  

Pembrolizumab: The nut cracker


Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India

Date of Submission01-Feb-2020
Date of Decision14-May-2020
Date of Acceptance09-Jun-2020
Date of Web Publication27-Jun-2020

Correspondence Address:
Dr. Gangothri Selvarajan
Department of Medical Oncology, Cancer Institute (WIA), 28, Sardar Patel Road, Adyar, Chennai - 600 036, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmpo.ijmpo_37_20

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  Abstract 

Anti-programmed cell death-1 (PD-1)/PD ligand-1 immune checkpoint inhibitors (ICIs) are the newest class of drugs approved for various advanced cancers. Pembrolizumab, an anti-PD1 inhibitor, is approved for treating advanced-stage solid malignancies and refractory lymphomas. Recently, it has been approved as tumor agnostic therapy for microsatellite instability-high advanced-stage disease. In all these studies, pembrolizumab has shown dramatic efficacy with lesser Grade3/4 immune-related adverse events. Contemporarily, immunotherapy paved the way for diagnostic assays and immunotherapy-related response assessment criteria definitions. No published Indian experience with ICIs exists other than isolated case reports. This article aims to review on pembrolizumab mechanism, its indications, and safety. The description of other ICIs is beyond the scope of this review.

Keywords: Advanced stage solid cancers, immune checkpoint inhibitors, lymphomas, pembrolizumab


How to cite this article:
Selvarajan G. Pembrolizumab: The nut cracker. Indian J Med Paediatr Oncol 2020;41:393-6

How to cite this URL:
Selvarajan G. Pembrolizumab: The nut cracker. Indian J Med Paediatr Oncol [serial online] 2020 [cited 2020 Jul 2];41:393-6. Available from: http://www.ijmpo.org/text.asp?2020/41/3/393/288096


  Introduction Top


The ability of cancer cells to evade immunity is the eighth hallmark of cancer.[1] The tumor cells survive by nil antigen expression and higher immune checkpoint expression.[1],[2] Pembrolizumab, a monoclonal antibody, plays a vital role in boosting the cancer immunity cycle.


  Discovery Top


In 1891, William Coley reported long-term regression of inoperable cancers when Coley's toxin (heat-inactivated Streptococcus) was administered.[1] In 1959, the concept that the immune system has the capability of killing malignant cells evolved.[1] In 1992, Tasuku Honjo discovered that mutation in programmed cell death 1 (PD-1) augments T-cell activity and inhibits the hematogenous dissemination of cancer cells. This anti-PD1 character was named as immune checkpoint inhibition.[1],[2]

Phase I trials of the first anti-PD-1 antibody, nivolumab in advanced solid cancers, showed durable response rates.[3] Simultaneously, the promising results of pembrolizumab (anti-PD-1) in KEYNOTE-001 study among advanced melanoma cases with previous ipilimumab exposure cemented the role of immune checkpoint inhibitors (ICIs) in oncology.


  Mechanism of Action Top


PD-1 protein (or CD279) is primarily expressed on the surface of activated T-cells, myeloid cells, and B-cells. It has two ligands, programmed cell death ligand 1 (PD-L1) and PD-L2. PD-L1 is broadly expressed on various organs, while PD-L2 is restricted to dendritic cells, macrophages, B-cells, and T-helper 2 cells.[4] Cancer cells express both PD-L1 and PD-L2. Binding of PD-1 to PD-L1/L2 induces phosphorylation of PD-1 cytoplasmic immunoreceptor tyrosine-based inhibition motif recruiting SHP2 phosphatase. SHP2 then dephosphorylates the T-cell receptor, leading to a reduction of target cell killing.[4] Pembrolizumab (MK-3475, lambrolizumab) is a humanized IgG4 kappa monoclonal antibody against PD-1. By blocking PD-1, the signals mentioned above are suppressed, and apoptosis is induced in tumor cells.[4]

Pembrolizumab distribution and metabolism in the body are not well characterized, and neither is its drug interactions. Its terminal half-life is 26 days.[5] There are no dose modifications with renal or hepatic dysfunction. It has no carcinogenic or infertility effects. The drug crosses the placenta, and animal studies have demonstrated fetal harm. Hence, it is contraindicated in pregnancy, and contraception is advised. Similarly, breastfeeding is to be avoided.[6],[7] Contraindicated in autoimmune disease since it can induce a disease flare, and the autoimmune therapy might reduce its efficacy.[8]


  Uses Top


Approval by the US Food and Drug Administration (based on landmark trials)

The indications for pembrolizumab are incorporated in [Table 1].[9],[10],[11],[12],[13],[14]
Table 1: Food and Drug Administration-approved indications for pembrolizumab

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KEYNOTE 522 suggests that adding pembrolizumab to neoadjuvant chemotherapy is beneficial in stage II/III triple-negative breast cancer (pCR 64.8% vs. 51%).[15],[16],[17] In the PURE-01 study of muscle-invasive bladder cancer, pT0 rate was 37% and the pT1 rate was 55%, irrespective of variant histology.[18]

Drug Controller General of India and Central Drugs Standard Control Organization approval

Drug Controller General of India and Central Drugs Standard Control Organization have approved pembrolizumab in metastatic melanoma and the first/second-line treatment of nonsmall cell lung carcinoma as a single agent.


  Dose and Administration Instructions Top


The fixed (200 mg every 3 weeks) and weight-based (2 or 10 mg/kg) dosing demonstrates similar pharmacokinetic and toxicity profiles.[19]

Pembrolizumab, in solution or lyophilized powder, should be reconstituted with sterile water along the walls of the vial and by gentle swirl. Do not shake the vial. Discard the solution if discoloration and particulate matter. If so, discard it. Withdraw the required volume and transfer into an intravenous bag containing 0.9% sodium chloride injection USP or 5% dextrose injection USP. Mix by gentle inversion. Infuse the solution over 30 min. Store the reconstituted solution at room temperature for <6 h and under refrigeration (2°C–8°C) for < 24 h.


  Toxicities Top


ICI has demonstrated a wide range of immune-related adverse effects (irAEs) as listed in [Table 2]. Toxicities are a reflection of the drug regimen combined with it and varieties of malignancies treated.[20]
Table 2: Immune checkpoint inhibitor-related adverse events with immune checkpoint inhibitors depending on the site

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Fatal toxicities such as pneumonitis, infections, myocarditis, colitis, hemorrhagic/thrombotic, and neurologic toxicities have been reported.[21] Others such as Stevens–Johnson syndrome and toxic epidermal necrolysis and infusion-related reactions can be fatal. Hyper-acute graft-versus-host disease and hepatic veno-occlusive disease can occur post allogeneic stem cell transplant.[22],[23]

For Grade 1 toxicity, use oral prednisone 0.51 mg/kg/day.[22],[23] For any Grade 2, withhold ICI and give oral or intravenous prednisone 12 mg/kg/day based on symptoms. Discontinue ICI if > Grade 1 hypophysitis, pneumonitis, or sarcoidosis and if any Grade 3 or more toxicities. Depending on the grade of toxicity, wean off-steroids at 2–4 weeks if moderate or 4–8 weeks if severe and resume therapy when the adverse reaction remains at Grade 1 or less. Permanently discontinue ICI for grade 4 or any life-threatening adverse event. Infliximab, mycophenolate mofetil, tocilizumab as well as plasmapheresis or immunoglobulin may be considered in steroid-refractory cases. Consider rituximab or cyclophosphamide in case of hematologic toxicity.[22],[23]


  Take Home Top


The broad activity of pembrolizumab against various malignancies implies that immune escape is indeed a crucial step in cancer survival. The optimal duration of treatment is still unknown – whether 2 years or until progression. The Food and Drug Administration has accepted supplemental Biologics License Applications for 400 mg every 6 weeks dosing schedule for pembrolizumab across several indications. This dose schedule will be more convenient for patients.[24]

The cost of treatment with pembrolizumab varies from 2 to 10 lakhs (INR) per dose, depending on the schedule and patient body weight. irAEs will add to the cost of treatment. These events complicate the decision on the sequence of management.


  Conclusion Top


Many upcoming trials will highlight the role of ICIs in the era of targeted therapies. Translational research is needed to develop predictive biomarkers, elucidate the mechanisms of resistance, and formulate rational combined modality treatment. Although immuno-oncology is promising, there are still unanswered questions from curative point of view as well as in pediatric cancers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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O'Donnell JS, Teng MWL, Smyth MJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol 2019;16:151-67.  Back to cited text no. 2
    
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Johnson DB, Peng C, Sosman JA. Nivolumab in melanoma: Latest evidence and clinical potential. Ther Adv Med Oncol 2015;7:97-106.  Back to cited text no. 3
    
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Borrie AE, Maleki Vareki S. T lymphocyte-based cancer immunotherapeutics. Int Rev Cell Mol Biol 2018;341:201-76.  Back to cited text no. 4
    
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Duan J, Cui L, Zhao X, Bai H, Cai S, Wang G, et al. Use of immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 inhibitors in patients with cancer: A systematic review and meta-analysis. JAMA Oncol 2019;6:375-84.  Back to cited text no. 5
    
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Traila A, Dima D, Achimas-Cadariu P, Micu R. Fertility preservation in Hodgkin's lymphoma patients that undergo targeted molecular therapies: An important step forward from the chemotherapy era. Cancer Manag Res 2018;10:1517-26.  Back to cited text no. 6
    
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Ellinger I, Fuchs R. HFcRn-mediated transplacental immunoglobulin G transport: Protection of and threat to the human fetus and newborn. Wien Med Wochenschr 2012;162:207-13.  Back to cited text no. 7
    
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Heinzerling L, Goldinger SM. A review of serious adverse effects under treatment with checkpoint inhibitors. Curr Opin Oncol 2017;29:136-44.  Back to cited text no. 8
    
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Li Z, Song W, Rubinstein M, Liu D. Recent updates in cancer immunotherapy: A comprehensive review and perspective of the 2018 China cancer immunotherapy workshop in Beijing. J Hematol Oncol 2018;11:142.  Back to cited text no. 9
    
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Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II Keynote158 study. J Clin Oncol 2020;38:1-10.  Back to cited text no. 10
    
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Balar AV, Kulkarni GS, Uchio EM, Boormans J, Moure L, Krieger LEM, et al. Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG). J Clin Oncol. 2019;37:350.  Back to cited text no. 11
    
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Cohen EE, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer 2019;7:184.  Back to cited text no. 12
    
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Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116-27.  Back to cited text no. 13
    
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Li D, Sedano S, Allen R, Gong J, Cho M, Sharma S. Current treatment landscape for advanced hepatocellular carcinoma: Patient outcomes and the impact on quality of life. Cancers (Basel) 2019;11:11.  Back to cited text no. 14
    
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Nanda R, Liu MC, Yau C, Asare S, Hylton N, Veer LVT, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2. J Clin Oncol 2017;15 Suppl 35:506.  Back to cited text no. 15
    
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Loibl S, Untch M, Burchardi N, Huober JB, Blohmer JU, Grischke EM, et al. Randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab to a taxane-anthracycline containing chemotherapy in triple negative breast cancer (TNBC). J Clin Oncol 2018;15 Suppl 36:104.  Back to cited text no. 16
    
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Schmid P, Park Y, Muñoz-Couselo E, Kim S-B, Sohn J, Im SA, et al. Abstract PD5–01: KEYNOTE-173: Phase 1b multicohort study of pembrolizumab (Pembro) in combination with chemotherapy as neoadjuvant treatment for triple-negative breast cancer (TNBC). Cancer Res 2019;4 Suppl 79:PD5-01.  Back to cited text no. 17
    
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Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò R, et al. Updated results of PURE-01 with preliminary activity of neoadjuvant pembrolizumab in patients with muscle-invasive bladder carcinoma with variant histologies. Eur Urol 2020;77:439-46.  Back to cited text no. 18
    
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Abdel-Rahman O. Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: A systematic review. Immunotherapy 2016;8:1383-91.  Back to cited text no. 19
    
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Marin-Acevedo JA, Chirila RM, Dronca RS. Immune checkpoint inhibitor toxicities. Mayo Clin Proc 2019;94:1321-9.  Back to cited text no. 20
    
21.
Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal toxic effects associated with immune checkpoint inhibitors: A systematic review and meta-analysis. JAMA Oncol 2018;4:1721-8.  Back to cited text no. 21
    
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Kennedy LB, Salama AK. A review of cancer immunotherapy toxicity. CA Cancer J Clin 2020;70:86-104.  Back to cited text no. 22
    
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Trinh S, Le A, Gowani S, La-Beck NM. Management of immune-related adverse events associated with immune checkpoint inhibitor therapy: A minireview of current clinical guidelines. Asia Pac J Oncol Nurs 2019;6:154-60.  Back to cited text no. 23
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24.
FDA Accepts Merck's Supplemental Biologics License Applications for KEYTRUDA® (Pembrolizumab) Six-Week Dosing Schedule for Melanoma and Multiple Other Indications. Kenilworth, NJ: Merck; July 9, 2019. Available from: https://bit.ly/2xzRfnE. [Last accessed on 2019 Jul 09].  Back to cited text no. 24
    



 
 
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  In this article
   Abstract
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