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Pembrolizumab: The Nut Cracker

CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2020; 41(03): 393-396

DOI: DOI: 10.4103/ijmpo.ijmpo_37_20

Author : Gangothri Selvarajan

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

Publication History

Received: 01 February 2020

Accepted: 09 June 2020

Article published online:
28 June 2021

© 2020. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

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

Introduction

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

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

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

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

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

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>

Toxicities

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]

Type of malignancy

Clinical trial evidence

↑Improved, *Accelerated approval by FDA based on tumor response rate and durability of response. OS – Overall survival; PFS – Progressionfree survival; ORR – Overall response rate; DOR – Duration of response; NMIBC – Nonmuscle invasive bladder cancer; CIS – Carcinoma in situ; TPS – Tumor proportion score; SCT -stem cell transplant; HBV – Hepatitis B virus; HCV – Hepatitis C virus; FDA – Food and Drug Administration; BCG – Bacillus Calmette-Guérin; UC – Urothelial carcinoma; EGFR – Estimated glomerular filtration rate; ALK – Anaplastic lymphoma kinase

Unresectable or metastatic melanoma

KEYNOTE-001 and 006 (↑PFS/OS)

Melanoma - Adjuvant therapy

KEYNOTE-054 (↑RFS in stage III)

Metastatic NSCLC with no EGFR/ALK rearrangement - First-line therapy

KEYNOTE 024 (TPS≥50%)

KEYNOTE 042 (↑OS without chemo)

KEYNOTE189 (nonsquamous)

KEYNOTE 407 (squamous) (↑OS with chemo, TPS ≥1%)

Metastatic NSCLC - Single agent/second line

KEYNOTE 010 (TPS ≥1%), ↑DOR, OS and ORR

Locally advanced or metastatic UC progressed on platinum-based chemotherapy

KEYNOTE 045 (↑OS)

UC progressed <12>

*KEYNOTE 052 (↑ORR, DOR)

High-risk NMIBC BCG unresponsive CIS (cystectomy ineligible/unwilling)

*KEYNOTE 057 (single-arm trial) ↑ORR/CR and DOR

First line in advanced renal cell carcinoma with axitinib

KEYNOTE 426 (in first-line versus sunitinib) ↑PFS/OS

First line in recurrent/metastatic head and neck squamous cell carcinoma

KEYNOTE 058 (with chemo ↑OS)

Recurrent/metastatic head and neck squamous cell carcinoma as second line

KEYNOTE 048 (↑OS)

Recurrent locally advanced or unresectable IIIB or metastatic Merkel cell carcinoma without any prior therapy

*KEYNOTE017 (Phase II) (↑PFS, ORR, and DOR

Hepatocellular carcinoma progressed on or after treatment with sorafenib or

*KEYNOTE 224 (↑ORR and DOR) single-arm

intolerant to it

open-label study

It is indicated in HBV and HCV seropositive patients with Child-Pugh Class A liver impairment

Second line in recurrent or metastatic cervical carcinoma patients

*KEYNOTE 158 (↑ORR, DOR)

Recurrent or metastatic gastric and gastroesophageal adenocarcinomas progressed on

*KEYNOTE 059 (cohort 1 as a single agent)

or after ≥2 lines of therapy

(↑ORR, DOR)

Mismatch repair deficient (dMMR) solid tumors when unresectable or metastatic,

*KEYNOTE 16 and 164 (colorectal cancers)

progressed after prior treatment, make pembrolizumab a biomarker defined tumor

(↑ORR and DOR)

site -agnostic approval from FDA

*KEYNOTE 158 (noncolorectal) basket study

Hodgkin’s lymphoma - Refractory or relapsed after ≥3 lines of therapy

*KEYNOTE O87 Nonrandomized open-label trial

(including auto-SCT)

(↑ORR and DOR)

Primary mediastinal large B cell lymphoma - Refractory or relapsed after ≥2 lines of therapy

*KEYNOTE 170 (↑ORR and DOR)

Progression on ≥2 lines of therapy in small cell lung carcinoma

*KEYNOTE 158 cohort G (basket study) KEYNOTE 028 cohort C1 (↑ORR and DOR)
Table 2

Immune checkpoint inhibitor-related adverse events with immune checkpoint inhibitors depending on the site

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

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

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.

Conflict of Interest

There are no conflicts of interest.

References

  1. Oiseth SJ, Aziz MS. Cancer immunotherapy: A brief review of the history, possibilities, and challenges ahead. J Cancer Metastasis Treat 2017; 3: 250-61
  2. O'Donnell JS, Teng MWL, Smyth MJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol 2019; 16: 151-67
  3. Johnson DB, Peng C, Sosman JA. Nivolumab in melanoma: Latest evidence and clinical potential. Ther Adv Med Oncol 2015; 7: 97-106
  4. Borrie AE, Maleki Vareki S. T lymphocyte-based cancer immunotherapeutics. Int Rev Cell Mol Biol 2018; 341: 201-76
  5. 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
  6. 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
  7. 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
  8. ed">8 Heinzerling L, Goldinger SM. A review of serious adverse effects under treatment with checkpoint inhibitors. Curr Opin Oncol 2017; 29: 136-44
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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. Cancer s (Basel) 2019; 11: 11
  15. 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
  16. 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: 14
  17. 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
  18. Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò B. 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
  19. 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
  20. Marin-Acevedo JA, Chirila RM, Dronca RS. Immune checkpoint inhibitor toxicities. Mayo Clin Proc 2019; 94: 1321-9
  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
  22. Kennedy LB, Salama AK. A review of cancer immunotherapy toxicity. CA Cancer J Clin 2020; 70: 86-104
  23. 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
  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].

Address for correspondence

Dr. Gangothri Selvarajan
Department of Medical Oncology, Cancer Institute (WIA)
28, Sardar Patel Road, Adyar, Chennai - 600 036, Tamil Nadu
India   

Publication History

Received: 01 February 2020

Accepted: 09 June 2020

Article published online:
28 June 2021

© 2020. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

Site

Incidence (%)

IRAE – Immune checkpoint inhibitor-related adverse events; ICI – Immune checkpoint inhibitor

Dermatological

40-60

Gastrointestinal

5-10

Endocrine

6

<1>

Pulmonary

4-5

Neurologic

<5>

Fatigue

16-24

Hematologic

<1>

Renal

2

Ocular

<1>

Cardiac

<0>

References

  1. Oiseth SJ, Aziz MS. Cancer immunotherapy: A brief review of the history, possibilities, and challenges ahead. J Cancer Metastasis Treat 2017; 3: 250-61
  2. O'Donnell JS, Teng MWL, Smyth MJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol 2019; 16: 151-67
  3. Johnson DB, Peng C, Sosman JA. Nivolumab in melanoma: Latest evidence and clinical potential. Ther Adv Med Oncol 2015; 7: 97-106
  4. Borrie AE, Maleki Vareki S. T lymphocyte-based cancer immunotherapeutics. Int Rev Cell Mol Biol 2018; 341: 201-76
  5. 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
  6. 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
  7. 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
  8. ed">8 Heinzerling L, Goldinger SM. A review of serious adverse effects under treatment with checkpoint inhibitors. Curr Opin Oncol 2017; 29: 136-44
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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. Cancer s (Basel) 2019; 11: 11
  15. 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
  16. 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: 14
  17. 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
  18. Necchi A, Raggi D, Gallina A, Madison R, Colecchia M, Lucianò B. 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
  19. 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
  20. Marin-Acevedo JA, Chirila RM, Dronca RS. Immune checkpoint inhibitor toxicities. Mayo Clin Proc 2019; 94: 1321-9
  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
  22. Kennedy LB, Salama AK. A review of cancer immunotherapy toxicity. CA Cancer J Clin 2020; 70: 86-104
  23. 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
  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].

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