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Programmed Cell Death-1 (PD-1) Pathway Checkpoint Inhibition: Immuno-oncology for Advanced Melanoma

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Pembrolizumab (KEYTRUDA) is an immunostimulatory monoclonal antibody that antagonizes the programmed cell death-1 (PD-1) receptor. The FDA granted accelerated approval to pembrolizumab in September 2014 for treatment of unresectable or metastatic melanoma in patients who were previously treated with ipilimumab.1

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MECHANISM OF ACTION

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Immune system response to foreign proteins, including tumor cells, is mediated by T-cells. Activation of the PD-1 checkpoint pathway in T-cells by PD-1 ligands (PD-L1/2) evokes a negative regulatory immune response, and inactivates T-cells. Tumor cells have exploited this pathway by presenting the PD-L1 ligand to attacking T-cells, shielding the tumor from T-cell-mediated destruction. Presentation of PD-L1 to activated T-cells results in T-cell exhaustion, allowing tumor cells to proliferate.2 Competitive binding of pembrolizumab to the PD-1 receptor on T-cells can restore anti-tumor immune function by blocking PD-1 checkpoint inhibition, otherwise mediated by PD-L1, and maintaining activation or re-activating the T-cell anti-tumor response (Figure 1).3

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The early immuno-oncology agent ipilimumab (YERVOY; Bristol-Myers Squibb), which gained FDA approval in 2011, blocks another T-cell receptor, called CTLA-4, which also evokes a negative regulatory T-cell response mediated by the B7 ligand on antigen presenting cells (APCs). These two agents act through independent mechanisms to exert the same effect. In fact, they may also cooperate to stimulate T-cell activation (Figure 1), essentially releasing the brakes on the immune system.

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KEY STRUCTURAL ELEMENTS

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Pembrolizumab (also known as lambrolizumab, MK-3475) is a high-affinity (KD = 29 pM), high potency (IC50 ~600 pM) humanized IgG4-kappa isotype antibody. This humanized antibody has a mouse variable region grafted onto a human antibody framework. Pembrolizumab has high affinity towards human and other primate PD-1 receptors, but no appreciable affinity for mouse or rat PD-1. This antibody structure also reduces toxicity arising from immunogenicity, thus preventing antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity.4

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EFFICACY

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This monoclonal antibody is the first PD-1 antagonist to receive FDA approval. In an expansion cohort from the phase I trial KEYNOTE-001 (NCT01295827), 178 patients with ipilimumab-refractory or advanced melanoma were enrolled and randomized to receive either 2 or 10 mg/kg pembrolizumab every three weeks. An update published in September 2014 on this expansion trial reported that of the 173 patients who received pembrolizumab, a similar overall response rate (ORR) of 26% was seen regardless of dose. Additionally, 1-year overall survival was 58% (2 mg/kg) and 63% (10 mg/kg) with a median progression-free survival (PFS) of 31 and 35 weeks for the 2 and 10 mg/kg groups, respectively.5 Although this cohort was heavily pretreated, an earlier dose-escalation study of ipilimumab-naïve and pretreated patients resulted in a 38% ORR and a median PFS for 135 patients of >7 months.3

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DOSE AND ADMINISTRATION

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Recommended dose and schedule for pembrolizumab is 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks.

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TOXICITY

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Serious adverse events associated with pembrolizumab include immune-mediated inflammations. Specifically, pneumonitis, colitis, hepatitis and hypophysitis have been observed. Thyroid-related morbidities (both hyper- and hypothyroidism) were present in 1.2% and 8.3% of a cohort of more than 400 patients on the KEYNOTE-001 study.3 Recommended amelioration of these off-target effects include administration of systemic corticosteroids for grade 2+ and withholding or discontinuing treatment following grade 3 or 4 level events. The most common related toxicities experienced by 20% of patients at the time of approval were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.6 An additional 10% of those treated experienced complications with infections or infestations (e.g., sepsis). Pembrolizumab is a pregnancy category D drug; it is predicted that this human IgG4 will cross the placenta and could potentially present fetal risk.6

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PHARMACOKINETICS

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Following a study of 479 patients receiving pembrolizumab from 1 to 10 mg/kg and either every 2 or every 3 weeks, the following pharmacokinetic properties are known. Population mean clearance was 0.22 L/day with an elimination half-life of 26 days. Pembrolizumab reached study-state concentrations after 18 weeks on an every-3-week schedule. Plasma concentrations of pembrolizumab increased according to increasing dose in the 2-10 mg/kg every-3-week regimen following evaluation of Cmax, Cmin, and AUCSS.6

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BREAKTHROUGH THERAPY DESIGNATION FOR PD-1 INHIBITORS

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In 2012, the US FDA passed the Safety and Innovation Act (FDASIA), which defined a breakthrough therapy drug as one which treats a serious or life-threatening disease or condition and has preliminary clinical evidence of improvement over existing therapies. The breakthrough therapy designation helps accelerate drugs with immediate clinical need through the approval process. It precedes and does not necessarily guarantee FDA approval.7,8 To date, two antibody-based PD-1 inhibitors have been granted breakthrough therapy designation. Pembrolizumab first received breakthrough for unresectable melanoma, for which it was eventually approved.1 Additionally, pembrolizumab received this designation for advanced non-small cell lung cancer, specifically for Epidermal Growth Factor Receptor (EGFR) mutation-negative, and Anaplastic Lymphoma Kinase (ALK) rearrangement-negative non-small cell lung cancer (NSCLC) whose disease has progressed on or following platinum-based chemotherapy.9 A second PD-1 inhibitor, nivolumab (BMX-936558, ONO-4538, OPDIVO Bristol Myers Squibb), has also received breakthrough designation for treatment of Hodgkin lymphoma patients following autologous stem cell transplant and brentuximab.10 Nivolumab is approved in Japan for treatment of unresectable melanoma.11

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THE FUTURE OF CHECKPOINT BLOCKADE THERAPY: BEYOND MELANOMA

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Both pembrolizumab and nivolumab are approved for treatment of unresectable melanoma (in the USA and Japan, respectively). PD-1 pathway inhibition has shown promising preliminary results in multiple other types of cancer, including Hodgkin lymphoma, and non-small cell lung cancer.12,13 Indeed, pembrolizumab has more than 20 industry-initiated trials under the KEYNOTE designation in both solid and liquid tumors (Table 1). Adding to the boon of promising data for the PD-1 checkpoint inhibitor antibodies, molecular profiling of patients has also led to the characterization of PD-1 ligands (PD-L1/2) as a clinically prognostic correlate.14,15 In one study of 20 relapsed Hodgkin lymphoma patients, focal copy number gains were seen in the PD-L1/2 genomic locus, which correlated with poor prognosis. These patients were treated with nivolumab, with an overall response rate of 87%.13 However, evidence is mounting that PD-L1 and PD-L2 not only interact with the PD-1 receptor, but also have activity toward the B7.1 receptor (Figure 1). Accordingly, multiple PD-L1-directed monoclonal antibodies are currently in clinical trials in addition to the initial PD-1 class of monoclonal antibodies (Table 2).

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Re-activation of the immune system through the PD-1 pathway checkpoint inhibition class of drugs, most notably pembrolizumab, is a notable departure from the myriad of targeted sub-cellular small molecule agents which have gained approval recently. Overall they hold much promise and are showing unprecedented efficacy in a wide spectrum of cancers, most of which are relapsed/refractory diseases. Transition to frontline therapy is currently being studied and with many agents in this class, head-to-head trials of PD-1 agents are also on the horizon.

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Reference(s) +
 1. United States Food and Drug Administration. Press Announcements - FDA approves Keytruda for advanced melanoma [WebContent]. [cited 2014 December 12]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412802.htm
 2. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer immunology, immunotherapy : CII. 2005 Apr;54(4):307-14.   [PubMed: 15599732]
 3. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. The New England journal of medicine. 2013 Jul 11;369(2):134-44.   [PubMed: 23724846]
 4. Iannone R. MK-3475 Pediatric Development Plan: Open Session Meeting on Optimizing the Development of Oncology and Hematology Drugs for Pediatric Use [cited 2014 December 16]. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM375645.pdf 
 5. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17.   [PubMed: 25034862]
 6. Merck. HIGHLIGHTS OF PRESCRIBING INFORMATION: KEYTRUDA 2014 [cited 2014 December 16]. Available from: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
 7. United States Food and Drug Administration. Frequently Asked Questions: Breakthrough Therapies [cited 2014 December 16]. Available from: http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/fdasia/ucm341027.htm 
 8. United States Food and Drug Administration. Fact Sheet: Breakthrough Therapies 2012 [cited 2014 December 16]. Available from: http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/fdasia/ucm329491.htm
 9. Merck. Merck Receives FDA Breakthrough Therapy Designation for KEYTRUDA® (pembrolizumab) in Advanced Non-Small Cell Lung Cancer Monday, October 27, 2014 [cited 2014 December 8]. Available from: http://www.mercknewsroom.com/news-release/oncology-newsroom/merck-receives-fda-breakthrough-therapy-designation-keytruda-pembroli
10. Bristol-Myers Squibb. Investigational PD-1 Immune Checkpoint Inhibitor Nivolumab Receives U.S. FDA Breakthrough Therapy Designation for Hodgkin Lymphoma Wednesday, May 14, 2014 [cited 2014 December 10]. Available from: http://news.bms.com/press-release/rd-news/investigational-pd-1-immune-checkpoint-inhibitor-nivolumab-receives-us-fda-bre
11. Carroll J. Anti-PD-1 cancer star nivolumab wins world's first regulatory approval July 7, 2014 [cited 2014 December 12]. Available from: http://www.fiercebiotech.com/story/anti-pd-1-cancer-star-nivolumab-wins-worlds-first-regulatory-approval/2014-07-07
12. Johnson DB, Rioth MJ, Horn L. Immune Checkpoint Inhibitors in NSCLC. Current treatment options in oncology. 2014 Dec;15(4):658-69.   [PubMed: 25096781]
13. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma. The New England journal of medicine. 2014 Dec 6.   [PubMed: 25482239]
14. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014 Oct 1;20(19):5064-74.   [PubMed: 24714771]
15. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014 Jun;28(6):1280-8.   [PubMed: 24270737]
16. Health USNIo. ClinicalTrials.gov [cited 2014 December 18]. Available from: https://clinicaltrials.gov/

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Graphic Jump Location

Figure 1 Mechanisms of action of approved T-cell-specific immuno-oncology agents ipilimumab and pembrolizumab, and other PD-1 or PD-L1 agents currently in clinical trials. When an antigen is presented to the T-cell, an immuno-stimulatory response (indicated as +++) is generated. This effect is enhanced by further interactions between the antigen-presenting cell’s (APC) B7.1 receptor and the T-cell CD28 receptor. However, additional immuno-inhibitory signals (indicated as ---) may also be transmitted through CTLA-4 on the T-cell. Blocking these inhibitory signals enhances T-cell-mediated tumor clearance. The newest class of inhibitors to enhance T-cell immune function is in the PD-1 pathway. Blocking signaling between PD-1 and PD-L1/2 can be achieved either by direct inhibition of the PD-1 receptor or by indirect inhibition of the PD-L1 cell surface ligand. PD-L1 has also been shown to interact with B7.1 on the T-cell. There is mounting evidence that PD-L2 is expressed on tumor cells and interaction of this ligand with PD-1 or B7.1 could be a path for future therapeutic development. MHC, major histocompatibility complex; TCR, T-cell receptor.

Table 1: Ongoing trials for pembrolizumab. +
Table Graphic Jump Location
Table 1: Ongoing trials for pembrolizumab.
Table 2: Selected PD-1 pathway monoclonal antibodies currently in clinical trials. +
Table Graphic Jump Location
Table 2: Selected PD-1 pathway monoclonal antibodies currently in clinical trials.

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