Background
Lung cancer accounts for 12.4% of all cancer diagnosis and contributes to 17.6% of all cancer deaths, posing a worldwide health crisis. It is more prevalent in men than in women and originates in the respiratory epithelium [1]. Pembrolizumab is a IgG4 kappa anti-PD1 antibody which is the choice of immunotherapy for metastatic Non-Small Cell Lung Cancer (NSCLC) with evidence of PD-L1 expression and has shown to increase the overall survival (OS) [2][3]. It is a part of the innovative 'immunotherapy' for cancer, and has raised the debate if it is more effective than chemotherapy (the conventional pharmacological intervention for all cancers). Unlike chemotherapy which directly destroys cancer cells, immunotherapy works by stimulating the immune system, to indirectly damage cancers. Additional indications of pembrolizumab include melanomas, urothelial carcinoma, and classical Hodgkin lymphoma, head and neck squamous cell carcinoma [4]. This review aims to assess the use of pembrolizumab in NSCLC by exploring the associated pathological and pharmacological parameters.
Disease
Smoking being the primary risk factor, NSCLC commonly manifests as chronic cough, haemoptysis, shortness of breath and weight loss [5]. After the initial diagnosis, treatment is determined by accurate staging of the cancer after a PET scan [6]. NSCLC is further divided into squamous, large cell and adenocarcinoma, with adenocarcinoma being the most common sub-type, as it makes up 75% of all lung cancer diagnosis in the United States. [7] Adenocarcinomas are associated with a mutation in the Kristen Rat Sarcoma Virus (KRAS) gene. KRAS is an oncogene, which, when mutated, causes cells to become cancerous. Mutated KRAS mice shows morphological changes in the mouse lung are reminiscent of the progression of NSCLC in humans.[8].
Molecular target
Programmed cell death protein (PD-1) is an immune checkpoint receptor expressed on the surface of activated T and B lymphocytes. PD-1 binds to PDL-1 expressed on self-cells, thereby supressing initiation of an immune response against the host’s own cells. However, some lung carcinomas also express PDL-1 on their surface, allowing them to appear as ‘self’, thereby avoiding destruction by lymphocytes. Pembrolizumab binds to the lymphocyte PD-1 receptors, preventing the PDL-1 of the cancer from binding, allowing the immune system to identify the cancer cells as foreign and launch an immune response against them [9].
Structure of the drug
To determine sufficient PD-1 blockade by pembrolizumab, an intermolecular interface comparison with the interaction of PD-1 with its natural ligand, PDL-1 is necessary.
Hydrophilic residues of PDL-1 form hydrogen bonds and salt bridges with the outer PD-1 residues. This information about the interaction of PD-1 with its natural ligand PDL-1 indicates that the epitope recognised with pembrolizumab resembles the residues in PD-1. Additionally, both PDL-1 and pembrolizumab form polar bonds with PD-1, but with different types and numbers of amino acids involved. This difference manifests as the dissociation constant (KD) for PD-1/PDL-1 being lower (8.2 uM) than PD-1/pembrolizumab (27 pM). This suggests a higher binding affinity between PD-1/PDL-1, owing to more polar interactions than in pembrolizumab/PD-1 [10]. IgG4 subtypes of antibodies are preferred for immunotherapy due to their selectivity. As they have low C1q and Fc affinity, they do not bind strongly to these regions. Activation of the Fc and C1q receptors is associated with the release of pro-inflammatory cytokines [11] [12] which can cause inflammation and cell damage. This property is perceived to be linked to the strained constant (Fc) region of pembrolizumab as IgG4 sub-class of antibodies have shorter and more compact hinge region. [12]
Pharmacokinetics
Pembrolizumab is not orally bioavailable owing to its large size, limited membrane permeability and peptide character making it susceptible to protease degradation [13] [14]. Therefore, it is given either intravenously (IV) or via subcutaneous (SC) injection. As with all IV administration, the bioavailability is 100%. A study examining the distribution of pembrolizumab administered patients with 5mg to the radiolabelled drug (89Zr-pembrolizumab), found high concentrations in the and tumour lesions in the lung, spleen, and lymph nodes [15]. IgG antibodies like pembrolizumab are eliminated via intracellular catabolism. After receptor-mediated endocytosis of pembrolizumab into the cell, lysosomal enzymes inside hydrolyse the antibody into amino acids. As pembrolizumab is cleared via this process, it does not rely on metabolism for its clearance [13] [14].
Adverse Events (AEs)
In an open label, phase 3 clinical trial, 305 patients with previously untreated NSCLC with PDL-1 expression were given either pembrolizumab or chemotherapy. It was found that 73.4% of the patients on pembrolizumab therapy experienced adverse events as compared to 90% in the chemotherapy group. The most common AEs being diarrhoea, fatigue, and pyrexia. However, immune related Adverse Events (ir-AEs) were observed exclusively with pembrolizumab i.e., arthralgia and pneumonitis [16]. A proposed mechanism is that there is an increased infiltration of lymphocytes in different organs, causing autoimmunity, thus ir-AEs. [17] However, a recent study shows that patients who developed ir-AEs had a significantly increased Progression Free Survival (PFS) than those who did not [18]. To assess the use of pembrolizumab in NSCLC, it is important to compare its benefits to that of chemotherapy, the classical treatment for all cancers. A study in which 500 patients had a PDL-1 tumour proportion score of 50% or greater were randomly assigned either pembrolizumab or chemotherapy. The study concluded that the Overall Survival (OS) of the pembrolizumab group was higher (80%) than that of the chemotherapy group (72%) [16].
Conclusion
To justify the use of pembrolizumab in lung cancer, the risks of use need to be weighed against the benefits. Pembrolizumab requires 50% of the tumour cells to express PDL-1 for it to be effective, which only 23-28% of patients express, limiting its accessibility, it is also associated with ir-AEs which are not seen in chemotherapy [16]. However, ir-AEs are linked to an increased PFS and its selective binding, better safety profile and higher OS rate than chemotherapy. Compared to cisplatin and carboplatin (chemotherapy) which rely on functioning kidneys for excretion, pembrolizumab is degraded intracellularly, which could mean that it can be given in patients with low Glomerular Filtration Rate (GFR), widening its accessibility. Pembrolizumab has also shown to be more cost-effective than platinum-based chemotherapy and shows an expected gain of 0.60 years of life, compared with 0.49 years of patients on chemotherapy [19]. Overall, pembrolizumab should be used in lung cancer, whether as combination, or monotherapy.
References
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Comparison of the structure of the pembrolizumab/PD-1 complex with the PD-L1/PD-1 complex. Horita S, Nomura Y, Sato Y, Shimamura T, Iwata S, Nomura N. High-resolution crystal structure of the therapeutic antibody pembrolizumab bound to the human PD-1. Sci Rep. 2016 Oct 13;6.
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