Pembrolizumab is an FDA approved monoclonal antibody directed against programmed cell death protein 1 (PD-1) and sold in the US. It initially received FDA accelerated approval for refractory, advanced melanoma in September 2014. Subsequently, it has received approval for the treatment of many other oncologic conditions, and many more are currently in clinical development.
FDA-approved indications (with clinical trial summaries)
Non-Small Cell Lung Cancer (NSCLC)
Head and Neck Squamous Cell Carcinoma (HNSCC)
Renal Cell Carcinoma (RCC)
FDA-approved indications under accelerated approval (with clinical trial summaries):
Classical Hodgkin Lymphoma (cHL)
Primary Mediastinal Large B-Cell Lymphoma (PMBCL)
Microsatellite Instability-High (MSI-H) Cancer
Hepatocellular Carcinoma (HCC)
Merkel Cell Carcinoma (MCC)
Small Cell Lung Cancer (SCLC)
Non-FDA approved indications in later-stage clinical trials
Pembrolizumab is a humanized monoclonal IgG4 kappa antibody directed against human cell surface PD-1 (programmed death receptor-1) on lymphocytes. The PD-1 receptor provides an important “immune checkpoint,” which helps prevent the immune system from attacking itself. Certain types of tumors have a high expression of PD-L1(programmed death receptor ligand-1). Other tumor types use adaptive immune resistance where they take the natural physiology of PD-L1 induction (protection of immune-mediated damage from infections) and adapt it towards anti-tumor responses. When PD-L1 engages with PD-1, the T-cell function becomes inhibited; pembrolizumab blocks the PD-1: PDL-1 complex formation allowing improved T-cell mediated killing.
Pembrolizumab is FDA approved for intravenous use. It comes in either a 50 mg lyophilized powder for reconstitution or a 25 mg/mL solution. The most common administration schedule is a 200 mg infusion given over 30 minutes every three weeks. Most monoclonal antibodies are dosed based on body size; however, studies have shown that pembrolizumab fixed-dosing provides adequate coverage and yields the advantage of reduced dosage errors, convenience, and less waste (for an expensive therapy). For adverse events, withholding or discontinuing is recommended, dose reductions are not. The drug should be administered within 6 hours from the time of reconstitution (24 hours if refrigerated) to minimize the chances of microbial growth.
Clinically significant adverse reactions include:
There are no contraindications for pembrolizumab.
Limitations of use:
Pembrolizumab is a relatively new biological agent, and even though effective, it does require close monitoring for safety; thus, besides the clinician who prescribes the agent, both the nurse and pharmacist are responsible for educating the patient on the potential side effects of the drug. Since some of the adverse effects are delayed-onset like colitis and hypophysitis, an outpatient oncology nurse should follow the patients. The clinician, nurse, and pharmacist team members should regularly check the renal and liver function. During IV administration, the drug is known to cause chills, fever, flushing, hypotension, hypoxemia, pruritis, rash, rigors, and wheezing. While checkpoint inhibitors have lower rates of infusion reaction than other monoclonal antibodies, it is still essential to monitor. More crucially, the drug may cause transient increases in blood glucose. Finally, because the drug can trigger an allergic reaction, the interprofessional team needs to have the necessary medications and equipment to counter it in the room.
PD-L1 expression levels and treatment decision making in NSCLC (Level 1).
Tumor-expressed PD-L1 has the potential to suppress immune system responses by downregulating anti-tumor lymphocyte activity upon binding PD-1. In theory, an antibody that can block this interaction should be an effective anti-cancer agent. In practice, clinical trials of pembrolizumab and other checkpoint inhibitors have shown meaningful responses in many oncology indications thus far. As a corollary, it would make sense that tumors that express the most PD-L1 would be the most susceptible to one of these antibodies. However, tumors that highly express PD-L1 would also be expected to evade better the host’s immune system resulting in a worse prognosis. Therefore, it is difficult to know who will benefit most from these new checkpoint inhibitors such as pembrolizumab, based on levels of PD-L1 expression.
In NSCLC, for example, Brody et al. conducted a large meta-analysis of thirty-five different clinical trials and showed many studies that linked higher PD-L1 expression with worse survival, but also several other studies that showed no such effect. Additionally, PD-L1 as a predictive biomarker for checkpoint inhibitor treatment effect showed better success in higher expressers in some studies, but also no association in several other studies. Consequently, although response and survival can correlate with PD-L1 expression, alternative methods are needed to stratify which specific patients are most likely to benefit.
The FDA recently changed the pembrolizumab NSCLC monotherapy approval label to include PD-L1 expressers greater than 1% (from greater than 50%). However, without adequate head-to-head studies, pembrolizumab may not provide optimal patient outcomes compared to other approved treatment options in patients with PD-L1 expression between 1 and 49%. Until better biomarkers and additional clinical trial data become available, it is unclear if the original label or the updated label is a better treatment regimen for these patients.
With the rapid developmental pace in the field of molecular therapeutics for lung cancer, treatment decisions are becoming more personalized and sophisticated. Therefore it will be of great importance to have support systems to help thoracic oncologists stay up-to-date. Beyond thoracic oncologists, it is also vital for other healthcare team-members (nurses, pharmacists, and other physicians) to keep up with all the newest developments as well. The pharmacist must carefully check the patient's medication record, as well as alert the other members of the team (nursing, clinicians) regarding the signs and symptoms of adverse events from pembrolizumab. Armed with this knowledge, nursing can do a much better job of monitoring the patient, as well as assessing treatment progress. With proper support and education, drugs such as pembrolizumab can be used safely and appropriately to maximize patient outcomes, but it will require an interprofessional effort on the part of the healthcare team. [Level V]
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