Continuing Education Activity

Pembrolizumab is a medication used in the management and treatment of various oncologic conditions. It is in the cancer immunotherapy class of drugs. This activity will highlight pembrolizumab's mechanism of action, indications, adverse event profile, and other key factors (e.g., non-approved indications currently in clinical trials, administration, dosing, monitoring, and relevant interactions) pertinent for members of the interprofessional team in the management of patients with advanced cancers.

Objectives:

• Identify the indications for pembrolizumab.
• Summarize the mechanism of action pembrolizumab.
• Explain the importance of monitoring for patients on pembrolizumab, including immune-mediated adverse events.
• Outline the importance of collaboration and coordination among the interprofessional team when dosing and monitoring pembrolizumab immunotherapy to improve patient outcomes with advanced cancers.

Indications

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)

Melanoma

• Unresectable or metastatic melanoma
  • In an advanced melanoma population naive to ipilimumab therapy, median overall survival was not reached in two different pembrolizumab doses (every two weeks, every three weeks dosing) as compared to ipilimumab alone at 16.0 months (hazard ratio = 0.68, p<0.001) at a median follow-up of 22.9 months.[1]
  • In previously treated, ipilimumab refractory, advanced melanoma, treatment with pembrolizumab resulted in overall survival of 13.4 months (2 mg/kg dose) and 14.7 months (10 mg/kg dose) as compared to investigator choice chemotherapy at 11.0 months (results were not statistically significant) at a median follow-up of 28 months.[2] 

• Adjuvant therapy following complete resection of lymph node involved melanoma.
  • In patients with completely resected stage III melanoma, pembrolizumab showed a recurrence-free survival of 75.4% vs. placebo of 61.0% (hazard ratio=0.57, p<0.001) at a median follow-up of 15 months.[3] 

Non-Small Cell Lung Cancer (NSCLC)

• First-line metastatic non-squamous NSCLC without EGFR/ALK tumor abnormality in combination with platinum chemotherapy and pemetrexed.
  • In patients with metastatic non-squamous NSCLC, first-line treatment of pembrolizumab plus chemotherapy (pemetrexed and carboplatin or cisplatin) showed a median progression-free survival of 8.8 months as compared to 4.9 months from chemotherapy alone (p<0.001) with a median follow up of 10.5 months.[4]

• First-line metastatic squamous NSCLC with paclitaxel (or paclitaxel protein-bound) and carboplatin
  • In patients with metastatic squamous NSCLC, first-line treatment of pembrolizumab plus chemotherapy (carboplatin plus paclitaxel or nanoparticle albumin-bound paclitaxel) showed a median overall survival of 15.9 months as compared to 11.3 months for chemotherapy alone (p<0.001) with a median follow up of 7.8 months.[5] 

• First-line single-agent use for nonresectable or metastatic NSCLC without EGFR/ALK tumor abnormality with tumor PD-L1 expression greater than 1%.
  • In patients with previously untreated advanced NSCLC with a PD-1 score greater than 50%, first-line treatment of single-agent pembrolizumab showed a median overall survival of 30.0 months as compared to chemotherapy (investigator’s choice platinum-based regimen) control arm of 14.2 months(hazard ratio = 0.63), with a median follow up of 25.2 months.[6] 

• Single-agent use for metastatic NSCLC with tumor PD-L1 expression greater than 1% who have progressed after platinum-based chemotherapy. (EGFR/ALK tumor abnormality patients with progression after targeted therapy for their respective tumor abnormality).
  • In patients with previously treated, advanced NSCLC with a PD-1 score greater than 50%, subsequent treatment with pembrolizumab (10mg/kg) showed a median survival of 17.3 months as compared to the docetaxel arm of 8.2 months (p<0.0001).[7] 

Head and Neck Squamous Cell Carcinoma (HNSCC)

• First-line metastatic or unresectable/recurrent HNSCC in combination with FU and platinum.
  • In patients previously untreated for locally incurable recurrent or metastatic head and neck cancer, treatment with pembrolizumab plus chemotherapy (cisplatin or carboplatin/5-FU) resulted in median overall survival of 13.0 months as compared to cetuximab plus chemotherapy(cisplatin or carboplatin/5-FU) of 10.7 months.[8]

• First-line single-agent use in metastatic or unresectable/recurrent HNSCC with tumor PD-L1 expression greater than 1%.

• Single-agent recurrent or metastatic HNSCC with progression after platinum-based chemotherapy
  • In patients with previously treated advanced head and neck squamous cell carcinoma, a single-arm study showed that treatment with pembrolizumab resulted in an 18% objective response rate; overall survival was 38% at 12 months (after a median follow up of 9 months).[9] 

Renal Cell Carcinoma (RCC)

• First-line advanced RCC in combination with axitinib
  • In patients previously untreated for advanced clear-cell renal cell carcinoma, treatment with pembrolizumab plus axitinib resulted in a 12-month survival rate of 89.9% compared to treatment with sunitinib at 78.3% (p<0.0001) at a median follow-up of 12.8 months.[10] 

Urothelial Carcinoma

• Locally advanced or metastatic urothelial carcinoma who have progressed on platinum-based chemotherapy

• Locally advanced or metastatic urothelial carcinoma within 12 months of neoadjuvant/adjuvant platinum-based chemotherapy.
  • In patients with previously treated advanced urothelial cancer, treatment with pembrolizumab resulted in a median one-year survival rate of 44.2% compared to 29.8% for chemotherapy (paclitaxel or docetaxel or vinflunine) alone. The median two-year survival rate was 26.9% for pembrolizumab compared to 11.0% for chemotherapy alone (at a median follow-up of 27.7 months).[11] 

FDA-approved indications under accelerated approval (with clinical trial summaries):

Classical Hodgkin Lymphoma (cHL)

• Refractory cHL for pediatric and adult patients who have relapsed after three or more treatments
  • In patients with relapsed/refractory classical Hodgkin lymphoma, pembrolizumab monotherapy resulted in a 69.9% objective response rate and a complete response rate of 22.5% at a median follow-up of 13 treatment cycles.[12]  

Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

• Refractory PMBCL for pediatric and adults who have relapsed after two or more treatments
  • In patients with relapsed/refractory Primary Mediastinal Large B-cell lymphoma, pembrolizumab treatment resulted in a 41% objective response rate and a 12-month overall survival rate of 62% after a median follow-up of 6.6 months.[13] 

 Urothelial Carcinoma

• Locally advanced or metastatic urothelial carcinoma with tumor expression PD-L1 of greater than 10%, ineligible for cisplatin-containing chemotherapy.
  • In patients with advanced urothelial carcinoma who were ineligible for cisplatin, treatment with pembrolizumab resulted in a 29% objective response rate and a median follow-up of 7.8 months.[14] 

• Locally advanced or metastatic urothelial carcinoma not eligible for any platinum-based chemotherapy

Microsatellite Instability-High (MSI-H) Cancer

• Previously treated adult and pediatric unresectable or metastatic MSI-H solid tumors with no remaining alternative treatments.

• Adult and pediatric unresectable or metastatic MSI-H colorectal cancer following treatment with irinotecan, oxaliplatin, and fluoropyrimidine
  • In patients with previously treated microsatellite instability-high colorectal cancer, treatment with pembrolizumab resulted in a 32% objective response rate, a 4.1 month PFS and a 76% 12-month overall survival rate after a median follow-up of 12.6 months.[15] 

Gastric Cancer

• Locally advanced, metastatic gastric or gastroesophageal junction adenocarcinoma with tumor PD-L1 expression greater than 1% with disease progression after at least two lines of therapy, including platinum or fluoropyrimidine chemotherapy (and HER2/neu targeted therapy, if appropriate)
  • In patients with previously treated gastric and gastroesophageal junction cancer, treatment with pembrolizumab resulted in an 11.6% objective response rate at a median follow-up of 5.8 months.[16] 

Cervical Cancer

• Metastatic or recurrent cervical cancer, following chemotherapy, with tumor expression of PD-L1 greater than 1%.
  • In patients previously treated for advanced cervical cancer, treatment with pembrolizumab resulted in an objective response rate of 12.2% at a median follow-up of 10.2 months.[17] 

Hepatocellular Carcinoma (HCC)

• HCC patients previously treated with sorafenib
  • In patients with previously treated hepatocellular carcinoma, treatment with pembrolizumab resulted in an objective response rate of 18% at a data cutoff of February 2018.[18] 

Merkel Cell Carcinoma (MCC)

• Pediatric and adult recurrent or locally advanced MCC.
  • In patients naive to systemic treatment for advanced Merkel cell carcinoma, treatment with pembrolizumab resulted in an objective response rate of 56% and 24-month overall survival of 68.7% at a median follow-up of 14.9 months.[19] 

Small Cell Lung Cancer (SCLC)

• Metastatic SCLC following platinum-based chemotherapy and at least one other therapy
  • In patients with previously treated advanced small cell lung cancer, treatment with pembrolizumab resulted in an 18.7% objective response rate and a median overall survival of 9.1months.[20]

Non-FDA approved indications in later-stage clinical trials

• Nasopharyngeal cancer
• Mesothelioma
• Liver cancer
• Esophageal cancer
• Cutaneous squamous cell carcinoma
• Colorectal cancer
• Breast cancer
• Prostate cancer
• Ovarian cancer

Mechanism of Action

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.[21] Certain types of tumors have a high expression of PD-L1(programmed death receptor ligand-1).[22] 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.[23] 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.[23][24]

Administration

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).[25] For adverse events, withholding or discontinuing is recommended; dose reductions are not. The drug should be administered within 6 hours from the reconstitution time (24 hours if refrigerated) to minimize the chances of microbial growth.

Adverse Effects

Clinically significant adverse reactions include:

• Immune-mediated skin adverse reactions (exfoliative dermatitis, bullous pemphigoid, Stevens-Johnson syndrome, and toxic epidermal necrolysis)
• Immune-mediated endocrinopathies (thyroid disorders, type 1 diabetes, hypophysitis)
• Immune-mediated colitis
• Immune-mediated pneumonitis
• Immune-mediated hepatotoxicity/hepatitis
• Immune-mediated renal dysfunction and nephritis
• Infusion-related reactions (anaphylaxis and hypersensitivity)
• Other immune-mediated adverse reactions (Guillain-Barre syndrome, uveitis, myasthenia gravis, pancreatitis, sarcoidosis, vasculitis, hemolytic anemia, arthritis, myositis, and encephalitis)

Common Side effects that occurred in over 10% of clinical trial participants include:[13][14][17][26]

• Nervous system (headache)
• Musculoskeletal (back pain, arthralgia)
• Skin (vitiligo, rash, pruritus)
• Metabolism (decreased appetite, weight loss, hyponatremia)
• Respiratory (cough, dyspnea)
• General (fatigue, pyrexia, asthenia, influenza-like illness, peripheral edema
• Gastrointestinal (diarrhea, constipation, abdominal pain, nausea, vomiting)
• Endocrine (hypothyroidism, hyperthyroidism)
• Infections (pneumonia, urinary tract infection, upper respiratory tract infection)
• Cardiac (arrhythmias)
• Blood/lymphatic (anemia)
• Hepatobiliary (hepatoxicity, elevated liver function tests)
• Renal and urinary (hematuria, increase blood creatinine)

Contraindications

There are no contraindications for pembrolizumab.

Limitations of use:

• Pembrolizumab is not recommended in PMBCL (primary mediastinal large B-cell lymphoma) patients who require urgent cytoreductive therapy.
• Pembrolizumab’s safety and effectiveness in MSI-H central nervous system pediatric cancer have not been established as this population met the exclusion criteria from clinical trials.[27]

Monitoring

• Monitor for signs and symptoms of colitis, pneumonitis, hypophysitis, and suspected severe skin reactions.
• Monitor for renal function changes as a sign of immune-mediated nephritis.
• Monitor for liver function changes as a sign of immune-mediated hepatitis.
• Monitor for thyroid function changes as a sign of a thyroid disorder.
• Monitor for infusion reactions such as 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 important to monitor.[28] 
• Monitor for hyperglycemia as a sign of type-1 diabetics.
• Monitor for hepatic function changes when given in combination with axitinib as a sign of hepatotoxicity. In one study, alanine aminotransferase and aspartate aminotransferase increased by over 25% of pembrolizumab plus axitinib-treated patients.[10]   

Toxicity

• Pembrolizumab has the potential to cause fetal harm.[29] Females with the ability to become pregnant should receive counseling regarding the risks of fetal injury and using effective contraception.
• Animal studies have shown increased severity in certain types of infections, including M. tuberculosis, lymphocytic choriomeningitis virus, and hepatitis B virus.
• Pembrolizumab has not been the subject of testing for potential carcinogenicity or genotoxicity.
• Pembrolizumab has an elimination terminal half-life of 27 days.[30] 

Enhancing Healthcare Team Outcomes

Pembrolizumab is a relatively new biological agent, and even though it is 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.

Outcomes

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.[31] However, tumors that highly express PD-L1 would also be expected to evade the host’s immune system better, resulting in a worse prognosis.[32] 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.[33] 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.[33] 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.[34]

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%.[26] 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.[35] Beyond thoracic oncologists, it is also vital for other interprofessional healthcare team members (nurses, pharmacists, and other physicians) to keep up with all the newest developments. The pharmacist must carefully check the patient's medication record and 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 and 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 5]