Review article of immune checkpoint inhibitors in cancer patients

Lavanya

Clinical Pharmacist, Cantonment, Trichy, Tamil Nadu

Introduction

Immune checkpoints can be naturally occurring proteins in our immune cells (like T cells). It can prevent an immune system from becoming overactive and attacking the cancer cells. The cancer cells can spoil these checkpoints to evade detection and destruction by immune system. Immune checkpoint inhibitors are a type of cancer immunotherapy and it works by block the protein and helps to keep our immune system safe from attacking cancer cells. Mainly T cells can be responsible to recognize and destroy cancer cells.

Immune Checkpoint Inhibitor Drugs

  1. PD-1 (Programmed Death receptor-1) inhibitors
  • Target PD-1 protein on T cells
  • Drugs – Nivolumab, Pembrolizumab
  1. PDL-1 (Programmed Death Ligand-1) inhibitors:
  • Target PDL-1 protein on cancer cells
  • Drugs- Atezolizumab (withdraw this drug from US), Durvalumab, Avelumab
  1. CTLA-4 (Cytotoxic T-Lymphocyte Associated protein-4) inhibitors:
  • Target CTLA-4 protein on T cells
  • Drugs- Ipilimumab, Tremelimumab

 I. Nivolumab Drug Profile

Injection Nivolumab was approved for medical use in US at 2014. It is made by using Chinese hamster ovary cells. It belongs to the class of PD-1 inhibitor.

Indications: Used for the treatment metastatic melanoma, used in combination with Ipilimumab can be used for non-small cell lung cancer, malignant pleural mesothioma, renal cell carcinoma, classical Hodgkin’s lymphoma, head and neck cancer, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer.

Dosage forms and strengths: 40mg/4ml; 100mg/10ml; 120mg/12ml; 240mg/24ml.

Recommended dosage regimens

  • For adults: 240mg every 2 weeks (or) 480mg every 4 weeks.
  • For pediatrics: age around 12 years or older less than 40kg have to give a dose of 3mg/kg every 2 weeks or 6mg/kg every 4 weeks.

Dilution: Dilute the Injection Nivolumab with either 0.9% sodium chloride or 5% dextrose injection. The total volume of infusion does not exceed 160ml.

Storage: store in refrigerator at 2-8°C and protect from light. If not use diluted solutions discard within 7days from the time of preparation.

Warnings: Injection Nivolumab may cause immune mediated pneumonitis, immune mediated colitis, immune mediated hepatitis & Hepatomegaly, immune mediated endocrinopathies, immune mediated nephritis with renal dysfunction.

Monitoring parameters: Before and during Nivolumab therapy lab tests include CBC (Complete Blood Count) with differential & clinical chemistry, TFT (Thyroid Function Test), LFT (Liver Function Test) & endocrine panel, cardiac markers sucha as Troponin I &T.

II. Avelumab Drug Profile

Injection Avelumab was first approved from US FDA on March 23, 2017. This drug belongs to the class of PDL-1 inhibitor.

Indications: Used for the treatment of Merkel cell carcinoma (rare form of skin cancer). Now it was used for advanced or metastatic urothelial carcinoma and renal cell carcinoma.

Dosage forms and strengths: 200mg/10ml (20mg/ml). It is a clear, colorless solution in single vial.

Recommended dosage regimen

  • For Merkel cell carcinoma (MCC) and Urothelial Carcinoma (UC) – 800mg as IV infusion over 60 min every 2 weeks until disease progression or unacceptable toxicity.
  • For Renal Cell Carcinoma (RCC) – 800mg as IV infusion over 60 min every 2 weeks in combination with axitinib 5mg orally taken twice daily with or without food until disease progression or unacceptable toxicity.

Dilution

  • Premedicate with an antihistamine and acetaminophen 30-60 mins prior to each initial 4 infusion of avelumab. Because this drug may cause occurrence and severity of previous infusion reactions.
  • Injection Avelumab concentrate 20mg/ml can dilute in infusion bag containing 250ml of 0.45% (or) 0.9% sodium chloride injection. After that do not shake (or) discard any partially used vials. If undiluted solution should be cloudy or discolored or contains precipitated in vials that can be strictly prohibited and do not use that vials.

Storage: Store refrigerate at 2°–8°C and protect from light. Do not freeze (or) shake vials. If diluted solution, store room temperature upto 25°C for not more than 4 hours. If that diluted solution store in refrigerator for 24 hours can be applicable.

Warnings: This drug may cause immune mediated pneumonitis, immune mediated hepatitis, immune mediated colitis, immune mediated endocrinopathies.

Monitoring parameters: Monitor Lab test can be prior or during therapy to evaluate Thyroid function test, Glucose monitoring, renal function test, Liver function test and to monitor signs and symptoms to the patients (Eg., Pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, urticaria) during therapy. Based on severity dose reduction or interrupt or permanently discontinue to the patient.

III. Ipilimumab Drug Profile

Injection Ipilimumab was first discovered by Dr. James Allison. On March 25, 2011 US FDA approved this drug for the treatment of metastatic melanoma. It comes under the class of Cytotoxic T- Lymphocyte Antigen-4 blocking antibody.

Indications: Used for the treatment of metastatic melanoma, adjuvant melanoma with pathologic involvement for the regional lymph nodes of more than 1mm.

Dosage forms& strengths: 50mg/10ml (5mg/ml), 200mg/40ml (5mg/ml).

Recommended dosage regimens

For metastatic melanoma: 3mg/kg administered IV over 90 min every 3 weeks for a total of 4 doses.

For adjuvant melanoma – 10mg/kg administered IV over 90 min every 3 weeks for 4 doses followed by 10mg/kg every 12 weeks for up to 3 years or until disease recurrence or unacceptable toxicity. If may cause severe adverse reactions, permanently discontinue to this drug.

Dilution: Dilute with 0.9% sodium chloride injection or 5% dextrose injection and administer diluted solution over 90 mins through an IV line containing a sterile, non-pyrogenic, low protein- binding in line filter.

Storage: Allow the vials at room temperature for approximately 5 min prior to preparation. Store the diluted solution in refrigerator at 2–8°C for not more than 24 hr.

Warnings: This drug may cause Immune mediated hepatitis, Immune mediated endocrinopathies, Embryo fetal toxicity.

Monitoring parameters: Before given Ipilimumab injection to evaluate Liver function test, monitor clinical chemistries, ACTH level and Thyroid function test.

Conclusion

The best treatment option can be depending on individual patient specific conditions, and their specific type of cancer. Immune checkpoint inhibitors are the valuable tool for the treatment of various cancer cells. But it is not universally better treatment than the chemotherapy, radiation therapy. It is a highly effective treatment for some patients but not benefit same level of effectiveness for all patients. It have shown the success rate for the treatment of various cancers particularly melanoma, lung cancer, urothelial carcinoma but the effectiveness to each patient can varies.

Reference

  • Haanen JB, Robert C. Immune checkpoint inhibitors. Prog Tumor Res. 2015 Jan 1;42(2015):55-66.
  • Li B, Chan HL, Chen P. Immune checkpoint inhibitors: basics and challenges. Current medicinal chemistry. 2019 May 1;26(17):3009-25.
  • Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (keytruda). Human vaccines & immunotherapeutics. 2016 Nov 1;12(11):2777-89.
  • Akinleye A, Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. Journal of hematology & oncology. 2019 Sep 5;12(1):92.
  • Barbee MS, Ogunniyi A, Horvat TZ, Dang TO. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Annals of Pharmacotherapy. 2015 Aug;49(8):907-37.
  • Xu C, Chen YP, Du XJ, Liu JQ, Huang CL, Chen L, Zhou GQ, Li WF, Mao YP, Hsu C, Liu Q. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. Bmj. 2018 Nov 8;363.
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