Pembrolizumab

Active substance from the group of humanised monoclonal antibodies. Approved in the US for the treatment of non-resectable or metastatic melanoma as a second-line treatment after ipilimumab or BRAF inhibitor therapy. Pembrolizumab is an IgG4 kappa immunoglobulin that interacts with the PD-1 receptor on T cells (Eggermont et al. 2018).

The mechanism of action is not limited to one tumor entity, such as melanoma.

Meanwhile, pembrolizumab has been successfully used in:

• Renal cell carcinoma,
• colorectal carcinoma
• non-small cell bronchial carcinoma
• Squamous cell carcinoma of the head and neck.

Back in June 2020, pembrolizumab was granted approval by the FDA in cutaneous squamous cell carcinoma=(cSCC) - as a monotherapy to treat patients with recurrent or metastatic cSCC that is not curable by surgery or radiation.

This approval has since been expanded: now patients with locally advanced cSCC can also be treated with pembrolizumab as monotherapy in the US. The approval for "locally advanced cSCC" is based on data from the phase II KEYNOTE-629 trial (Grob JJ et al 2020). Patients received pembrolizumab 200 mg every three weeks for 24 months or until disease progression or unacceptable toxicity. The objective response rate (ORR) in the cohort of 54 patients with locally advanced cSCC was 50%, (95% confidence interval CI, 36-64) (n=54). A complete response rate was registered in 17% and a partial response rate in 33% of patients. 81% of responders responded to treatment for more than six months, and 37% had a response duration of more than 12 months (Grob JJ et al. 2020).

Pembrolizumab has antitumoral and immunomodulating properties. It blocks the binding of the ligands PD-L1 and PD-L2 to the PD-1 receptor (programmed death receptor) on T cells.

Tumour cells use this signalling pathway, also known as checkpoint signalling, to inhibit an immune response (checkpoint modifier).

Pembrolizumab binds to the PD-1 receptor as an antibody. This stimulates T-cell proliferation, cytokine formation and the immune response against the cancer cells.

The half-life is 26 days.

In some patients who were diagnosed with progression of the tumor under anti-PD-1 therapy, a functional loss mutation associated with the resistance could be detected. The mutations took place in genes encoding the Janus kinases JAK1 and JAK2 linked to the interferon receptor. Another mutation was found in the gene encoding the antigen-presenting beta-2 microglobulin.

Fatigue, cough, nausea, pruritus, skin rash, lack of appetite, constipation, joint pain, diarrhea. Lichen planus pemphigoides and eruptive occurrence of multiple keratoacanthomas have been described as additional dermatologic side effectswn of pembrolizumab therapy (Schmidgen MI et all. 2017; Fradet M et al. 2019). Anemia, headache, dizziness, dry eyes, dyspnea, and dysgeusia are also common.

Furthermore, maculopapular, psoriasiform, lichenoid, and, in rarer cases, autoimmune bullous exanthema (see Lichen ruber pemphigoides below) and vitiligo have been reported (Mueller KA et al. 2021).

Approved in 2014 in the USA for malignant melanoma (Keytruda®), as a second-choice treatment

1. Eggermont AMM et al (2018) Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789-1801.
2. Fradet M et al (2019) Multiple keratoacanthoma-like lesions in a patient treated with pembrolizumab. Acta Derm Venereol 99:1301-1302.
3. Grob JJ et al (2020) Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: A single-arm phase II trial (KEYNOTE-629). J Clin Oncol 38:2916-2925.
4. Hamid O. et al (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369: 134-144.
5. Mueller KA et al (2021) A case of severe nivolumab-induced lichen planus pemphigoides in a child with metastatic spitzoid melanoma. Pediatr Dermatol 40: 154-156.
6. Robert C et al (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109-1117.
7. Schmidgen MI et al (2017) Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma. J Dtsch Dermatol Ges 15:742-745.
8. Zaretsky JM et al (2016) Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med 375:819-829