Pembrolizumab

Active substance from the group of humanized monoclonal antibodies. Approved in the USA for the treatment of non-resectable or metastatic melanoma as a second-line treatment after therapy with ipilimumab or a BRAF inhibitor. 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.

Pembrolizumab is now used in:

• Renal cell carcinoma,
• colorectal carcinoma
• non-small cell lung cancer
• squamous cell carcinoma of the head and neck.

In June 2020, pembrolizumab was approved by the FDA for cutaneous squamous cell carcinoma (cSCC) as a monotherapy for the treatment of patients with recurrent or metastatic cSCC that cannot be cured by surgery or radiation, and this approval has now been extended: patients with locally advanced cSCC can now also be treated with pembrolizumab as a monotherapy in the USA.

The approval for "locally advanced cSCC" is based on the 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 recorded 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 antitumor and immunomodulatory properties. It blocks the binding of the ligands PD-L1 and PD-L2 to the PD-1 receptor (programmed death receptor) on T cells (see immune checkpoint inhibitors below). Tumor cells use this signaling pathway, also known as the checkpoint signaling pathway, to inhibit an immune response. Pembrolizumab binds as an antibody to the PD-1 receptor. This stimulates T-cell proliferation, cytokine production and the immune response against the cancer cells.

The half-life is 26 days.

In some patients who experienced tumor progression or hyperprogression during anti-PD-1 therapy, a loss-of-function mutation associated with resistance was detected. The mutations occurred in genes encoding the Janus kinases JAK1 and JAK2, which are linked to the interferon receptor. Another mutation was found in the gene encoding the antigen-presenting beta-2 microglobulin.

Fatigue, cough, nausea, itching, skin rash, lack of appetite, constipation, joint pain, diarrhea. Lichen planus pemphigoides and the eruptive occurrence of multiple keratoacanthomas have been described as further dermatological side effects of treatment with pembrolizumab (Schmidgen MI et all. 2017; Fradet M et al. 2019). Anemia, headaches, dizziness, dry eyes, dyspnea and dysgeusia are also common.

Furthermore, maculopapular, psoriasiform and 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 the USA in 2014 for malignant melanoma (^Keytruda®), as a second-line treatment.

Pembrolizumab is the third available PD-1 antibody alongside nivolumab and cemiplimab . However, its indication differs from that of the other two.

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