Pembrolizumab (Keytruda) is the first checkpoint inhibitor drug that targets PD-1 and has been approved by the USFDA to treat metastatic melanoma under its Fast Track development programme.
PD-1 or programmed cell death protein-1, found on T cells, normally acts as a type of “off switch” that helps keep these immune cells from attacking other cells in the body. PD-1 attaches to PD-L1, a protein found on some normal and cancer cells. This interaction basically tells the T cell to leave the other cell alone and not attack it. Some cancer cells have large amounts of PD-L1, which helps them hide from immune system attacks.
Therapies that target either PD-1 or PD-L1 can stop these from attaching and prevent cancer cells from hiding.
Since its approval in 2014, pembrolizumab has been given the green light to treat a variety of cancers. Keytruda is currently the top-selling drug in the
PD-(L)1 class, with sales on track to hit $11 billion in 2019.
In 2015, the agency cleared pembrolizumab for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumours express PD-L1.
It may be used alone as a first-line treatment when the lung cancer has not spread outside (stage III) in patients who do not have an abnormal EGFR or ALK gene.
In July 2016, the US FDA accepted pembrolizumab for priority review as a first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) along with fluorouracil and a platinum-based chemotherapy.
The drug has also been indicated for recurrent classical Hodgkin’s lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL) in adults and children as well as for urothelial carcinoma.
The US regulator also gave approval to the PD-1 inhibitor to treat certain cancers originating due to microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumour in 2017.
Accelerated approval has been granted to the drug to treat patients with hepatocellular carcinoma (HCC).
In addition, US regulators gave their nod to use the drug for advanced gastric cancer, cervical cancer and Merkel cell carcinoma (MCC) in both adults and children.
It was granted an orphan drug designation for small cell lung cancer and accelerated approval for metastatic small cell lung cancer (SCLC) in 2019. Pembrolizumab, in combination with chemotherapy, staved off disease progression longer than chemo alone in patients with SCLC. But the immunotherapy didn’t appear to keep patients alive significantly longer.
At the same time, two competing checkpoint blockers — atezolizumab (Tecentriq), targeting PD-L1, and durvalumab (Imfinzi), a PD-1 inhibitor, demonstrated significantly delayed progression and death.
Again, in the same year, pembrolizumab was granted approval for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the oesophagus (ESCC) with a companion test for PD-1 detection.
In January 2020, pembrolizumab became the first PD-1/L1 inhibitor approved to treat patients with superficial, but high-risk non-muscle invasive bladder cancer (NMIBC) that is unresponsive to standard BCG treatment.
Merck, the innovator of pembrolizumab, presented data from KEYNOTE522 Phase III studies at Society for Medical Oncology (ESMO) 2019 Congress in Barcelona in Sept, showing that the use of a combination of the pembrolizumab and chemotherapy before surgery to remove early-stage, triple-negative breast cancer led to a better pathologic complete response than chemotherapy alone.
The efficacy of pembrolizumab is also being evaluated in combination with other agents or as a monotherapy for a wide range of cancers, including chronic myeloid leukaemia, desmoplastic melanoma, recurrent endometrial cancer, mesothelin-positive pleural mesothelioma, advanced uveal melanoma, paediatric lymphoma, myelodysplastic syndrome, malignant glioma with hypermutator phenotype, locally advanced cutaneous squamous cell carcinoma, recurrent/metastatic Epstein-Barr Virus-associated nasopharyngeal carcinoma, diffuse large B cell lymphoma, differentiated thyroid cancer, HER2-positive stage IV esophagogastric cancer, stage IV oestrogen receptor-positive breast cancer, early-stage oestrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+ / HER2-) breast cancer, recurrent glioblastoma, metastatic anal cancer, metastatic or advanced epithelial tumours, unresectable biliary tract carcinoma, ovarian epithelial, fallopian tube, or peritoneal cancers, multiple myeloma, resectable pancreatic cancer, metastatic neuroendocrine cancer, soft tissue sarcomas and recurrent high grade meningioma.