On 30th March 2023, the FDA[1] granted full approval to pembrolizumab (Keytruda) for the treatment of adult and paediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumours.
This marks the first-ever FDA approval for immunotherapy based on a predictive biomarker (programmed cell death protein [1] – PD1), regardless of solid tumour type.
The programmed cell death protein[1] (PD1)[2] is one of the checkpoints that regulate the immune response. The expression of PD1 is an important mechanism contributing to the tumour cell’s ability to evade anti-tumour T-cell mediated immunity. Pembrolizumab[2] is a humanized monoclonal IgG4 kappa anti-PD1 antibody, with 100 mg given in IV forms over 30 minutes each time. The blockade of PD1 prevents T-cell PD1/tumour cell PDL[1] interaction, leading to restoration of T-cell mediated anti-tumour immunity.
Back in September 2014, FDA approved[3] the use of pembrolizumab for advanced melanoma. The list of FDA-approved indications [4] kept expanded in the past 8 years. Prior to the most recent approval, it has been approved by FDA for:
- Melanoma
- Cutaneous squamous cell carcinoma
- Non-small cell lung cancer
- Head and neck squamous cell cancer
- Urothelial carcinoma
- Certain types of colon and rectal cancer
- Oesophageal or certain gastroesophageal junction carcinoma
- Cervical cancer positive for PDL[1]
- Renal cell carcinoma
- Advanced endometrial carcinoma
- Triple-negative breast cancer
Over the years, pembrolizumab-related clinical trials are published in a series of KEYNOTE studies. In 2017[5], it was granted accelerated approval for the treatment of unresectable or MSI-H or dMMR solid tumours. The current conversion[1] to full approval is based on results from phase 2 KEYNOTE-051/158/164 trials which altogether cover 504 patients with more than 30 types of cancer.
The KEYNOTE-051[6] study demonstrated that pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. In KEYNOTE-158[7] study, 233 patients enrolled with 27 different tumour types. The data demonstrated that almost one-half of patients experienced 30% or greater reductions in tumour size from baseline. Patients with MSI-H/dMMR endometrial cancer had particularly positive outcomes, with 70% (33 of 47 with change from baseline data) experiencing a tumour size reduction of 30% or more. The KEYNOTE-164[8] study included 124 patients with MSI-H/dMMR CRC, which concluded that pembrolizumab is effective with a manageable safety profile in patients with this condition.
Despite the fact that clinical trials have demonstrated manageable safety profiles, the following side effects can occur and warranty immediate medical attention:
- Generalized discomfort: headache, extreme tiredness, polydipsia, tachycardia, feeling hot and cold etc
- Intestinal problems, diarrhoea, blood in stool, nausea and vomiting, abdominal pain
- Liver problems: jaundice, dark urine, bruising
- Kidney problems: reduced urine amount, blood in urine, peripheral swelling
- Skin problems: itch, rash, blister, etc
Patients are encouraged to see their prescriber immediately if the above symptoms or any other new onset symptoms occur after taking this medication.
Reference
- FDA Grants Full Approval to Pembrolizumab for MSI-H and dMMR Solid Tumors [Internet]. Targeted Oncology. 2023 [cited 2023 Apr 8]. Available from: https://www.targetedonc.com/view/fda-grants-full-approval-to-pembrolizumab-for-msi-h-and-dmmr-cancers
- Kwok G, Yau TCC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Human Vaccines & Immunotherapeutics [Internet]. 2016 Jul 11;12(11):2777–89. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137544/pdf/khvi-12-11-1199310.pdf
- Keytruda Approval History [Internet]. Drugs.com. Drugs.com; 2020. Available from: https://www.drugs.com/history/keytruda.html
- Results From Clinical Trials With KEYTRUDA® (pembrolizumab) [Internet]. www.keytruda.com. [cited 2023 Apr 8]. Available from: https://www.keytruda.com/clinical-trial-results/#indication
- Pembrolizumab Approved by the FDA for Microsatellite Instability-High and Mismatch Repair Deficient Cancers [Internet]. Targeted Oncology. [cited 2023 Apr 8]. Available from: https://www.targetedonc.com/view/pembrolizumab-approved-by-the-fda-for-microsatellite-instabilityhigh-and-mismatch-repair-deficient-cancers
- Geoerger B, Kang HJ, Yalon-Oren M, Marshall LV, Vezina C, Pappo A, et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1–2 trial. The Lancet Oncology. 2020 Jan;21(1):121–33.
- Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. Journal of Clinical Oncology. 2020 Jan 1;38(1):1–10.
- Le DT, Kim TW, Van Cutsem E, Geva R, Jäger D, Hara H, et al. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164. Journal of Clinical Oncology. 2020 Jan 1;38(1):11–9.
