On 21 January 2021, the European Commission amended the marketing authorisation granted for
pembrolizumab to include the first-line treatment of
microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic
colorectal cancer (mCRC) in adults. The recommended dose of
pembrolizumab was either 200 mg every 3 weeks or 400 mg every 6 weeks by
intravenous infusion.
Pembrolizumab was evaluated in a phase III, open-label, multicentre, randomised trial versus standard of care (SOC: FOLFOX6/FOLFIRI alone or in combination with
bevacizumab/
cetuximab) as first-line treatment of locally confirmed mismatch repair-deficient or
microsatellite instability-high stage IV CRC. Subjects randomised to the SOC arm had the option to crossover and receive
pembrolizumab once disease progressed. Both progression-free survival (PFS) and overall survival were primary endpoints.
Pembrolizumab showed a statistically significant improvement in PFS compared with SOC, with a hazard ratio of 0.60 [95% confidence interval (CI): 0.45-0.80], P = 0.0002. Median PFS was 16.5 (95% CI: 5.4-32.4) versus 8.2 (95% CI: 6.1-10.2) months for the
pembrolizumab versus SOC arms, respectively. The most frequent adverse events in patients receiving
pembrolizumab were diarrhoea,
fatigue,
pruritus,
nausea, increased
aspartate aminotransferase,
rash,
arthralgia, and
hypothyroidism. Having reviewed the data submitted, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) considered that the benefit-risk balance was positive. This is the first time the CHMP has issued an opinion for a target population defined by
DNA repair deficiency biomarkers. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union.