Can Pembrolizumab or Nivolumab be efficiently used against colorectal cancers with defective mismatch repair and high index of microsatellite instability?

Patients with metastatic colorectal cancer (CRC) presenting defective mismatch repair (dMMR) and/or high index of microsatellite instability (MSI-H) are suitable candidates for immunotherapy with immune checkpoint inhibitors (ICIs), such as pembrolizumab and nivolumab. However, the use of these ICIs as neoadjuvant treatment for non-metastatic and metastatic CRCs with these specific molecular alterations is still controversial. Thus, this systematic review (PROSPERO CRD42021258676) evaluated the benefits, toxicity profile, and clinical outcomes of pembrolizumab and nivolumab as neoadjuvant therapy for CRC with dMMR and/or MSI-H. For this, MEDLINE, Scopus, Cochrane Library, and Science Direct databases were used. Twenty-five case reports and four randomized clinical trials were included, and the main outcomes analyzed were overall survival, progression-free survival, pathological response through RECIST 1.1, and the Eastern Cooperative Oncology Group (ECOG) performance status, respectively. In general, the evaluated studies were well conducted according to the assessment tools, and the evidence suggests that combinations of nivolumab plus ipilimumab were more effective to treat metastatic CRC with dMMR and/or MSI-H than nivolumab alone. Regarding pembrolizumab, clinical evidence demonstrated its safety and efficiency for patients with this subtype of CRC in metastatic and locally advanced stages. This review indicates therapeutic promising potential of ICIs for patients with dMMR and/or MSI-H CRCs. Additionally, alterations in PI3K and JAK pathways are important mechanisms of resistance and represent an opportunity for the development of new drugs. Therefore, molecular investigations should be performed to uncover causes of therapeutic failure.