Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody, that blocks binding of PD-1 (programmed cell death-1) to PD-L1 and PD-L2. Since PD-L1 is upregulated in some tumours, the blockade of these interactions can retrieve T-cell activity and cell-mediated immune response against these tumour cells. In July 2017, the US Food and Drug Administration (FDA) granted accelerated approval for nivolumab for the treatment of patients that are 12 years and older with DNA mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC), that have progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Currently, nivolumab is not approved for CRC in Europe.

The FDA approval is based on the CheckMate 142 study - a trial that is separated into two parts, one part investigating nivolumab monotherapy and the other nivolumab in combination with ipilimumab. The part of the study that is examined in the present report was conducted to assess the activity and safety of nivolumab monotherapy in 74 patients with metastatic dMMR/MSI-H CRC. At the time of data cut-off (3 January 2017) 23 (31.1%) of the 74 included patients demonstrated an objective response (OR) – all responses were partial (investigator-assessed). An OR assessed by blinded independent central review (BICR) occurred in 24 (32%) patients (dMMR/MSI-H per local assessment), out of those 2 (3%) patients had a complete response and 22 (30%) a partial one. After the occurence of 36 investigator-assessed progression events, the median progression-free survival (PFS) was 14.3 months, but was not mature at the time of data cut-off. In addition, median overall survival (OS) (23 deaths) had not been reached, at the time of the interim analysis. Regarding safety outcomes, drug-related adverse events (AEs) have occurred in 70% of patients, out of those 20% of patients had grade ≥3 AEs (most frequent: increased lipase and amylase). Serious AEs related to the study treatment of grade 3 or higher occurred in 12% of patients.

In conclusion, the treatment of nivolumab offers durable responses, 31.1% demonstrated partial responses with an acceptable safety profile at high costs. However, the immature OS data in combination with the lack of evidence for the actual patient population affected most by CRC in clinical practice highlight the requirement for long-term data. Moreover, head-to-head comparisons will be necessary to identify the best treatment option for CRC patients with dMMR/MSI-H. Ultimately, trustworthy biomarker testing will be needed to select those patients who benefit most from nivolumab.