No abstract

Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.

BackgroundImmune checkpoint inhibitors (ICIs) have become a revolution in the treatment of many tumoral diseases, resulting in a significant increase in terms of life expectancy and quality of life.Despite these outstanding advances in long-life survival, a new spectrum of adverse events has been developed and is known to be one of the biggest challenges in clinical practice nowadays.Immune-mediated neurotoxicity stands out as a rather unusual complication, but its potentially lethal consequences make the characterization and right management of this adverse event a crucial issue in this field.MethodsThis is a retrospective study including all the cancer patients that have developed any neurological adverse event related to ICIs treatment, in a period of 4 years (from 2017 to 2020).Results13 patients were included in the study (8 were treated with antiPD-1/PD-L1 immunotherapy, 1 with antiCTLA-4 and 4 with the combination of both strategies). 4 patients developed generalized myasthenia gravis (GMG), 4 immune-mediated encephalitis (IME), 3 immune-related encephalopathy without radiological/analytical evidence of encephalitis, 1 mixed-polyneuropathy, and 1 polymyositis.3 patients with GMG were seropositive, 3 developed the clinical feature within the first 21 days of immunotherapy treatment and all of them received anti-PD-1/PD-L1 treatment. All patients with IME showed pleocytosis in cerebrospinal fluid, without any data in brain MRI.12 patients suspended ICIs treatment after the event and were treated with high doses of intravenous corticosteroids. Half of them required treatment with intravenous immunoglobulins. 10 showed total or partial resolution as clinical outcome. However, 4 patients passed away due to toxicity (2 with GMG). In severe cases that precise ICU admission, 4 out of 6 patients (66%) showed a spectacular clinical improvement with complete recovery after early treatment with high doses of methylprednisolone and intravenous immunoglobulins.ICIs withdrawal was sustained indefinitely in all patients, showing a progression-free survival at six-months of 50%. In patients with tumoral diseases that have an indication of treatment with ICIs, the PFS at 6 and 12 months stands at 66%.ConclusionsIn this series, the majority of neurotoxicity was related to anti-PD1/PD-L1 treatment, appearing in the first 21 days within the treatment. Most of the patients showed a favourable clinical outcome. In severe cases, an improvement in clinical features was objective after an early onset of treatment with high doses of intravenous corticosteroids and immunoglobulins.ICIs withdrawal did not suppose harm in terms of PFS in patients with tumoral types where ICIs are already indicated.