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Efficacy and safety of anti-PD-1 agents in patients with dMMR metastatic solid tumours: A retrospective, real-world study
Background
Immune checkpoint inhibitors (ICIs) have been a revolution in the treatment of solid tumours with a significant increase in overall survival rates. High microsatellite instability/mismatch repair deficiency status (MSI-H/dMMR) is considered the first predictive marker of efficacy for ICIs. MSI-H/dMMR, sporadic or hereditary condition, increase tumor immunogenicity with the generation of a high level of neoantigens, suggesting that immunotherapy could be an interesting approach. This condition, more frequently in colorectal cancer, may be present in other tumor types, like endometrial or gastric cancer. The aim of our study is to evaluate the efficacy and safety of treatment with anti-PD-1 agents in patients with dMMR metastatic solid tumours in a single centre.
Methods
Retrospective study including patients (p) with dMMR tumours treated with ICIs (pembrolizumab or nivolumab) in the University Healthcare Complex of Salamanca from January-2015 to February-2022. Variables related to the patient, the tumour (stage at diagnosis and genotyping of genes involved in dMMR) and treatment (schedules of treatment previously used, maximum response achieved and degree of adverse effects during immunotherapy treatment) were recorded and analyzed. Progression-free survival and overall survival were calculated using the Kaplan-Meier analysis method (SPSS v26).
Results
15p were included. Age (median): 76 years [27-82]. Male: 40%. Tumour distribution: colorectal cancer: 6p, small bowel cancer: 2p, gastric cancer: 2p, endometrial cancer: 2p, breast cancer: 1p, cholangiocarcinoma: 1p and pancreatic cancer: 1p. Stage IV at diagnosis: 5p (33.3%). In all cases we identified alterations in genes involved in the dMMR system: loss of MLH1 and PMS2 expression (53.3%) followed by MSH2 (-) and MSH6 (-) deficiency (26.7%). In 4p (26.7%) immunotherapy was used as first line of treatment for metastatic disease. In 11p (73.3%) immunotherapy was initiated after progression to at least 1 prior chemotherapy treatment. In terms of treatment efficacy: 10p (66.7%) had disease control defined as complete response; 3p (20%), partial response; 3p (20%) or stable disease; 4p (26.7%). Median progression-free survival was 7.23 months (95% CI, 0.0-19-36). With a median follow-up of 15 months, median overall survival had not been reached at the time of analysis. Treatment-related adverse events were identified in 9p (60%): pneumonitis, alterations in liver function and hepatitis, skin alterations, hypothyroidism, myalgia or asthenia. In 2 of them (13.3%) had grade 3-4 toxicity and led to definitive discontinuation of treatment.
Conclusions
Our findings confirm previous evidence. Immune checkpoint inhibitors are shown as a hopeful option in the dMMR tumours approach. They have an adequate safety profile with mostly mild immuno-related toxicity, although close monitoring and management of possible serious adverse effects is necessary.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
