Introduction
In the realm of oncology, severe side effects from immunotherapy have been observed as potential indicators of treatment effectiveness, particularly in dMMR/MSI digestive cancers. This conclusion stems from a comprehensive European multicenter study presented at the 2025 Francophone Days of Hepato-Gastroenterology and Digestive Oncology (JFHOD 2025).
Understanding dMMR/MSI Digestive Cancers
Approximately 10% of digestive cancers exhibit a dMMR/MSI tumor phenotype, characterized by microsatellite instability. These cancers are notably aggressive and often resistant to chemotherapy. However, they are highly sensitive to immunotherapy, with a three-year survival rate reaching 70% in metastatic stages, compared to about 10% with chemotherapy. The correlation between immunotherapy effectiveness and the occurrence of immune-mediated adverse effects is well-documented in several non-MSI/non-digestive cancers, such as hepatocellular carcinoma, melanoma, and non-small cell lung cancer.
The Study’s Objective and Methodology
The primary aim of the study was to assess the impact of severe immune-mediated adverse effects (grade ≥ 3) on the progression-free survival (PFS) of patients with dMMR/MSI digestive cancer. Conducted across 34 expert centers in France, Italy, Spain, the United States, and Belgium, the study involved 1,175 adult patients (median age 63.5 years) treated with either mono or dual immunotherapy from 2014 to 2023. Notably, 83% of these patients were diagnosed with colorectal cancer, while 17% had esogastric, pancreatic, small intestine tumors, or cholangiocarcinomas. At the initiation of immunotherapy, 94% had metastases, and 85% were diagnosed at stage 3/4.
Findings on Severe Immune-Mediated Adverse Effects
After a follow-up period of 34 months, 10% of patients developed grade 3, 4, or 5 immune-mediated adverse effects. The most common were digestive (33%, primarily colitis), hepatic (17%), and rheumatological (8%, notably arthritis), along with hypothyroidism and dermatitis. Among these patients, four experienced two grade 3 adverse effects, and five patients (4% of those included) died due to severe adverse effects such as hepatitis, myocarditis, pneumopathy, colitis, and acute graft rejection.
The median time to the onset of severe effects was 107 days. Corticosteroid treatment resolved 86% of these cases. Of the patients, 27% resumed immunotherapy, and among them, 56% experienced a recurrence of adverse effects. Recurrence rates upon resuming immunotherapy were 100% for initial cutaneous effects, 29% for colic, and 50% for hepatic effects.
Implications of Dual Immunotherapy
The study identified dual immunotherapy as the sole risk factor for grade ≥ 3 adverse effects, which, as expected, proved more effective than monotherapy. Severe side effects were associated with longer progression-free survival (not reached versus 43.3 months, p=0.002), a higher tumor response rate (48% versus 34%, p<0.0001), and, although not significant, better overall survival (median not reached versus 84.2 months, p=0.058).
Expert Insights and Recommendations
Dr. Charles Kauffmann from the University Hospital of Poitiers summarized the findings, emphasizing that progression-free survival is significantly better in patients who experienced severe immune-mediated adverse effects. Although overall survival was not significantly improved, the tumor response rate was higher. Consequently, resuming immunotherapy after a severe adverse effect is not recommended due to the durable clinical response and high risk of recurrence, unless tumor progression is observed, in which case chemotherapy should be considered.
Characteristics of dMMR/MSI Cancers and Immunotherapy Side Effects
dMMR/MSI cancers are marked by a significant lymphocytic infiltrate (CD8+ T cells) caused by immunogenic neo-peptides induced by microsatellite instability. However, this infiltrate can be ineffective due to the tumor’s expression of negative immune checkpoints (PD-L1 and/or B7), explaining the efficacy of immune checkpoint inhibitors. Nonetheless, immunotherapy can lead to autoimmune-like adverse effects affecting various organs, with no predictive factors identified.
Conclusion
The study highlights the complex relationship between severe side effects and the effectiveness of immunotherapy in dMMR/MSI digestive cancers. While severe adverse effects may indicate a more effective treatment response, they also pose significant risks, necessitating careful consideration in treatment planning.
🔗 **Fuente:** https://francais.medscape.com/voirarticle/3612747