Introduction: This study evaluates the efficacy of immunotherapy with PD-1 inhibitors, such as pembrolizumab, in advanced cancers associated with defects in the DNA mismatch repair (dMMR) system and high microsatellite instability (MSI-H). Method: A systematic review was conducted using six databases (Medline (PubMed), Virtual Health Library (BVS/VHL), Cochrane, Scopus, Web of Science, and ScienceDirect) to identify articles related to the treatment of patients receiving pembrolizumab with MMR alterations. The search strategy included descriptors selected from the Medical Subject Headings (MeSH). The research was conducted from August 15 to September 15, 2024, and the results were managed using EndNote to remove duplicates. Articles were included if they provided full-text access, evaluated patients treated with pembrolizumab, and reported MMR alterations. Reviews, abstracts, studies involving non-human organisms, and unavailable articles were excluded. Data extraction followed a form developed by the authors, encompassing basic study information, patient characteristics, and therapy details, in accordance with the PRISMA protocol. Results: The review demonstrated that patients with dMMR or MSI-H tumors, especially those with colorectal cancer, exhibited significantly higher progression-free survival (PFS) compared to patients without these mutations. These patients also showed improved overall survival (OS), with some studies reporting an OS that was not reached during follow-up, reflecting the positive clinical impact of immunotherapy in these subgroups. In addition to genetic profiles, tumor mutational burden (TMB) emerged as an important factor influencing treatment response. Patients with high TMB, such as those with non-small cell lung cancer, tended to respond better to immunotherapy, regardless of the specific type of dMMR or MSI-H mutation. Discussion: The combination of therapies, such as pembrolizumab with enzalutamide for castration-resistant prostate cancer, was also analyzed and showed improved clinical outcomes, including prolonged survival. However, the response to immunotherapy was not uniform. Factors such as the tumor microenvironment, lymphocytic infiltration, and PDL1 expression influenced treatment efficacy. The continuation of immunotherapy for extended periods, such as up to two years, was noted as crucial for disease control, particularly in more aggressive cancers. In contrast, patients with low T-cell infiltration or tumors lacking specific mutations did not demonstrate the same clinical benefits. Conclusion: The heterogeneity of therapeutic responses among different cancer types suggests that personalized treatment based on molecular profiles is essential for optimizing outcomes. This study concludes that identifying biomarkers such as MSI-H and dMMR should be integrated into therapeutic strategies to improve patient selection and maximize the benefits of anti-PD-1 immunotherapy.
Garcia et al. (Tue,) studied this question.