1. MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.
- Author
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Pignata S, Califano D, Lorusso D, Arenare L, Bartoletti M, De Giorgi U, Andreetta C, Pisano C, Scambia G, Lombardi D, Farolfi A, Cinieri S, Passarelli A, Salutari V, De Angelis C, Mignogna C, Priolo D, Capoluongo ED, Tamberi S, Scaglione GL, Arcangeli V, De Cecio R, Scognamiglio G, Greco F, Spina A, Turinetto M, Russo D, Carbone V, Casartelli C, Schettino C, and Perrone F
- Subjects
- Humans, Female, Middle Aged, Aged, Carboplatin administration & dosage, Carboplatin pharmacology, Carboplatin therapeutic use, Immunotherapy methods, PTEN Phosphohydrolase genetics, Adult, Progression-Free Survival, Biomarkers, Tumor genetics, Tumor Suppressor Protein p53 genetics, DNA-Binding Proteins genetics, High-Throughput Nucleotide Sequencing, Transcription Factors, Class I Phosphatidylinositol 3-Kinases, Antibodies, Monoclonal, Humanized therapeutic use, Endometrial Neoplasms drug therapy, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Microsatellite Instability, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Paclitaxel therapeutic use, Paclitaxel administration & dosage, Mutation
- Abstract
Background: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor., Patients and Methods: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab., Results: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002)., Conclusion: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2024
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