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 nonsignificant 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 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.
MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy / 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, E. D.; Tamberi, S.; Scaglione, G. L.; Arcangeli, V.; De Cecio, R.; Scognamiglio, G.; Greco, F.; Spina, A.; Turinetto, M.; Russo, D.; Carbone, V.; Casartelli, C.; Schettino, C.; Perrone, F.. - In: ANNALS OF ONCOLOGY. - ISSN 0923-7534. - 35:7(2024), pp. 667-676. [10.1016/j.annonc.2024.04.007]
MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy
Lombardi, D.;De Angelis, C.;Tamberi, S.;Casartelli, C.;
2024
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 nonsignificant 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 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.
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