MITO END-3: efficacy of Avelumab immunotherapy according to molecular profiling in first line endometrial cancer therapy
Creators
- Sandro Pignata1
- Daniela Califano1
- Domenica Lorusso2
- Laura Arenare1
- Michele Bartoletti3
- Ugo De Giorgi4
- Claudia Andreetta5
- Carmela Pisano1
- Giovanni Scambia2
- Davide Lombardi3
- Alberto Farolfi4
- Saverio Cinieri6
- Anna Passarelli1
- Vanda Salutari7
- Carmine De Angelis8
- Chiara Mignogna1
- Domenico Priolo9
- Ettore Domenico Capoluongo10
- Stefano Tamberi11
- Giovanni Luca Scaglione12
- Valentina Arcangeli13
- Rossella De Cecio1
- Giosuè Scognamiglio1
- Filippo Greco14
- Anna Spina1
- Margherita Turinetto15
- Daniela Russo1
- Vittoria Carbone7
- Chiara Casartelli16
- Clorinda Schettino1
- Francesco Perrone1
- 1. Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples, Italy.
- 2. Gynecologic Oncology Unit, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy and Catholic University of Sacred Heart, Rome, Italy.
- 3. Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano 33081 (PN), Italy.
- 4. Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy
- 5. Dipartimento di Oncologia - ASU FC S. Maria della Misericordia -Udine.
- 6. U.O.C. Oncologia Medica - Ospedale Senatore Antonio Perrino, Brindisi, Italy.
- 7. Gynecologic Oncology Unit, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy.
- 8. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
- 9. Oncology Unit, S Vincenzo Hospital, Taormina, Italy.
- 10. Department of Molecular Medicine and Medical Biotechnology, Università degli Studi di Napoli Federico II and Azienda Ospedaliera per L'Emergenza, Cannizzaro, Catania, Italy. Naples, Italy
- 11. Oncology Unit, Santa Maria hospital, Ravenna AUSL Romagna, Italy.
- 12. Istituto Dermopatico Dell'Immacolata IDI-IRCSS, Rome, Italy.
- 13. UO Oncologia – Ospedale degli Infermi Rimini (RN), Italy.
- 14. Medical Oncology Unit, AULSS 9 Regione Veneto, Scaligera - Ospedale Generale Mater Salutis, Legnago, Italy
- 15. Department of Oncology, University of Turin, Ordine Mauriziano Hospital, 10128 Turin, Italy.
- 16. Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy.
Description
Immunotherapy combined to chemotherapy significantly improves progression free survival compared to first line chemotherapy alone in advanced endometrial cancer, with a much larger effect size in microsatellite-instability high (MSI-H) cases. New biomarkers might help to select patients that may have benefit among those with a microsatellite-stable (MSS) tumor.
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 (NGS) analysis and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA) there were 29 cases MSI-H, 26 MSS TP53 wild type (wt), 47 MSS TP53 mutated (mut), and one case with POLE mutation. Four mutated genes were present in more than 30 % of cases: TP53, PIK3CA, ARID1A, PTEN. Eleven patients (10 %) had a BRCA 1/2 mutation (5 in MSI-H and 6 in MSS). High TMB (≥ 10Muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53mut, and in no case in the MSS/TP53wt category. The effect of avelumab on progression-free survival (PFS) significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53mut (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, that was better in 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 poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced endometrial cancer.
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