MITO END-3: Efficacy of Avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy

S Pignata; D Califano; D Lorusso; L Arenare; M Bartoletti; U De Giorgi; C Andreetta; C Pisano; G Scambia; D Lombardi; A Farolfi; S Cinieri; A Passarelli; V Salutari; C De Angelis; C Mignogna; D Priolo; E D Capoluongo; S Tamberi; G L Scaglione; V Arcangeli; R De Cecio; G Scognamiglio; F Greco; A Spina; M Turinetto; D Russo; V Carbone; C Casartelli; C Schettino; F Perrone

doi:10.1016/j.annonc.2024.04.007

MITO END-3: Efficacy of Avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy

Ann Oncol. 2024 May 2:S0923-7534(24)00128-5. doi: 10.1016/j.annonc.2024.04.007. Online ahead of print.

Authors

S Pignata¹, D Califano², D Lorusso³, L Arenare⁴, M Bartoletti⁵, U De Giorgi⁶, C Andreetta⁷, C Pisano⁸, G Scambia³, D Lombardi⁵, A Farolfi⁹, S Cinieri¹⁰, A Passarelli⁸, V Salutari¹¹, C De Angelis¹², C Mignogna¹³, D Priolo¹⁴, E D Capoluongo¹⁵, S Tamberi¹⁶, G L Scaglione¹⁷, V Arcangeli¹⁸, R De Cecio¹³, G Scognamiglio¹³, F Greco¹⁹, A Spina², M Turinetto²⁰, D Russo², V Carbone¹¹, C Casartelli²¹, C Schettino⁴, F Perrone⁴

Affiliations

¹ Uro-Gynecological Medical Oncology, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples, Italy. Electronic address: s.pignata@istitutotumori.na.it.
² Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples, Italy.
³ Gynecologic Oncology Unit, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy; Catholic University of Sacred Heart, Rome, Italy.
⁴ Clinical Trial Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples, Italy.
⁵ Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano 33081 (PN), Italy.
⁶ Dipartimento Oncologico, IRCCS Istituto Romagnolo per lo studio dei Tumori (IRST Dino Amadori, Meldola (FC).
⁷ Dipartimento di Oncologia - ASU FC S. Maria della Misericordia -Udine.
⁸ Uro-Gynecological Medical Oncology, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples, Italy.
⁹ Clinical and Experimental Oncology Unit, Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, IRCCS, Meldola, Italy.
¹⁰ U.O.C. Oncologia Medica - Ospedale Senatore Antonio Perrino, Brindisi, Italy.
¹¹ Gynecologic Oncology Unit, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy.
¹² Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
¹³ Division of Anatomic Pathology and Cytopathology. Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy.
¹⁴ Oncology Unit, S Vincenzo Hospital, Taormina, Italy.
¹⁵ Department of Molecular Medicine and Medical Biotechnology, Università degli Studi di Napoli Federico II, Naples, Italy; Azienda Ospedaliera per L'Emergenza, Cannizzaro, Catania, Italy.
¹⁶ Oncology Unit, Santa Maria hospital, Ravenna AUSL Romagna, Italy.
¹⁷ Istituto Dermopatico Dell'Immacolata IDI-IRCSS, Rome, Italy.
¹⁸ UO Oncologia - Ospedale degli Infermi Rimini (RN), Italy.
¹⁹ Medical Oncology Unit, AULSS 9 Regione Veneto, Scaligera - Ospedale Generale Mater Salutis, Legnago, Italy.
²⁰ Department of Oncology, University of Turin, Ordine Mauriziano Hospital, 10128 Turin, Italy.
²¹ Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy.

PMID: 38704093
DOI: 10.1016/j.annonc.2024.04.007

Abstract

Background: Immunotherapy combined with 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, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High TMB (≥10 Muts/Mb) was observed in all MSI-H patients, in four out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on progression-free survival 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 endometrial cancer.

Keywords: Avelumab; Cancer Genome Atlas; Chemotherapy; Endometrial Cancer; Next Generation Sequencing.