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Carcinoma Gastrico Avanzato HER2+: per ENHERTU (trastuzumab deruxtecan) inizia lo studio testa-a-testa di fase 3 DESTINY-Gastric04

Il carcinoma gastrico è associato a una prognosi sfavorevole, in particolare se in stadio avanzato, con solo il 5-10% dei pazienti che sopravvive a 5 anni. Un carcinoma gastrico su cinque risulta HER2-positivo, ma dopo la progressione con terapia sistemica anti-HER2 di prima linea, le opzioni di trattamento di seconda linea sono limitate, e per questi pazienti sono necessarie nuove terapie anti-HER2. Parte oggi DESTINY- Gastric04, uno studio globale di Fase 3 con trastuzumab deruxtecan, l’anticorpo monoclonale coniugato di Daiichi Sankyo e Astrazeneca

Tokyo, Monaco e Basking Ridge, NJ – (8 luglio 2021) – Inizia oggi, con la somministrazione della terapia al primo paziente, DESTINY-Gastric04, uno studio globale di fase 3 che valuta la sicurezza e l'efficacia di ENHERTU® (trastuzumab deruxtecan), rispetto alla terapia costituita dall’associazione ramucirumab/paclitaxel in pazienti affetti da adenocarcinoma dello stomaco o della giunzione gastroesofagea HER2-positivo metastatico e/o non resecabile, che è progredito durante o dopo un regime terapeutico a base di trastuzumab.

Nel recente report dell’ASCO Clinical Cancer Advances 2021,  l’anticorpo monoclonale coniugato di Daiichi Sankyo e Astrazeneca ENHERTU, è stato definito come uno dei due progressi significativi nel contesto dell’ “Evoluzione Clinica dell’Anno: La profilazione molecolare che guida il progresso nei carcinomi gastrointestinali” (ASCO Clinical Advance of the Year: Molecular Profiling Driving Progress in GI Cancers), sulla base dei dati degli studi DESTINY-CRC01 e DESTINY-Gastric01.

Attualmente è in corso un ampio e completo programma di sviluppo per valutare l’efficacia e la sicurezza di ENHERTU in monoterapia per il trattamento di diversi tumori con espressione di HER2, inclusi i carcinomi della mammella, dello stomaco, del polmone e del colon-retto.

"Con il trial DESTINY-Gastric04 valuteremo se ENHERTU migliora la sopravvivenza rispetto ad un regime terapeutico in associazione che è comunemente usato come trattamento di seconda linea nel carcinoma gastrico metastatico HER2-positivo. - Spiega Gilles Gallant, BPharm, PhD, FOPQ, Vice Presidente Senior, e direttore Globale dello Sviluppo oncologico, del Dipartimento R&D di Daiichi Sankyo – I risultati di studi precedenti avevano portato in due regioni  all’approvazione di ENHERTU per il trattamento del carcinoma gastrico metastatico HER2-positivo, e siamo entusiasti di continuare la nostra ricerca su questa popolazione di pazienti per potenziare il nostro sforzo di offrire una nuova opzione di trattamento a sempre più persone nel mondo”.

Il carcinoma gastrico è associato a una prognosi sfavorevole, in particolare se in stadio avanzato, con solo il 5-10% dei pazienti che sopravvive a 5 anni. [i]  Un carcinoma gastrico su cinque risulta HER2-positivo tuttavia, dopo il trattamento con trastuzumab, è stata osservata una perdita di espressione di HER2 tra il 29 e il 69% dei tumori, suggerendo che con questo regime terapeutico una diminuzione dell'espressione di HER2 può portare a una progressione e può essere associata a scarsi risultati. [ii] [iii] [iv],[v],[vi]  Dopo che la malattia progredisce a seguito di terapia sistemica anti-HER2 di prima linea, le opzioni di trattamento di seconda linea sono limitate, e per questi pazienti sono necessarie nuove terapie anti-HER2.1, 7,8      

ENHERTU (Trastuzumab deruxtecan) è un anticorpo monoclonale coniugato (ADC) specifico per il recettore HER2. Realizzato con l’impiego della tecnologia DXd brevettata di Daiichi Sankyo, trastuzumab deruxtecan è l’ADC leader del portfolio oncologico di Daiichi Sankyo e il programma più avanzato nella piattaforma scientifica ADC di AstraZeneca. È costituito da un anticorpo monoclonale coniugato ad un inibitore della topoisomerasi I, un derivato exatecan, tramite un legame stabile e scindibile a base tetrapeptidica.

ENHERTU (5,4 mg /kg) è approvato negli Stati Uniti con valutazione accelerata, e in UE e in Giappone con autorizzazione condizionata, per il trattamento di pazienti adulte con carcinoma mammario HER2-positivo non resecabile o metastatico, le quali hanno ricevuto due o più precedenti regimi di trattamento anti-HER2. L’approvazione si basa sullo studio DESTINY-Breast01. ENHERTU (6,4 mg /kg) è anche approvato in U.S.A. e Giappone per il trattamento di pazienti adulti affetti da adenocarcinoma gastrico HER2-positivo localmente avanzato o adenocarcinoma della giunzione gastroesofagea, precedentemente trattati con regimi a base di trastuzumab. L’approvazione si basa sui risultati del trial DESTINY-Gastric01. ENHERTU è approvato negli USA con l’avvertenza per malattia polmonare interstiziale e tossicità embrio-fetale.

DESTINY- Gastric04 è uno studio globale di fase 3, in aperto, randomizzato, che valuta la sicurezza e l'efficacia di ENHERTU (6.4mg/kg) rispetto alla terapia in associazione di ramucirumab/paclitaxel in pazienti affetti da adenocarcinoma gastrico o della giunzione gastroesofagea HER2+positivo metastatico e/o non resecabile, con progressione della malattia durante o dopo un regime terapeutico contenente trastuzumab.

DESTINY-Gastric04 arruolerà circa 490 pazienti in diversi centri in Asia, Europa e Sud America. I pazienti saranno randomizzati a ricevere ENHERTU o ramucirumab/paclitaxel. L'endpoint primario di DESTINY-Gastric04 è la sopravvivenza globale. Gli endpoint secondari includono la sopravvivenza libera da progressione valutata dallo sperimentatore, il tasso di risposta obiettiva, la durata della risposta, il tasso di controllo della malattia, la sicurezza, la farmacocinetica e l'immunogenicità. Per ulteriori informazioni sulla sperimentazione, visita il sito ClinicalTrials.gov.

Riferimenti

References:

[1] Casamayor M, et al. Ecancermedicalscience. 2018;12:883.

[1] Zhao D, et al. J Hematol Oncol. 2019;12(1):50.

[1] Seo S, et al. Gastric Cancer. 2019;22(3):527-535.

[2] Kijima T, et al. Anticancer Res. 2020;40(1):75-80.

[3] Thuss-Patience PC, et al. Lancet Oncol. 2017;18(5):640-653.

[4] Satoh T, et al. J Clin Oncol. 2014;32(19):2039‐2049.

[5] Sung H, et al. CA: A Cancer Journal for Clinicians.

[6] WHO. International Agency of Cancer Research. Cancer Today. Accessed May 2021.

[7] Oditura M, et al. World J Gastroenterol. 2014 Feb 21;20(7):1635-49.

[8] SEER Cancer Stat Facts: Stomach Cancer. Accessed May 2021.

[9] Cancer Research UK. Stomach Cancer Survival Statistics. Accessed May 2021.