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Personalized therapeutic strategies in HER2-driven gastric cancer

2021; Springer Science+Business Media; Volume: 24; Issue: 4 Linguagem: Inglês

10.1007/s10120-021-01165-w

1436-3305

Stefano Ughetto, Cristina Migliore, Filippo Pietrantonio, Maria Apicella, Annalisa Petrelli, Laura D’Errico, Stefania Durando, Daniel Moya‐Rull, Sara E. Bellomo, Sabrina Rizzolio, Tânia Capelôa, Salvatore Ribisi, Maurizio Degiuli, Rossella Reddavid, Ida Rapa, Uberto Fumagalli, Stefano De Pascale, Dario Ribero, Carla Baronchelli, Giovanni Sgroi, Emanuele Rausa, Gian Luca Baiocchi, Sarah Molfino, Stefania Manenti, Maria Bencivenga, Michele Sacco, Claudia Castelli, Salvatore Siena, Andrea Sartore‐Bianchi, Federica Tosi, Federica Morano, Alessandra Raimondi, Michele Prisciandaro, Annunziata Gloghini, Silvia Marsoni, Antonino Sottile, Ivana Sarotto, Anna Sapino, Caterina Marchiò, Paola Cassoni, Simonetta Guarrera, Simona Corso, Silvia Giordano,

Monoclonal and Polyclonal Antibodies Research

Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors.We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials.Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting.These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.