Abstract CT082: Pertuzumab and trastuzumab-emtansine in HER2-positive colorectal cancer: the HERACLES B trial
Authors: Trusolino Livio , Bertotti Andrea , Lonardi Sara , Sartore-Bianchi Andrea , Martino Cosimo , Cottino Francesca , Vurchio Valentina , Valtorta Emanuele , Lauricella Calogero , Regge Daniele , Vanzulli Angelo , Zagonel Vittorina , Leone Francesco , Racca Patrizia , Ciardiello Fortunato , Ardizzoni Andrea , Marsoni Silvia , Siena Salvatore 
Published: July 2016

Abstract
Rationale: The HERACLES A trial showed that a clinical sizeable subset of 3% of metastatic colorectal cancers (mCRC), identifiable by the amplification of the HER2 gene, can be targeted for effective, durable and safe anti-HER2 treatment with a combination of the small molecule kinase inhibitor lapatinib (L) and the monoclonal antibody trastuzumab (T) [Siena et al. J Clin Oncol 33, 2015.(suppl; abs 3508)]. As with any other targeted therapy, however, the L+T combination was not active in all patients, and even in responders its efficacy was limited in time by the engagement of growth-promoting cues that compensate for inhibition of the targeted kinase, eventually leading to disease progression. In both primary and secondary resistant HERACLES A patients the amplification of the HER2 gene was nevertheless present in more than 50% of the tumor cells. We reasoned that this finding could be exploited by adding to the anti HER2 strategy a ‘precision chemotherapy’ component, embodied by the HER2 antibody-drug conjugate trastuzumab-emtansine (T1). To this end, we conducted a preclinical trial in CRC0186, the only patient-derived xenograft (PDX) of our HER2+ mCRC PDX collection (N = 7), showing tumor inhibition rather than tumor shrinkage after L+T treatment. Six mice per arm were randomized to either control, pertuzumab (P), T1 or P+T1. Optimal tumor shrinkage, mirroring clinical complete response, was only observed in the T1 and the P+T1 arms, and persisted after treatment stop only in the latter arm (Bertotti, unpublished data). Notably, this post treatment response was not observed in comparable experiments testing the L+T or P+T combinations in more sensitive HER2+ PDXs (Bertotti et al., Cancer discovery 2011; Leto et al., Clin Cancer Res 2015). In light of the above results we designed the HERACLES B trial.
Trial design: HERACLES B is an independent phase II trial of P+T (accrual starting March 2016). Response rate is the primary endpoint, progression free survival the secondary. Sample size was calculated according to the Fleming & A’Hern one stage design under the following assumptions: H0 = RR 10%, H1 = RR 30%. With a = 0.05 and β = 85%, we need to accrue 27 patient and observe ? 6 responses to declare the study positive. The clonal evolution of each patient tumor's is monitored via fortnightly liquid biopsies.
Eligibility criteria: mCRC patients HER2+ according to HERACLES criteria (Valtorta E. et al, Modern Pathology, 2015) and wild type for KRAS, NRAS and BRAF; prior treatment with fluoropirimidines, oxaliplatin, and irinotecan containing regimens, ± anti EGFR or antiangiogenic treatment; measurable disease (RECIST v1.1), ECOG PS ?1, and adequate organ function.
Treatment: Pertuzumab (840 mg/kg iv load followed by 420mg/kg IV) in combination with TDM1 (3,6 mg/kg) both q3wks. EudraCT number: 2012-002128-33; Funded by AIRC Grant # 9970.
Citation Format: Livio Trusolino, Andrea Bertotti, Sara Lonardi, Andrea Sartore-Bianchi, Cosimo Martino, Francesca Cottino, Valentina Vurchio, Emanuele Valtorta, Calogero Lauricella, Daniele Regge, Angelo Vanzulli, Vittorina Zagonel, Francesco Leone, Patrizia Racca, Fortunato Ciardiello, Andrea Ardizzoni, Silvia Marsoni, Salvatore Siena. Pertuzumab and trastuzumab-emtansine in HER2-positive colorectal cancer: the HERACLES B trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT082.