Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial.

Gastrointestinal (Colorectal) Cancer
Session Type and Session Title: 
Oral Abstract Session, Gastrointestinal (Colorectal) Cancer
Abstract Number: 


J Clin Oncol 33, 2015 (suppl; abstr 3508)
Salvatore Siena, Andrea Sartore-Bianchi, Sara Lonardi, Livio Trusolino, Cosimo Martino, Katia Bencardino, Francesco Leone, Vittorina Zagonel, Emanuele Valtorta, Valter Torri, Giulia Siravegna, Alessio Amatu, Erica Francesca Bonazzina, Francesca Rusconi, Silvia Ghezzi, Fortunato Ciardiello, Silvio Veronese, Paolo Maria Comoglio, Alberto Bardelli, Silvia Marsoni; Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milan, Italy; Istituto Oncologico Veneto IRCCS, Padova, Italy; Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy; Ospedale Niguarda Ca' Granda, Milan, Italy; Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology-IRCCS, Padua, Italy; Istituto Di Ricerche Farmacologiche Mario Negri, Milan, Italy; Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy; Medical Oncology, Second University of Naples, Naples, Italy

Abstract Disclosures


Background: We conducted a phase II of trastuzumab (T) and lapatinib (L) in HER2-amplified, KRAS exon 2 wild-type, mCRC pts resistant to standard therapies (HERACLES Trial EudraCT 2012-002128-33). Methods: Pts progressing after fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab were eligible if tumor was HER2+ [IHC3+ or 2+ and FISH positive (HER2:CEP17 > 2) in > 50% cells]. L was given po qd, T iv qw at standard doses. Response was assessed q 8 wks. The primary end-point was objective response (OR, RECIST v1.1). To consider the study positive 6/27 ORs had to be observed (α = 0.05; β = 85%; H1 = 30%). Serial liquid biopsies for HER2 ctDNA (ddPCR/NGS) and ectodomain (ECD) plasma levels (ELISA) were collected until progression. Results: As of Jan 31 2015, 913 pts were screened, 44 found HER2+ (4.8%), and 23 eligible and evaluable: 2F/21M, median age 63 (r = 40-86), ECOG PS ≤ 1, median prior regimens 5 (r = 3-8). Primary endpoint was met with 8/23 ORs [7 PR, 1 PRunc (too early); ORR = 35% (95% CL 20-55)]; 7/8 ORs were observed in HER2 IHC3+ pts. Responses lasted: 8+, 12+, 14+, 24, 24.5+ 32, 54+ and 55+ weeks. Median time to progression was 5.5 months (95% CL 3.7-9.8). Toxicity was limited to G2 diarrhea, fatigue, and rash (1 G3). HER2+ ctDNA and ECD levels decreased in 2/3 ORs and 0/2 non responders and in 2/2 ORs 0/6 with SD or PD, respectively. Exploratory correlative analyses of HER2 gene dosage will be presented together with exome analysis of index cases. Conclusions: HER2 is amplified in 5% of WT exon 2 KRAS mCRC patients. The HERACLES trial met its primary endpoint with 8/23 objective responses in pts heavily pretreated with standard therapies, including EGFR-targeted agents, indicating that the dual anti HER2 therapy is effective and deserves further clinical assessment in earlier lines of treatment of HER2+ mCRC patients. HERACLES is funded by Associazione Italiana Ricerca Cancro. Clinical trial information: 2012-002128-33.