Therapeutic dual inhibition of HER2 pathway for metastatic colorectal cancer (mCRC): The HERACLES trial.

Abstract

565 Background: HER2 amplification in mCRC associates with resistance to anti-EGFR moAbs and, based on studies in patient-derived xenografts (Bertotti et al, Cancer Discov 2011), predicts response to combined therapy with anti-HER2 moAbs and lapatinib (L). Accordingly, we conducted an independent proof-of-concept phase II study of trastuzumab (T) and L in HER2+ mCRC after failure of standard therapies (HERACLES Trial - EudraCT 2012-002128-33). Methods: mCRC patients (pts) progressing after fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab were eligible if tumors were HER2+ [IHC 3+ or 2+ and FISH positive (HER2:CEP17 >2) in >50% cells]. L was given po daily and T iv weekly at standard doses. Tumor response was assessed every 8 weeks. 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 ctDNA (ddPCR), and HER2 ectodomain (ECD) plasma levels (ELISA) were collected until progression. Results: We screened 646 pts with KRAS exon 2 WT mCRC and found 28 (4.3%) HER2+; 18 (2.8%) were fully eligible and evaluable for response as of September 10, 2014. Pts had a median of 5 (r=3-8) prior therapies, median age 61 (r=41-86), ECOG PS ≤1, 2F/16M. Primary endpoint was met with 6/18 ORs (1 CR, 4 PR, 1 PRunc; ORR=33.3%, 95% CI 0.16-0.56). Stable disease (SD) lasting > 4 mos. was obtained in four further pts. Five of six ORs and the longest SD (10 mos.) were observed in pts with HER2 gene copy number variations (CNVs) ≥20 copies. Treatment was well tolerated with toxicities limited to grade 2 diarrhea, fatigue, and skin toxicities (one grade 3). HER2 CNV in ctDNA decreased in 2/3 ORs and 0/2 non responders. HER2 ECD plasma levels also decreased in 2/2 ORs but not in 6/6 pts with SD or progression. Exome analysis of index cases will be presented. Conclusions: As predicted by HER2+ mCRC xenografts, the combination of T and L was remarkably active in standard therapy refractory mCRCs with HER2 amplification. HERACLES represents the first precision medicine trial with positive results in mCRC. HERACLES is funded by Associazione Italiana Ricerca Cancro. Clinical trial information: 2012-002128-33.