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Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial.
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.
Abstracts by Salvatore Siena:
Clinical and molecular landscape of metastatic colorectal cancer (mCRC) harboring ALK, ROS1, or NTRK 1, 2, 3 (NTRKs) rearrangements.Meeting: 2017 Gastrointestinal Cancers Symposium | Abstract No: 589
Mutation enrichment next-generation sequencing for quantitative detection of KRAS mutations in urine cell-free DNA from patients with advanced colorectal and other cancers.Meeting: 2017 Gastrointestinal Cancers Symposium | Abstract No: 602
HER2 amplification as a ‘molecular bait’ for trastuzumab-emtansine (T-DM1) precision chemotherapy to overcome anti-HER2 resistance in HER2 positive metastatic colorectal cancer: The HERACLES-RESCUE trial.Meeting: 2016 Gastrointestinal Cancers Symposium | Abstract No: TPS774