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.
2016; Lippincott Williams & Wilkins; Volume: 34; Issue: 4_suppl Linguagem: Inglês
10.1200/jco.2016.34.4_suppl.tps774
ISSN1527-7755
AutoresSalvatore Siena, Alberto Bardelli, Andrea Sartore‐Bianchi, Cosimo Martino, Giulia Siravegna, Alessandro Magrì, Francesco Leone, Vittorina Zagonel, Sara Lonardi, Alessio Amatu, Federica Tosi, Patrizia Racca, Agostino Ponzetti, Fortunato Ciardiello, Silvia Marsoni,
Tópico(s)Gastric Cancer Management and Outcomes
ResumoTPS774 Background: We previously documented HER2 amplification in 5% of KRAS wild-type metastatic colorectal cancer (mCRC; Valtorta E. et al, Modern Pathology, 2015). Despite refractoriness to standard chemotherapy and to cetuximab, patients with HER2 amplified mCRC achieve 30% response rate (RR) and long lasting objective responses (median duration 8.5 mos.) when treated with lapatinib (L) and trastuzumab (T) [HERACLES trial - EudraCT 2012-002128-33; Siena et al. J Clin Oncol 33, 2015 (suppl; abs 3508)]. We sampled responding HERACLES patients at progression, and found persistent high levels of HER2 tested by IHC and FISH on tissue re-biopsies, or by droplet digital liquid biopsy in plasma ctDNA (LB). We reasoned that HER2 in these tumors could still be exploited as “molecular bait” for T-DM1, an antibody-drug conjugate of trastuzumab linked to the cytotoxic agent emtansine. We thus conducted a preclinical trial in a patient-derived xenograft (PDX) model generated from the viable biopsy of a acquired-resistant HERACLES patient. In a 2-arm trial against control (6 PDXs per arm), we compared T-DM1 to pertuzumab, and found that only T-DM1 treated animals achieved tumor responses. We therefore designed a proof-of-concept trial of T-DM1 in HER2 amplified mCRC patients progressing or relapsing after T+L treatment. Methods: HERACLES-RESCUE is an independent phase II trial assessing the efficacy of T-DM1 in HER2 amplified mCRC progressing after anti-HER2 (L+T) therapy within the HERACLES trial. Response rate is the primary endpoint. Using the A’Hern approach to retrofit the sample size from the constrained sample size of patients treated in HERACLES, and assuming α = 0.15, β = 0.85 and H 0 = 5%, if 2 responses will be observed in 13 patients we would be able to define a clinically relevant true response rate of 25% (H 1 ). Eligibility: progression/relapse within HERACLES L+T treatment, lack of KRAS mutations by LB, measurable disease (RECIST v1.1), ECOG PS ≤ 1, and adequate organ function. Treatment: T-DM1: 3,6 mg/kg q21d. A first patient was treated on August 2015. EudraCT number: 2015-003275-30; Funded by AIRC Grant # 9970. Clinical trial information: 2015-003275-30.
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