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Phase II Study of Pertuzumab and Trastuzumab-emtansine (T-DM1) in Patients with HER2-positive Metastatic Colorectal Cancer: the HERACLES-B (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification, cohort B) Trial


29 Sep 2019


Poster Discussion – Gastrointestinal tumours, colorectal


Andrea Sartore-Bianchi


Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394


A. Sartore-Bianchi1, C. Martino2, S. Lonardi3, E. Fenocchio4, A. Amatu5, S. Ghezzi5, V. Zagonel3, F. Ciardiello6, A. Ardizzoni7, F. Tosi8, E. Valtorta9, V. Torri10, E. Bonoldi9, A. Sapino2, A. Bardelli11, G. Cappello12, A. Vanzulli1, S. Marsoni13, L. Trusolino14, S. Siena1

Author affiliations

  • 1 Dipartimento Di Oncologia Ed Emato-oncologia, Università degli Studi di Milano, 20162 - Milan/IT
  • 2 Scientific Direction, Candiolo Cancer Institute, FPO-IRCCS, 10060 - Candiolo/IT
  • 3 Medical Oncology 1, Istituto Oncologico Veneto IRCCS, 35128 - Padova/IT
  • 4 Gastrointestinal Cancer Unit, Candiolo Cancer Institute, FPO-IRCCS, 10060 - Candiolo/IT
  • 5 Dipartimento Di Ematologia E Oncologia, Grande Ospedale Metropolitano Niguarda, 20124 - Milano/IT
  • 6 Dipartimento Di Medicina Di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80131 - Napoli/IT
  • 7 Dipartimento Dell'oncologia Ed Ematologia, Policlinico S. Orsola-Malpighi, 40138 - Bologna/IT
  • 8 Dipartimento Di Oncologia Ed Emato-oncologia, Università degli Studi di Milano, 20124 - Milan/IT
  • 9 Dipartimento Medicina Di Laboratorio, Grande Ospedale Metropolitano Niguarda, 20124 - Milano/IT
  • 10 Department Of Oncology, IRCCS- Istituto di Ricerche Farmacologiche Mario Negri, 20156 - Milan/IT
  • 11 Molecular Oncology, Istituto di Candiolo - FPO - IRCCS, 10060 - Candiolo/IT
  • 12 Radiodiagnostic, Candiolo Cancer Institute, FPO-IRCCS, 10060 - Candiolo/IT
  • 13 Precision Oncology, IFOM-FIRC Institute of Molecular Oncology, 20139 - Milano/IT
  • 14 Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, 10060 - Candiolo/IT


Abstract 3857


HER2 amplification (HER2+) is a therapeutic target for 2% (unselected)-6% (RAS wild-type) metastatic colorectal cancer (mCRC). In the HERACLES-A Trial of trastuzumab and lapatinib (Lancet Oncology, 2016), HER2+ KRAS wild-type mCRC patients achieved an overall objective response rate (CR+PR = ORR) of 30%. Based on this result and on preclinical trials, we activated HERACLES-B, evaluating a targeted chemotherapy precision approach by combining pertuzumab with T-DM1.


HERACLES-B is an open-label phase II trial in RAS/BRAF wild-type HER2+ mCRCs (as defined in Valtorta et al, 2015). ORR and Progression-Free Survival (PFS) are the primary and secondary end-points, respectively. With a Fleming/Hern design (H0=ORR 10%; α = 0.05; power=0.85), 7 OR/30 were required to demonstrate an ORR ≥30% (H1). Main inclusion criteria were: PS 0-1, progression after 5FU, oxaliplatin, irinotecan, and anti-EGFR containing regimens. Pertuzumab was dosed at 840 mg iv load, followed by 420 mg iv q3 weeks and T-DM1 at 3.6 mg/Kg q3 weeks. NGS-based molecular analyses of tumor tissue/plasma were performed.


From 8/2016 to 3/2018, 30 patients were enrolled, treated and evaluable for efficacy. Patients received a median of 3 prior regimens. Data lock and centralized radiological revision were completed by 30/7/2019. ORR was 10% [95% CI: 0-28] and stable disease (SD) 70% [95% CI: 50-85]. Median PFS was 4.8 mos. [95% CI: 3.6-5.8]. Higher HER2 IHC score (3+ vs 2+) was associated with objective response/SD ≥4 mos. [p = 0.03]. Drug-related G3 adverse events were observed only in 2 patients (thrombocytopenia); G ≤ 2 events in 84% of cycles (N = 296), mainly nausea and fatigue.


Although HERACLES-B did not reach its primary endpoint, disease control was achieved in 80% of patients with a median PFS of 4.8 mos. that is superimposable to the 4.2 mos. achieved in the positive HERACLES-A trial. While the ORR could have been weakened by the lower trastuzumab dose delivered with T-DM1, the retained favorable PFS might be due the combined ‘broad-brush’ effect of emtansine and the synergy with pertuzumab. Preliminary molecular results will be presented.

Clinical trial identification

EudraCT: 2012-002128-33.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione del Piemonte per l’Oncologia IRCC di Candiolo.


Fondazione Piemontese per l’Oncologia - FPO funded by Associazione Italiana per la Ricerca sul Cancro (AIRC). Roche provided pertuzumab and T-DM1 for free.


A. Sartore-Bianchi: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi. A. Amatu: Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: Amgen. A. Ardizzoni: Advisory / Consultancy: Roche. L. Trusolino: Research grant / Funding (self): Symphogen; Research grant / Funding (self): Merus; Research grant / Funding (self): Servier; Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Merck KGaA. S. Siena: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: CheckMab; Advisory / Consultancy: Celgene; Advisory / Consultancy: Clovis; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Incyte; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche-Genentec; Advisory / Consultancy: Seattle Genetics. All other authors have declared no conflicts of interest.

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