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

Abstract Background 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. Methods 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. Results 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. Conclusions 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. Legal entity responsible for the study Fondazione del Piemonte per l’Oncologia IRCC di Candiolo. Funding Fondazione Piemontese per l’Oncologia - FPO funded by Associazione Italiana per la Ricerca sul Cancro (AIRC). Roche provided pertuzumab and T-DM1 for free. Disclosure 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.