Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial

Abstract

Background: HER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting.

Methods: HERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1).

Results: Thirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue.

Conclusions: HERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource.

Trial registration number: 2012-002128-33 and NCT03225937.

Keywords: ERBB2; HER2; T-DM1; colorectal; pertuzumab.

Conflict of interest statement

Competing interests: AS-B is advisory board member for Amgen, Bayer, Sanofi and Servier. SL reports consulting or advisory roles in Amgen, Bayer, Merck, Lilly and Servier; speakers’ bureau roles at Lilly, Roche and BMS, and research funding from Amgen and Merck. VZ is advisory board member for Bristol-Myers Squibb and Merck; speakers’ bureau for AstraZeneca and Lilly; reports personal fees from Bayer, Roche, Servier. FC reported recepit of honoraria or consultation fees for speaker, consultancy or advisory roles at Amgen, Bayer, Bristol-Myers Squibb, Celgene, Merck Serono, Pfizer, Roche, Servier; direct research funding as the principal investigator for institutional research projects from Amgen, Bayer, Merck Serono, Roche, Ipsen; institutional financial interests, financial support for clinical trials or contracted research from Merck Serono, Roche, Symphogen, Array; leadership Positions in Professional Societies (non-financial interests) including ESMO past president, and president of the Associazione Italiana Oncologia Toracica. AAr reports grants and personal fees from BMS, personal fees from MSD, personal fees from Eli-Lilly, personal fees from Boehringer, personal fees from Pfizer, grants from Celgene, grants and personal fees from Roche, outside the submitted work. AAm is advisory Board from Amgen, Roche, Bayer. LT reports grants from Symphogen, grants from Servier, grants from Merus, grants from Pfizer, grants from Menarini, personal fees from AstraZeneca, personal fees from Merck KGaA, personal fees from Eli Lilly, outside the submitted work. SS is advisory board member for Amgen, Bayer, BMS, CheckmAb, Clovis, Daiichi-Sankyo, Merck, Roche-Genentech, Seattle Genetics.

© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.

Figures

Figure 1

Efficacy in preclinical trials of pertuzumab and T-DM1 in patient-derived HER2+ CRC xenografts (HER2-PDXs). Tumour growth curves in tumour graft cohorts from individual patients with ERBB2 amplification treated with placebo or indicated HER2-targeted treatments (n=6 mice per group), showing long-lasting growth inhibition achieved with pertuzumab and T-DM1. TDM1: 10 mg/kg once weekly; pertuzumab: 20 mg/kg once weekly; lapatinib: 100 mg/kg/day.

Figure 2

Consolidated Standards of Reporting Trials diagram of HERACLES-B trial. Between August 2012 and March 2018, 1536 patients with KRAS exon 2 and BRAF wild type (WT) (from 15 March 2016 exons 2, 3, 4 KRAS and NRAS and BRAF WT) were screened by immunohistochemistry (IHC) and in situ hybridisation (ISH) as per HERACLES criteria. Ninety patients (5.9%) had a HER2+ tumour. HERACLES cohort A comprised overall 35 patients (27 original cohort plus 8 expansion cohort), of whom 32 were evaluable for response. Enrolment in cohort B (HERACLES B trial) started in August 2016, data were collected until March 2019 and final analysis and centralised radiological revision were completed by 30 July 2019. One patient signed consent but developed rapid disease progression and was locally indicated as not evaluable for efficacy. The patients was duly substituted as per protocol. However, the centralised revision of the treatment history subsequently revealed instead that patient was fully evaluable for both safety and efficacy as for protocol since two full cycles of treatment were delivered. For this reason, all analyses have been performed on 31 rather than 30 patients as originally intended. *From 15 March 2016 RAS WT (KRAS, NRAS exon 2, 3, 4).

Figure 3

Dynamic of response in patients in HERACLES-B trial. Individual lines represent for each patient the percentage of change from treatment start (day 0) to the day of objective disease progression. Red lines are for patients with progressive disease (PD), blue lines for patients with stable disease (SD) and green lines for patients who achieved a partial response (PR). Pt number 122 053 rapidly progress after two cycle of pertuzumab and trastuzumab-emtansine and was not represented in the spaghetti plot.