Abstract 370P
Background
The HERACLES-A trial demonstrated trastuzumab and lapatinib (T+L) activity in HER2-amplified (HER2+) KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). We conducted the HERACLES RESCUE trial to test whether therapeutic sequencing with another anti-HER2 regimen at progression to T+L is active in these patients.
Methods
HERACLES RESCUE (NCT03418558) is a proof-of-concept phase II, open label, multicenter trial. Patients (pts) with HER2+ [IHC 3+ or 2+ FISH-positive (HER2:CEP17 > 2) in > 50% cells] mCRC progressing to prior T+L received the antibody-drug conjugated T-DM1 3.6 mg/kg IV every 3 weeks until PD or unacceptable toxicity. Tumor response was assessed within 6 weeks from first T-DM1 dose and every 9 weeks until PD. The primary endpoint was objective response (OR, RECIST v1.1). To consider the study positive 2 ORs out of 13 patients had to be observed (α=0.15; β=85%; H1=25%). Secondary endpoints were safety, disease control rate (DCR) and time-to-progression (TTP).
Results
As of July 31, 2020, 9 patients were included in the trial and 8 in the efficacy analysis. The study was closed prematurely since target accrual was not met. Median age, number of prior regimens and ECOG PS were 61 [38-78], 4 [2-6] and 0 (5) or 1 (4), respectively. 3/9 (33.3%) pts had an intervening treatment between T+L and T-DM1. HER2 IHC 3+/amplification was retained on solid biopsy or circulating tumor DNA, respectively, in 5/5 (1 PR, 1 SD, 3 PD) and 2/3 pts (2 PD). OR was obtained in 1/8 [OR rate = 12.5% (95% CL 0.3-52)], while 2/8 (25.0%) had stable disease, accounting for 37.5% DCR. Median TTP was 1.6 months (95% CI 0.7-7.8). None of the pts achieving PD as best response to T+L had disease control. No G3 or higher drug related toxicities were observed.
Conclusions
HERACLES-RESCUE did not achieve its pre-planned patient accrual and thus no definitive conclusions on T-DM1 sequencing after T+L can be made. Achieving disease control to T+L and having a retained HER2 3+ status appear to be necessary but not sufficient conditions for clinical benefit. Preplanned exploratory analyses are ongoing to assess molecular mechanisms of sensitivity/resistance in this setting.
Clinical trial identification
NCT03418558.
Editorial acknowledgement
Not applicable
Legal entity responsible for the study
Fondazione del Piemonte per l’Oncologia –FPO-IRCCS.
Funding
AIRC via 2010 Special Program Molecular Clinical Oncology 5 × 1000 (project 9970). Roche provided the study drug.
Disclosure
A. Sartore Bianchi: Financial Interests, Personal, Advisory Board: Amgen, Bayer, Novartis, Sanofi, Servier. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol -Myers Squibb. A. Amatu: Financial Interests, Personal, Advisory Board: Roche, Bayer; Financial Interests, Personal, Other, Honoraria: CheckmAb. F. Bergamo: Financial Interests, Personal, Invited Speaker: Lilly; Other, Other, congress: Bayer, Ipsen. A. Bardelli: Financial Interests, Personal, Advisory Board: Neophore, Inivata; Financial Interests, Personal, Stocks/Shares: Neophore; Financial Interests, Personal, Funding, Research support: AstraZeneca, Boehringer Ingelheim. L. Trusolino: Financial Interests, Institutional, Research Grant: Symphogen, Servier, Pfizer, Menarini, Merck KGaA, Merus. S. Siena: Financial Interests, Personal, Advisory Board: Agenus, Astrazeneca, Bayer, BMS, CheckmAb, Daiichi-Sankyo, Guardant Health, Menarini, Merck, Novartis, Roche-Genentech, Seagen. All other authors have declared no conflicts of interest.