Advanced colorectal cancer still has a poor prognosis and more active drugs are urgently needed Interview with:
Silvia Marsoni, M.D.
Director Clinical Research Office
FPO – Istituto di Candiolo IRCCS
Institute for Cancer Research @ Candiolo
10060 Candiolo (TO) – Italy What is the background for this study? What are the main findings?

Dr. Marsoni: In the Lancet Oncology of April 20 2016, clinical investigators of 4 major Italian academic institutions presented the results of the HERACLES trial, the first phase 2 trial in patients with refractory colorectal cancer and HER2 amplification. HERACLES is based on robust preclinical data, previously generated by the same authors in patient-derived xenografts (PDX) of metastatic colorectal cancers harboring amplification of the HER2 oncogene. The HER2 positive PDXs responded to the anti HER2 combination of trastuzumab and lapatinib, but not to either drug alone.

After validation of the commercial assays to test for HER2 positivity in colorectal cancer specimens, the authors tested the experimentally selected combination of trastuzumab plus lapatinib in HER2-amplified metastatic colorectal cancer patients. They screened 914 patients who were refractory to chemotherapy and had KRAS codon 12/13 wild-type colorectal carcinoma, identifying 46 patients as having HER2-positive disease, enrolling 27 eligible patients into the study. Eight (30%) patients achieved objective responses — the highest proportion ever reported in treatment-refractory patients. One (4%) patient achieved a complete response; 20 (74%) achieved eithera complete response, partial response, or stable disease; median response duration was 9·5 months, median progression-free survival was 5·2 months (95% CI 4–8); and median overall survival was 11·5 months (95% CI 8–17). In this heavily pretreated population – all patients had received and failed standard chemotherapies and anti EGFR antibodies, and mostly also anti-agiogenic therapy – , these outcome data are extraordinary, and they show the relevance of HER2 as a target in the treatment of colorectal cancer. These results represent a breakthrough, even though they apply to a limited subgroup of patients of a very common and lethal malignancy. What should clinicians and patients take away from your report?

Dr. Marsoni: This is the first trial to assess the combination of trastuzumab and lapatinib in patients with HER2-positive colorectal carcinoma. Our findings show that the dual HER2-targeted therapy of trastuzumab and lapatinib is active, in the absence of any chemotherapy backbone, in heavily pretreated patients with metastatic disease. Additionally, our results indicate that the extent of HER2 gene copy number elevation and HER2 expression might be associated with response to treatment.

Dr. Marsoni: What recommendations do you have for future research as a result of this study?

Dr. Marsoni: The results of this study could change the day-to-day clinical care management of patients with advanced HER2-positive colorectal cancer. Our findings could lead to the use of trastuzumab and lapatinib in earlier lines of treatment, with a possibility of chemotherapy-free regimens, for patients with HER2-positive tumors. A phase 3 trial is warranted to provide more definitive data. Is there anything else the authors would like to state?

Silvia Marsoni, the trial clinical coordinator at the Candiolo Cancer Institute in Turin, states that “Our results show that HER2 amplification is a clinically relevant genetic alteration in metastatic colorectal cancer. This alteration can be screened for with established diagnostic tools, can be acted on at the therapeutic level, and occurs in 3–5% of patients with KRAS codon 12/13 wild-type metastatic colorectal cancer, similar to that of other genetic alterations for which licensed drugs are effective (eg, in lung cancer).”

Livio Trusolino, who conducted the preclinical studies at the Candiolo Cancer Institute, states that “Our results have been achieved through a precision oncology programme that started with preclinical findings in pertinent in-vivo models, was strengthened by a rigorous methodological effort for molecular diagnosis, and finally resulted in the identification of a new therapeutic option for patients with HER2-positive colorectal cancer tumours”.

Finally, Salvatore Siena from the Niguarda Cancer Center in Milan, the principal investigator of the clinical programme, states “We are proud to provide positive results of a targeted therapy for metastatic colorectal cancer, several years after the first publication in 2004 of the efficacy of EGFR-targeted monoclonal antibody. HER2-targeted therapy is a new tool in the therapeutic armamentarium for HER2-positive metastatic colorectal cancer”.

HERACLES is an independent research trial funded by the major Italian cancer charity AIRC (Associazione Italiana per la Ricerca sul Cancro – Programma Speciale AIRC 5per1000) and by the Fondazione Oncologia Niguarda. We also acknowledge contributions from F Hoffman-La Roche.


Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial

Sartore-Bianchi, Andrea et al. Published Online: 20 April 2016

The Lancet Oncology , Volume 0 , Issue 0 ,

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