Therapeutic Dual Inhibition of HER2 Pathway in the HERACLES Trial

Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients

HER2 Amplification for Colo-RectaL Cancer Enhanced Stratification (HERACLES), a precision medicine trial, discovers that a dual HER2-targeted therapy may be a new valuable option for HER2-positive metastatic colorectal cancer (mCRC). It was rationally designed (based on findings in xenopatient model) phase II study that tested a combination of trastuzumab and lapatinib in patients with HER2-positive mCRC. The patients were primarily resistant to cetuximab or panitumumab, indicating that the dual anti-HER2 therapy is effective and deserves further clinical assessment in earlier lines of treatment of HER2-positive mCRC patients, in anti-EGFR naive setting. The findings were reported by Dr Salvatore Siena of the Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milan, Italy on behalf of Italian research team at the 2015 ASCO Annual Meeting (29 May – 2 June, Chicago, USA). 

HER2 amplification is a driver of resistance to cetuximab in mCRC patient-derrived xenografts (xenopatients)

Previous research of the same group has showed that HER2-positive mCRC xenopatients are sensitive to dual HER2 blockade with lapatinib and trastuzumab, but not to either drug alone. Therefore, the researchers conducted a phase II study of trastuzumab plus lapatinib (arm A) or trastuzumab plus pertuzumab (arm B) in HER2-amplified, KRAS exon 2 wild-type, mCRC patients resistant to standard therapies.

The results of arm A with 27 patients recruited in 4 centers were presented at ASCO 2015. Patients with histological diagnosis of CRC and metastatic disease not amenable to R0 surgery, who progressed after fluoropyrimidines, oxaliplatin, irinotecan, oxaliplatin, cetuximab or panitumumab (bevacizumab, aflibercept or regorafenib were allowed but not mandatory), ECOG performance status 0 or 1, no symptomatic CNS metastases, normal blood, liver, renal and cardiovascular function, were eligible if their tumour was HER2-positive (immunohistochemistry-IHC 3+ or IHC 2+ and FISH positive in > 50% cells).

The primary endpoint was objective response rate (ORR) according to RECIST v1.1 criteria; central independent radiology review was foreseen. To consider the study positive, it was needed to record in each cohort 6 responses out of 27 (α = 0.05; β = 85%; H1 = 30%). The secondary endpoints were time to progression (TTP) and safety. Patients have entered into the study until 28 February 2015; the data were locked for analysis on 1 May 2015.

Translational study consisted from a serial liquid biopsies for HER2 ctDNA in plasma (ddPCR), HER2 ectodomain (ECD) in serum (ELISA), next generation sequencing in tissue and plasma in de novo resistant patients and upon progression.

From 849 patients with mCRC KRAS exon 2 wild-type patients, 46 (5.4%) were HER2-positive; 22 were not eligible for the study because their performance status was at least 2 or they had tumour-related comorbidities; 24 patients were enrolled but 23 were evaluable for response.

Median age was 63 patients; there were 21 males and 3 females; 18 patients had HER2 IHC 3+ tumours and 6 patients had HER2 IHC 2+ tumours. In 83% of patients, the primary site of tumour was left colon. Median number of prior lines of therapy was 5 (range 2-8) with 83% of patients who received more than 3 prior therapy regimens. All patients were treated previously with cetuximab or panitumumab. However, previous response to EGFR monoclonal antibodies was 0%.

The study treatment was well tolerated, with no grade 4-5 toxicities. Main toxicities were related to gastrointestinal tract and maximally grade 2, one patient experienced skin toxicity grade 3 and one patient had fatigue grade 3. There was no cardiac toxicity.

The compliance was good with 96,4% of dosage received as planned. There was no patient off-treatment due to toxicities. More than 50% of responders were on treatment for more than 6 months (range 5,3-16+ months).

The primary endpoint was met with 8 out of 23 objective responses in patients heavily pretreated with standard therapies, including EGFR-targeted agents. The response rate (partial response plus complete response) was 34,7%. Stable disease of at least 4 months was recorded in 30,4% of patients. The disease control rate was 78%.

Median TTP was 5,5 months. The TTP by HER2 score was 7,3 months in patients with HER2 3+ and 4,2 months in HER2 2+.

The authors underlined that the estimated number of HER2-positive mCRCs is comparable to other malignancies with actionable molecular targets.

Dr Sabine Tejpar, who was the study discussant, said that these results represent important scientific advancement in the field. The authors found HER2 amplified in 5% of wild type exon 2 KRAS mCRC patients. If tested broader, this number could be even higher. The results from the arm B of the HERACLES trial are awaited.

The HERACLES is funded by Associazione Italiana Ricerca Cancro. GSK and Roche provided the study drugs free of charge and Roche partially funded clinical trial services.


Siena S, Sartore-Bianchi A, Lonardi S, et al. Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 33, 2015 (suppl; abstr 3508).