HER2 Therapy in Advanced Colorectal Cancer: 'Extraordinary'

Pam Harrison

May 03, 2016

A small group of patients with treatment-refractory, HER2-positive metastatic colorectal cancer achieved a remarkable response with a common targeted therapy regimen used to treat HER2-positive breast cancer with no need of a chemotherapy backbone.

Patients were treated with a combination of trastuzumab (Herceptin, Genentech/Roche) and lapatinib (Tykerb, GlaxoSmithKline).

The new data come from a proof-of-concept study published online April 20 in the Lancet Oncology.

"In this heavily pretreated population, these outcome data are extraordinary, and they show the relevance of HER2 as a target in the treatment of colorectal cancer," Hans-Joachim Schmoll, MD, PhD, Martin Luther University of Halle-Wittenberg, Germany, writes in an accompanying editorial.

These results represent a breakthrough, even though they apply only to a small subgroup of patients. Dr Hans-Joachim Schmoll

"These results represent a breakthrough, even though they apply only to a small subgroup of patients," he adds.

Small Study, Impressive Results

The study, known as HERCULES, was conducted by Andrea Sartore-Bianchi, MD, Niguarda Cancer Center, Grande Ospedale, Milano, Italy, and colleagues at four Italian academic cancer centers.

From August 2012 to May 2015, investigators screened 914 patients with KRAS exon 2 (codons 12 & 13) wild-type metastatic colorectal cancer and identified 5% of patients who had HER2-positive tumors. Two patients died before being enrolled; 27 patients were eligible for the trial.

"Most patients had extensive metastatic disease and distal colon tumours," Dr Sartore-Bianchi notes.

Almost 75% of the group had received at least four prior treatment regimens and had spent a median total time of 20 months on previous treatments.

Notably, all patients had also previously been treated with epithelial growth factor receptor–targeted antibodies, but none of 15 patients who were evaluable achieved an objective response to either cetuximab (Erbitux, ImClone Systems Incorporated) or panitumumab (Vectibix, Amgen Inc), she said.

Patients then received the HER2-targeted therapy combination. Trastuzumab, an anti-HER2 antibody, was given intravenously at a loading dose of 4 mg/kg, followed by 2 mg/kg once a week. Lapatinib, a tyrosine kinase inhibitor, was given by mouth at a dose of 1000 mg/day in 21-day treatment cycles, so patients received one dose of trastuzumab each week and one dose of lapatinib each day.

At a median follow-up of 94 weeks, one of the 27 patients (4%) had achieved a complete response, seven patients (26%) had achieved a partial response, and disease stabilized in another 12 patients (44%).

Eight patients, or 30% of the group overall, achieved an overall objective response, determined in accordance with RECIST 1.1 criteria, Dr Sartore-Bianchi points out.

Among the 12 patients in whom disease stabilized, duration of response lasted 16 weeks or longer in eight patients.

Overall, 59% of the group achieved either a complete response, a partial response, or stable disease lasting longer than 16 weeks. Responses were also durable, lasting a median of 38 weeks.

Furthermore, "of the 25 patients assessed for radiological response, 21 (84%) had tumour shrinkage," Dr Sartore-Bianchi notes.

Median progression-free survival was 21 weeks, and median overall survival, calculated post hoc, was 46 weeks.

Quite remarkably, 12 patients, or 45% of all patients receiving the proof-of-concept regimen, were alive at 1 year.

Adverse Events

More than three quarters of the group developed diarrhea, and almost half developed a rash or fatigue in response to treatment.

One third reported paronychia, but there were no treatment-related grade 4 or 5 toxicities, and no patient developed treatment-related cardiotoxicity.

None of the patients were obliged to stop treatment because of adverse events, and there were no instances of withdrawal from treatment, although the dose of lapatinib was reduced in three patients because of side effects.

As Dr Sartore-Bianchi notes, results from the HERACLES study are "particularly meaningful" when they are compared with other third-line therapies. For example, the multikinase inhibitor regorafenib (Stivarga, Bayer HealthCare Pharmaceuticals) has shown objective responses in only 1% to 4% of patients, and the trifluridine-tipiracil combination TAS-102 has shown objective responses in only 2% of patients in this setting.

"Our results show that HER2 amplification is a clinically relevant genetic alteration in metastatic colorectal cancer," Dr Sartore-Bianchi concludes.

Established diagnostic tools can now be used to screen colorectal cancer patients for the presence of HER2, and results can be acted upon if tumors prove to be HER2 positive.

Clinical Implications

Asked to comment further on the clinical implications of the HERACLES study, Dr Schmoll said that for any patient with colorectal cancer who has already received several lines of treatment, "there is no chance for regression of the metastases ― not even a minimal chance, since there are no drugs available that have at least some activity for patients like these," he said.

In light of this, the remission rate reported by the Italian team is extremely high and in fact has never before been achieved in patients with this type of treatment-refractory tumor, he added.

"Clearly, this relates only to a small minority of patients," Dr Schmoll cautioned.

"But this is characteristic of the new molecular targeted treatments ― there are several different molecular subgroups of colorectal cancer, with different specific treatments — and now there is a new subgroup," he said.

"This trial was done in patients who were refractory to all available treatment options, and to see such a high efficacy in patients who would be expected to die very soon means that this new regimen must and will be evaluated as a first-line treatment. In fact, clinical trials to evaluate the new regimen in this setting are starting."

The HER2 genetic alteration occurs in 3% to 5% of patients with KRAS codon 12/13 wild-type metastatic cancer.

Roche and GlaxoSmithKline (Novartis Pharmaceuticals Corporation since March 2015) donated the study drugs, and Roche donated funding to partly support clinical trial services. Dr Sartore-Bianchi has received personal fees for being an advisory board member for Amgen, Bayer, Lilly, and Roche. Dr Schmoll has received grants and personal fees from Roche and personal fees from both Bayer and Amgen.

Lancet Oncol. Published online April 20, 2016. Abstract, Editorial


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