Dual HER2 Blockade Promising in HER2-Positive Metastatic CRC

Dual HER2 blockade with trastuzumab and lapatinib yielded good response rates in HER2-amplified, RAS wild-type, treatment-refractory metastatic colorectal cancer (CRC) patients, according to results of the HERACLES study.

“Amplification and mutations in the gene HER2 are found in 6% to 8% of RAS/RAF wild-type CRCs,” said Salvatore Siena, MD, of the Niguarda Cancer Center at Grande Ospedale Metropolitano Niguarda in Milan, Italy, in a press release. He presented results of the HERACLES study at the 2017 American Association for Cancer Research (AACR) Annual Meeting, held April 1–5 in Washington, DC.

The study included 33 patients with HER2-positive, RAS wild-type metastatic CRC. These were heavily pretreated patients, with a median of five prior treatment regimens. All patients were refractory to standard of care including cetuximab or panitumumab, and had a performance status of 0 or 1. They received a 4 mg/kg loading dose of trastuzumab followed by 2 mg/kg weekly, along with lapatinib at a dose of 1,000 mg daily, until progression.

Ten of the 33 patients (30.3%) achieved an objective response, including two complete responses and eight partial responses. Another 13 patients had stable disease as their best response, for a disease control rate of 70%. Siena noted that historically the response rate for metastatic CRC after second-line therapy is below 5% with chemotherapy, and approximately 10% to 20% in patients on anti-EGFR therapy, depending on whether they are selected for RAS/RAF mutation status.

Six patients (18%) experienced a grade 3 adverse event; these included fatigue (four patients), skin rash (one patient), and elevated bilirubin (one patient). There were no drug-related serious adverse events reported in the study.

The two patients who achieved a complete response were disease free for 1 year and nearly 4 years since the start of treatment, Siena said. “Both had tumors refractory to cetuximab and had become resistant to all standard chemotherapies,” he said. “This means that HER2-targeted therapy can be a potential stand-alone, low-toxicity treatment approach for this patient population.”

The study was limited by its inclusion of only those with HER2-amplified CRC, rather than HER2-mutated patients as well. Still, Siena suggested that “oncologists determine HER2 status at diagnosis of metastatic disease in CRC patients, and collect information about anti-EGFR response in HER2-positive cases.”