August 2017 VOL 8, NO 8

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Colorectal Cancer

New Approach to HER2-Positive Colorectal Cancer Promising

Using a “double whammy” of 2 HER2-directed therapies achieved a clinical benefit rate of 70% and an objective response rate (ORR) of 30% in patients with heavily pretreated, HER2-positive metastatic colorectal cancer (CRC), according to final results from the phase 2 HERACLES-A trial. These patients have a suboptimal response to traditional chemotherapy, and this targeted approach represents a new treatment option, according to investigators.

“HER2-positive patients, though only 3% of all CRC, will account for 2.4 million cancers worldwide by the year 2035. This study shows that patients with as many as 5 prior lines of therapy can still have responses and durable responses with a nonchemotherapy regimen,” stated senior author Silvia Marsoni, MD, Torino, Italy, who presented final results at the 2017 Annual Meeting of AACR.

To arrive at the study of the combination of lapatinib and trastuzumab, Dr Marsoni and colleagues first treated approximately 1000 patient avatars (mice with implanted CRC xenografts) with cetuximab. Then they did a genomic study of nonresponding avatars and found 7 that were HER2-amplified.

“We treated them and saw that they were sensitive to blockade with lapatinib plus trastuzumab, but not to either drug alone. The combination had a frank impact. If we didn’t study the combination of the 2 HER2-directed therapies, we would have missed this,” she explained.

The Italian group uses a strict definition of HER2 positivity: immunohistochemistry (IHC) 2+ and IHC 3+, confirmed by fluorescence in situ hybridization. “The difference between us and the rest of the world is that we wanted to select truly HER2-addicted patients, so our cutoff was that at least 50% of the cells had to be positive. Breast and gastric cancers have a cutoff of 10%, and this difference leads to confusion about what HER2-positivity means,” she noted.

These observations led to the HERACLES-A, HERACLES-B, and 4 other trials in the HERACLES series that will enroll patients with HER2-positive metastatic CRC.

HERACLES-A screened 1277 patients to identify 44 patients with HER2-positive disease (according to their definition): 33 enrolled in HERACLES-A and 11 enrolled in HERACLES-B.

In HERACLES-A, treatment with lapatinib plus trastuzumab achieved a disease control rate of 70% (23 patients); 30% (10 patients) had an objective response, and 2 patients had a complete response. Of the 2 complete responders, 1 is still alive with no evidence of disease progression at 36 months.

“When the tumor is truly addicted [to HER2], radiology scans show responses are impressive and durable. There is little toxicity—20% less than when lapatinib is used to treat breast cancer,” Dr Marsoni noted.

The combination was well tolerated, and no patient went off treatment due to toxicity.

These results in HER2-positive CRC put lapatinib plus trastuzumab in a response bracket with immunotherapy (ORR 30% and 35%, respectively). Response rates are approximately 15% for anti-EGFR therapy, 12% for anti-BRAF combinations, and 5% for chemotherapy as third-line options.

The HERACLES-B trial will treat patients with trastuzumab emtansine to determine response. Thus far, only 8 patients have enrolled, and 7 have clinical benefit. Results will be reported at a later date.

“These findings are pretty important, that now 2 HER2-directed therapies are effective in this subset of colorectal cancer patients who don’t respond well to other options,” said George Demetri, MD, Dana-Farber Cancer Institute, Boston, MA, who moderated a press conference at AACR.

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