Dual HER2 Targeting of HER2-Positive Metastatic Colorectal Cancer Shows Clinical Benefit

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The combination of trastuzumab (Herceptin) plus lapatinib (Tykerb) achieved positive results in patients with heavily pretreated, HER2-positive metastatic colorectal cancer, according to the final results of the phase II HERACLES-A trial. This two-pronged, HER2-directed approach achieved clinical benefit in 70% of patients and an overall response rate of 30%. These patients typically do not respond well to available therapies for colorectal cancer.

With an overall clinical benefit of 70%, … this combination represents a potential new treatment option for HER2-positive colorectal cancer.
— Silvia Marsoni, MD

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“Even if HER2-positive patients represent only 3% of all colorectal cancers, they are an important piece of the pie. By 2035, the yearly incidence of colorectal cancer will be 2.4 million, so there will be 70,000 HER2-positive patients. This study shows that patients with as many as five prior lines of therapy can still have responses—and durable responses—with a nonchemotherapy regimen. We have 1 patient still in complete response with no evidence of disease at 36 months,” said senior author Silvia Marsoni, MD, of Fondazione del Piemonte per l’Oncologia IRCCS, in Turin, Italy. Dr. Marsoni presented the final results of HERACLES-A at the 2017 American Association for Cancer Research (AACR) Annual Meeting.1

“With an overall clinical benefit of 70%, since these are patients who do not respond to cetuximab [Erbitux] or panitumumab [Vectibix], this combination represents a potential new chemotherapy-free treatment option for HER2-positive colorectal cancer,” she stated.

Study Background

“We started using targeted therapy for colorectal cancer in 2004, but we really didn’t have a target. We targeted the epidermal growth factor receptor (EGFR), but that oncogene is neither mutated, amplified, nor translocated in 99% of colorectal cancers. This makes colorectal cancer ­‘targeted’ therapy different,” she explained, “and is the reason why the anti-EGFR cetuximab or panitumumab are not that effective,” she added.

Dr. Marsoni and colleagues sought to identify treatment targets in metastatic colorectal cancer via molecular investigation. They studied mouse avatars—an experimental technique for identifying the best treatment choice for particular patients—totaling about 1,000 mice with implanted colorectal tumor xenografts from

Treating HER2-Positive Colorectal Cancer

  • The phase II HERACLES-A study used meticulous biomarker selection of patients with HER2-amplified colorectal cancer, who typically do not respond well to conventional treatment options.
  • A two-pronged strategy using HER2-directed therapies yielded positive results in this subset of patients.
  • Lapatinib plus trastuzumab is a potential new treatment option for treatment-refractory HER2-positive colorectal cancer.

“We wanted to capture mutations in a low-frequency population, so we needed big numbers. Our ‘mouse oncologists’ Livio Trusolino and Andrea Bertotti treated the avatars with cetuximab and then studied the genomic landscape in nonresponding avatars. These avatars had mostly KRAS-, BRAF-, and NRAS-mutated disease but also had other aberrations. We had seven avatars that were HER2-amplified,” she explained.

“When we treated them, we saw they were sensitive to blockade with lapatinib plus trastuzumab but not to either drug alone. The combination had a clear impact. If we didn’t study the combination of the two HER2-directed therapies, we would have missed this. The problem is that research tends to go from discovery to the clinic without the studies that show interplay between tumor cells and tissue lineage,” she told listeners.

Dr. Marsoni explained that the definition of HER2-positive was stringent in this trial. Patients had to be immunohistochemistry (IHC) 2+ or IHC 3+ and confirmed by fluorescence in situ hybridization (FISH). “The difference between us and the rest of the world is that we wanted HER2-addicted tumors, 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 increases the ambiguity about what HER2 positivity means,” she noted. “Our definition of HER2 positivity selects for truly addicted tumors,” she added.

Seven HERACLES Trials

These observations led to a series of seven trials: two diagnostic, three therapeutic (HERACLES-A, ­HERACLES-B, and HERACLES ­RESCUE), and two translational studies. HERACLES-B is evaluating pertuzumab (Perjeta) and ado-trastuzumab emtansine (also known as T-DM1 [Kadcyla]), and HERACLES RESCUE is looking at ado-trastuzumab emtansine monotherapy in metastatic colorectal cancer that has progressed on lapatinib and trastuzumab in HERACLES-A. At the AACR meeting, Dr. Marsoni presented final results of the proof-of-concept phase II ­HERACLES-A trial.

Of 1,277 screened patients with metastatic, KRAS exon 2 wild-type colorectal cancer, 69 were HER2-positive (25 of them not eligible). The researchers enrolled 44 patients with HER2-positive disease [according to the IHC/FISH criteria described above]—33 in ­HERACLES-A and 11 in HERACLES-B.


In HERACLES-A, treatment with lapatinib plus trastuzumab achieved disease control in 23 patients (70%); 10 patients (30%) had an objective response, and 2 patients (6%) 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 also little toxicity, because we used 20% less dosage than when lapatinib is used to treat breast cancer,” Dr. Marsoni noted.

The combination was well tolerated, with grade 3 toxicity only in a handful of patients (1 case of diarrhea, 4 cases of fatigue, and 1 case of skin toxicity). No patient went off treatment due to toxicity.

In the context of historical response rates for standard and emerging third-line therapy and beyond in colorectal cancer, lapatinib plus trastuzumab did almost as well as immunotherapy (overall response rate = 30% and 35%, respectively). Response rates are about 15% for anti-EGFR therapy, 12% for anti-BRAF combinations, and 5% for chemotherapy as third-line options.

In HERACLES-A, 75% of patients had received 4 or more prior lines of therapy. All cases were resistant to ­cetuximab or panitumumab.

Next Steps

“We were not satisfied, so we decided to tweak the combination by adding to the HER2-targeting component a HER2-driven chemotherapy using [ado-trastuzumab emtansine] to deliver the toxic cargo into the cells. We enrolled 12 patients in HERACLES-B who will receive pertuzumab plus [ado-trastuzumab emtansine]. This may be a way to optimize therapy for HER2-positive colorectal cancer,” Dr. Marsoni said, “because in the only avatar that did not respond well to the HERACLES-A combination of lapatinib plus trastuzumab, this new strategy was very effective.”

Of eight response-evaluable patients in HERACLES-B, seven had a clinical benefit (two partial responses) from pertuzu­mab plus ado-trastuzu­mab emtansine. Thus far, the numbers are too small to draw any conclusions, but “preliminary results are exciting,” she commented. “We are also satisfied because HERACLES is academically driven and powered by a fantastic mix of translational scientists and clinicians led by Salvatore Siena of ­Niguarda Cancer Center in Milano.”

George ­Demetri, MD

George ­Demetri, MD

“These investigators went about this in a thoughtful, systematic way…. They maximized the chance of response by using high expressers of HER2, and they set the bar higher for HER2 expression. These findings are important: Now we know two HER2-directed therapies are effective in this subset of colorectal cancer patients who don’t respond well to other options,” said George ­Demetri, MD, of Dana-Farber Cancer Institute, Boston. Dr. Demetri moderated a press conference where these data were ­discussed. ■

Disclosure: Dr. Marsoni is on advisory boards for Ignyta, Merrimack, and Roche. Dr. Demetri reported no potential conflicts of interest


1. Siena S, Sartore-Bianchi A, Trusolino L, et al: Final results of the HERACLES trial in HER2-amplified colorectal cancer. 2017 AACR Annual Meeting. Abstract CT005. Presented April 2, 2017.

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