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HER-2–targeted therapy effective for treatment-refractory metastatic colorectal cancer
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The combination of trastuzumab plus lapatinib appeared clinically beneficial for patients with treatment-refractory HER-2–positive metastatic colorectal cancer, according to results of the phase 2 HERACLES trial presented at the American Association for Cancer Research Annual Meeting.
Amplification and mutations in HER-2 are found in 6% to 8% of RAS/RAF–wild type colorectal cancers, which account for approximately 60% of colorectal cancers.
Preclinical studies demonstrated that shutting down the HER family of proteins through multiple mechanisms may be necessary to effectively treat HER-2–positive colorectal cancer.
Dual HER-2 blockade use with trastuzumab (Herceptin, Genentech) — a monoclonal antibody that targets HER-2 — and lapatinib (Tykerb, Novartis), a HER-1/HER-2 tyrosine kinase inhibitor, are known to inhibit tumor growth in patient-derived tumor grafts of HER-2–amplified metastatic colorectal cancer.
Salvatore Siena, MD, professor of medical oncology at Università degli Studi di Milano and director of Niguarda Cancer Center at Grande Ospedale Metropolitano Niguarda in Italy, and colleagues conducted the HERACLES trial to evaluate the use of HER-2–targeted therapies in patients with heavily pretreated metastatic colorectal cancer.
Patients in cohort A received a 4-mg/kg trastuzumab loading dose, followed by 2 mg/kg weekly, plus 1,000 mg lapatinib daily until disease progression.
Patients in cohort B received pertuzumab (Perjeta, Genentech) — another monoclonal antibody that targets HER-2, and ado-trastuzumab emtansine (Kadcyla, Genentech), an antibody–drug conjugate that pairs trastuzumab with the cytotoxic drug emtansine.
Overall response rate served as the primary endpoint. Secondary endpoints included PFS and safety.
Siena and colleagues identified 69 (5.3%) RAS wild-type tumors out of 1,299 HER-2–positive cancers.
Cohort A of the HERACLES trial included 33 heavily refractory patients evaluable for response.
Ten patients (30.3%) achieved an objective response. Two achieved complete responses and eight achieved partial responses.
Thirteen patients (39.3%) demonstrated stable disease, contributing to a 70% (95% CI, 52-82) disease control rate.
“These are very positive results, bearing in mind that these patients had received an average of five previous treatments,” Siena said.
The two patients who achieved complete response remained disease free at the time of analysis, which occurred 4 years after treatment initiation for one patient and a year after treatment initiation for the other.
“Both had tumors refractory to cetuximab (Erbitux, Eli Lilly) and had become resistant to all standard chemotherapies,” Sienna added. “This means that HER-2–targeted therapy can be a potential standalone, low-toxicity treatment approach for this patient population.”
Toxicity appeared mild. Six (18%) patients experienced grade 3 side effects, including fatigue, skin rash and elevated bilirubin. Researchers observed no drug-related serious adverse events.
“It is also clear from our results that HER-2 amplification is both a positive predictor of response to anti–HER-2 treatment and a negative predictor of response to anti-EGFR therapy,” Siena said.
Ten patients are enrolled in cohort B of the HERACLES trial. Of the eight who are evaluable for response, seven have demonstrated tumor shrinkage, and two have met RECIST criteria for objective response.
“We believe that HERACLES demonstrated the efficacy of HER-2 targeting because the right patients were selected for the right treatment,” Siena said. “We suggest that oncologists determine HER-2 status at diagnosis of metastatic disease in colorectal cancer patients, and collect information about anti-EGFR response in HER-2–positive cases.” – by Kristie L. Kahl
Reference:
Siena S, et al. Abstract CT005. Presented at: American Association for Cancer Research Annual Meeting; April 1-5, 2017; Washington, D.C.
Disclosure: Siena reports clinical investigator and advisory board roles with Amgen, Bayer, Celgene, Eli Lilly, Merck, Merrimack, Novartis, Roche and Sanofi.
Perspective
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Wafik S. El-Deiry, MD, PhD, FACP
HERACLES is an exciting trial that has been going on for the last few years, and earlier reports have caught our attention. It is great to see the final results coming out this year.
This is an important trial because of the number of patients each year who die of colorectal cancer — almost 45,000 in the United States — and the number who may benefit from these findings, estimated at more than 1,000.
It is clear HER-2 is a relevant, important and underappreciated therapeutic target in colorectal cancer.
The response rate of 30% and patient benefit in up to 70% should significantly impact the care of patients with advanced colorectal cancer.
Advanced tumors should be tested for this target, because the treatments are available immediately.
More studies need to be conducted in other subtypes of colon cancer — such as those that are not wild-type for RAS — to determine potential benefit, if any, for more patients.
There are other questions. For example, if an early-stage tumor has a targetable HER-2 alteration, should they be treated differently?
Another question is whether the HER-2 alteration is mostly happening as a resistance mechanism to anti-EGFR therapy, or do some patients inherently have this abnormality that drives their tumor.
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