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Combination of trastuzumab, XELOX shows promise for advanced gastric cancer
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The addition of trastuzumab to the standard first-line regimen of capecitabine plus oxaliplatin created a highly effective and well-tolerated combination for the treatment of advanced gastric cancer, according to results of a phase 2 study.
Advancements in the understanding of gastric cancer biology have led to targeted therapies focused on HER-2.
Trastuzumab (Herceptin, Genentech), a monoclonal antibody, was the first biological agent approved for the treatment of advanced gastric cancer. It is used in combination with fluoropyrimidine plus cisplatin for the treatment of HER-2–positive advanced gastric cancer.
Capecitabine plus oxaliplatin (XELOX) is a standard first-line regimen for advanced gastric cancer, but the combination of XELOX plus trastuzumab has not been studied.
Yoon-Koo Kang, MD, PhD, professor of medicine in the department of oncology at Asan Medical Center at University of Ulsan College of Medicine in Seoul, South Korea, and colleagues conducted an open-label, multicenter, single-arm study to evaluate trastuzumab in combination with XELOX.
Objective response rate served as the primary endpoint. Secondary endpoints included PFS, OS and toxicity.
Researchers identified 55 patients with HER-2–positive advanced gastric cancer at seven tertiary referral hospitals in Korea enrolled between August 2011 and February 2013. The median age of the patients was 57 years (range, 29-74).
Treatment was administered in 3-week cycles.
Patients received trastuzumab intravenously in an 8 mg/m² dose on day 1 of the first cycle, followed by a 6 mg/m² dose on day 1 of each additional cycle. They received 1,000 mg/m² oral capecitabine twice daily on days 1 to 14, as well as 130 mg/m² oxaliplatin via IV on day 1.
Median follow-up was 13.8 months (range, 6.1-23.9).
The confirmed ORR was 67% (95% CI, 54-80). Researchers reported a complete response in 4% of patients and a partial response in 64% of patients. The disease control rate — which included patients who demonstrated complete or partial response, as well as those who demonstrated stable disease — was 89% (95% CI, 78-95).
Median PFS was 9.8 months (95% CI, 7-12.6), and the 6-month PFS rate was 69%. Median OS was 21 months (95% CI, 6.4-35.7), and the 1-year OS rate was 63%.
Grade 3 or grade 4 adverse events occurred in 62% of patients. The most frequent were neutropenia (18%), anemia (11%) and peripheral neuropathy (11%). There was one treatment-related death caused by severe diarrhea and complicated sepsis.
“Our study demonstrates that a combination of trastuzumab and XELOX has a favorable toxicity profile and promising efficacy in patients with metastatic or unresectable HER-2–positive gastric cancer,” the researchers wrote. “Although [this] study was not a randomized trial, our results provide background for further validation of XELOX as a first-line backbone chemotherapy in combination with trastuzumab.” – by Anthony SanFilippo
Disclosure: The study was funded by Roche Korea. The researchers report research funding and honoraria from Roche and Sanofi.
Perspective
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Jimmy Hwang, MD
Ryu and colleagues reported the results of their multi-institutional phase 2 study of the combination of trastuzumab (Herceptin, Genentech) with oxaliplatin and capecitabine (CapeOx) in patients with unresectable, HER-2–positive gastric and gastroesophageal adenocarcinoma. Their findings extend, and perhaps improve, upon the results from the pivotal TOGA study, which demonstrated that in patients with HER-2–positive gastric and gastroesophageal adenocarcinoma, the addition of trastuzumab to a cisplatin/fluoropyrimidine improved survival and response. CapeOx/trastuzumab produced an impressive 64% overall response rate, 9.8-month median PFS and 21-month median survival. Survival at 1 year was 63%. The regimen was very well tolerated. A potentially important aspect of this report is that the trastuzumab is stated as having been dosed at 8 mg/m2 and 6 mg/m2 every 21 days, compared with 8 mg/kg and 6 mg/kg in TOGA. If this is correct, the study by Ryu and colleagues suggests an anti-cancer effect of trastuzumab at a significantly lower dose that TOGA demonstrated, reinforcing the question of optimal biological dose of targeted therapies.Regardless of the trastuzumab dose, these results are promising, but whether the CapeOx–trastuzumab combination is superior to cisplatin/fluoropyrimidine/trastuzumab is uncertain. In Ryu’s study, patients were selected for the study based on the central assessment of the presence of HER-2–positive disease, as defined by HER-2 3+ by immunohistochemistry (IHC), as was the case in 89% of patients, or HER-2 2+ by IHC and HER-2 amplified by fluorescence in situ hybridization. It has been demonstrated that the former group of patients have a greater benefit of chemotherapy with trastuzumab than the latter group, so it is possible that these impressive results simply reflect patient selection. However, even if CapeOx/trastuzumab is not superior to the “standard” chemotherapy combinations, the toxicity profile will likely lead many oncologists to adapt this regimen, especially as it has been demonstrated in several randomized studies that oxaliplatin and capecitabine are noninferior to cisplatin and infusional 5-fluorouracil, respectively.
The predominant question now is if there is an optimal chemotherapy backbone to combine with anti–HER-2 therapy, but whether we can improve upon anti–HER-2 therapy. Although tyrosine kinase inhibitors such as lapatinib (Tykerb, GlaxoSmithKline) have not demonstrated clear benefits in HER-2–positive gastric cancer, attempting to replicate the results in breast cancer, there are several randomized studies ongoing with newer antibodies, including pertuzumab (Perjeta, Genentech) and ado-trastuzumab emtansine (Kadcyla, Genentech).
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