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T-DM1 not Superior to Taxane in HER-2–Positive Gastric, GE Junction Cancer
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SAN FRANCISCO — Among patients with previously treated HER-2–positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, second-line trastuzumab emtansine did not demonstrate superior efficacy compared with a taxane in a phase 2/3 trial, according to data presented at the Gastrointestinal Cancers Symposium.
Trastuzumab emtansine, or “T-DM1, is an antibody drug conjugate of DM1 linked by a stable thioether to trastuzumab,” Yoon-Koon Kang, MD, PhD, from the department of oncology, Asan Medical Center, University of Ulsan College of Medicine in Seoul, South Korea, said during his presentation. “The EMILIA study demonstrated that T-DM1 significantly improved overall survival for patients with HER-2–positive metastatic breast cancer previously treated with trastuzumab plus taxane. T-DM1 has shown preclinical activity in HER-2–positive gastric cancer models, and as suggested in the trastuzumab pharmacokinetics, there is a possibility of lower T-DM1 [pharmacokinetics] in metastatic gastric cancer than in metastatic breast cancer.”
Yoon-Koon Kang
The open-label, global GATSBY trial enrolled 415 patients with HER-2–positive unresectable locally advanced or metastatic gastric or gastroesophageal (GE) junction cancer who progressed during or after first-line fluoropyrimidine plus platinum therapy with or without HER-2–targeted therapy. Overall, 109 centers from 28 countries participated from September 2012 to February 2015.
In the first stage of the trial for T-DM1 regimen selection, patients were randomly assigned to receive 3.6 mg/kg T-DM1 every 3 weeks, 2.4 mg/kg T-DM1 every week, or for controls, a physician’s choice of 80 mg/m2 paclitaxel every week or 75 mg/m2 docetaxel every 3 weeks. The weekly T-DM1 dose was selected for the second stage of the trial by an independent data monitoring committee, after which patients were randomly assigned to receive weekly T-DM1 or taxane. Overall survival (OS) served as the primary endpoint.
The end of June 2015 was the clinical cutoff date, by which point 228 patients had been randomized to weekly T-DM1 and 117 to taxane. Overall, 77.4% had previously received HER-2–targeted therapy, 29.9% had undergone gastrectomy and 46.1% were Asian.
“The baseline characteristics of the patients were well balanced between arms,” Kang said. “Briefly, men were predominant, about 40% of the patients were aged over 65 … and about 30% of the patients had GE junction [as the] primary site. Most of the patients had metastatic disease, and only a few patients had local advanced disease.”
Median OS was 7.9 months for the weekly T-DM1 group vs. 8.6 months for the taxane group (HR = 1.15; 95% CI, 0.87-1.51). Moreover, median progression-free survival was 2.7 months and 2.9 months, respectively. Grade ≥3 adverse events were numerically lower in the T-DM1 group (59.8% vs. 70.3%), while rates of serious adverse events, fatal adverse events and discontinued treatment due to adverse events were similar.
“The primary endpoint was not met,” Kang said. “In subgroup analysis, there was no subgroup favoring the T-DM1 arm. Notably … the hazard ratio was the same regardless of the prior HER-2–targeted therapy, and regarding the HER-2 immunohistochemistry testing, there was a trend favoring the taxane arm in patients who [were] HER-2 immunohistochemistry 2 positive. The results of the secondary endpoints were … consistent with [the] primary endpoint.
“We conclude that T-DM1 was well tolerated but did not show an efficacy benefit over taxane for HER-2–positive local advanced or metastatic gastric or gastroesophageal junction cancer.” – by Adam Leitenberger
Reference:
Kang Y-K, et al. Abstract 05. Presented at: Gastrointestinal Cancers Symposium; Jan. 21-23, 2016; San Francisco.
Disclosure: Kang reports consulting or advisory roles with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech and Taiho Pharmaceutical; and research funding from Bayer, Novartis and Roche/Genentech. Please see the abstract for a full list of all other researchers’ relevant financial disclosures.
Perspective
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Andrew H. Ko, MD
Are all HER-2–directed therapies that are approved for breast cancer destined to find their place in the treatment of gastric and gastroesophageal junction (GEJ) cancers as well? The answer, at least thus far, is no.
Following the initial approval of trastuzumab in 2010 for HER-2–positive gastric/GEJ cancers (based on ToGA trial data demonstrating a significant survival benefit when this agent was added to standard front-line chemotherapy), there has naturally been considerable interest in assessing other anti–HER-2 therapies for this indication. In addition to two negative phase 3 trials of the EGFR/HER-2 oral tyrosine kinase inhibitor lapatinib in the first- and second-line settings that failed to meet their survival endpoints (LOGiC, TyTAN), we now have results of the global phase 2/3 randomized GATSBY trial, in which the drug-antibody conjugate trastuzumab emtansine (T-DM1) did not demonstrate superiority compared to paclitaxel in the second-line setting for patients with advanced HER-2–positive gastric/GEJ cancer (even, interestingly, in the quarter of patients who had not received prior anti–HER-2 therapy).
Clearly, further elucidation of the differences in HER-2 biology between breast and gastric cancers is necessary, including understanding intrapatient tumor heterogeneity in HER-2 expression; the relative importance of HER-2 as a key oncogenic driver in different malignancies; and changes in HER-2 expression over the course of time and following selective pressure from serial lines of therapy. This also may lend insight into a current clinical uncertainty we face: should we be continuing patients with HER-2–positive advanced gastric/GEJ cancer on trastuzumab beyond front-line therapy at the point of switching chemotherapies? Additionally, we eagerly await readout of the JACOB trial, a randomized phase 3 study evaluating the addition of pertuzumab to chemotherapy plus trastuzumab in the first-line setting, to determine whether more comprehensive abrogation of HER-2 signaling has any significant impact in this disease.
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