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9-week vs standard trastuzumab course improves cardiotoxicity but not survival

Jairia Dela Cruz
19 Oct 2018

An adjuvant trastuzumab treatment course shortened to 9 weeks has failed to demonstrate noninferiority to the standard 1-year course in terms of disease-free survival (DFS) in breast cancer patients, although the shortened course confers benefits for the risk of severe cardiac toxicity, according to the results of the phase III randomized Short-HER study.

“The noninferiority of 9 weeks trastuzumab cannot be claimed on the basis of the frequentist approach,” investigators said, adding that the 1-year course remains the standard.

“However, a 9-week administration could be an option for those patients who experience cardiac events and for those with a low risk of relapse. Moreover, this regimen might facilitate the access to trastuzumab to patients living in countries with limited resources,” they said.

Short-HER included 1,253 HER2-positive breast cancer patients (median age 55 years; 64 percent postmenopausal) randomized to receive sequential anthracycline-taxane combinations plus either 1-year (long; n=627) or 9-weeks trastuzumab (short; n=626). Patients were node-positive or, if not, showed at least one risk factor for lymph node positivity.

Over a median follow up of 6 years, 200 DFS events were documented: 95 (15 percent) in the long arm and 105 (17 percent) in the short arm. The primary endpoint of DFS at 5 years was 88 vs 85 percent, respectively. On Cox analysis, the estimated hazard ratio (HR) for DFS was 1.13 (90 percent CI, 0.89–1.42), with the upper limit of CI crossing the noninferiority margin. [Ann Oncol 2018;doi:10.1093/annonc/mdy414]

The 5-year overall survival rates were 95.2 percent in the long arm vs 95.0 percent in the short arm (HR, 1.07; 0.74–1.56).

“According to the preplanned Bayesian analysis, the probability that a short treatment is not inferior to the long one is 80 percent, supporting that the hypothesis of noninferiority cannot be ruled out,” the investigators noted.

Results for the secondary endpoint of cardiac events, however, were significantly more favourable in the short arm. Specifically, grade >2 events occurred with greater frequency in the long arm (13.1 percent vs 4.3 percent; risk ratio, 0.33; 0.22–0.50; p<0.0001).

Permanent discontinuation of treatment was reported in 53 patients (8.5 percent) in the long arm and 21 (3.4 percent) in the short arm. The 2-year failure rate was 9.4 percent vs 8.6 percent, respectively (risk ratio, 0.92; 0.64–1.30).

Taken together, the findings may be “clinically relevant as up to 8 percent of patients in pivotal trials could not start trastuzumab and up to 15 percent had to discontinue trastuzumab because of cardiac events,” the investigators said.

“The issue of treatment de-escalation is an increasingly relevant topic due to the availability of more effective treatments and more favourable patient outcomes,” they continued.

Aside from Short-HER, de-escalated trastuzumab duration has been previously addressed in Phare, SOLD and PERSEPHONE. The first two trials evaluated the noninferiority of 9-week administration, while the third one assessed a 6-month treatment course. [Lancet Oncol 2013;14:741-748; JAMA Oncol 2018;4:1199-1206; J Clin Oncol 2018;36(suppl):abstract 506]

“Phare, SOLD and ShortHER, can be considered nonconclusive, not having proven noninferiority, while the larger PERSEPHONE study has proven the noninferiority of 6 months trastuzumab. Noteworthy, all the four trials have consistently shown that a significant proportion of patients is at low risk of relapse and a shorter trastuzumab treatment administration would not compromise the outcome, while reducing the risk of cardiac events,” they pointed out.

The investigators said they are planning to conduct a meta-analysis of individual patient data from all randomized controlled trials evaluating shortened trastuzumab course in order to identify subgroups of patients in which a shorter treatment can provide equivalent outcomes with lower toxicity.

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Most Read Articles
Jairia Dela Cruz, 14 Jan 2019
The potassium-competitive acid blocker vonoprazan demonstrates superior efficacy in the treatment of patients with erosive oesophagitis compared with the proton pump inhibitor lansoprazole, with the results of a small trial showing that the former more rapidly provides complete sustained heartburn relief during the first week of therapy.
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08 Jan 2019
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