Trastuzumab for the treatment of HER2-positive metastatic adenocarcinoma of the
stomach or gastro-oesophageal junction.
Author(s): Norman G, Rice S, Spackman E, Stirk L, Danso-Appiah A, Suh D, Palmer S, Eastwood
A.
Affiliation(s): Centre for Reviews and Dissemination, University of York, York, UK.
gn5@york.ac.uk
Publication date & source: 2011, Health Technol Assess. , 15 Suppl 1:33-42
This paper presents a summary of the evidence review group (ERG) report into
trastuzumab for the treatment of human epidermal growth factor receptor 2
(HER2)-positive metastatic adenocarcinoma of the stomach (mGC) or
gastro-oesophageal junction. HER2 positivity is defined by immunohistochemistry
(IHC)3+ or IHC2+/fluorescence in situ hybridisation (FISH)+. The decision problem
addressed was the testing of the whole mGC population with IHC and, for IHC2+
patients, also with FISH, followed by treatment of HER2-positive patients with
trastuzumab combined with cisplatin and either capecitabine or 5-fluorouracil
(5-FU) [HCX (trastuzumab, cisplatin, capecitabine)/fluorouracil (F)] compared
with current standard NHS therapy. The manufacturer's submission contained direct
evidence from the ToGA trial, a well-conducted, multinational, phase III
randomised controlled trial (RCT) that compared HCX/F with cisplatin and a
fluoropyrimidine alone [cisplatin, capecitabine (CX)/F]. HCX/F showed
statistically significantly better overall survival in the European Medicines
Agency-licensed population subgroup (74%) (hazard ratio 0.65, 95% confidence
interval 0.51 to 0.83), corresponding to median survival of 16 months versus 11.8
months. No other evidence exists for the efficacy of any therapy in a known
HER2-positive mGC population; other comparisons extrapolate from trials in mixed
HER2 status populations. The ERG accepted the manufacturer's view that a
meaningful network meta-analysis to establish a comparison for HCX/F compared
with current standard NHS therapy [epirubicin, cisplatin, capecitabine
(ECX)/epirubicin, oxaliplatin, capecitabine (EOX)/epirubicin, cisplatin, 5-FU
(ECF)] was not possible, but was unconvinced by arguments advanced in the
alternative narrative synthesis. These involved disregarding evidence from a
meta-analysis and interpreting non-significant results of small RCTs comparing
epirubicin-containing triplets with cisplatin, 5-FU (CF)/capecitabine (X)
doublets as evidence of no difference between triplet and doublet regimens. The
high CX/F dose in the ToGA trial was an additional basis for the contention of
equivalence. An appropriate de novo economic evaluation, including an economic
model that separately compared HCX or trastuzumab, cisplatin, 5-FU (HCF) with the
triplet regimens ECX, EOX and ECF, based on a simple, three-state cohort model
(progression-free, disease, progression and death), was submitted. Utility
weights were applied to estimate quality-adjusted life-years (QALYs). Costs were
assessed from an NHS perspective, and incorporated the acquisition and monitoring
costs of the alternative regimens, HER2 testing, adverse events and other
supportive care costs. An 8-year time horizon was used to represent a lifetime
analysis. Results from the ToGA trial were combined with a series of assumptions
on relative treatment effects and testing strategies. The manufacturer's results
produced an incremental cost-effectiveness ratio (ICER) of £ 53,010 per QALY for
HCX versus ECX. Although the manufacturer undertook a detailed set of sensitivity
analyses, several alternative model assumptions were not evaluated. The ERG
undertook a series of alternative base-case analyses. As a result of these
analyses, EOX replaced ECX as the appropriate comparator, and the ICER for the
comparison of HCX vs EOX increased to between £ 66,982 and £ 71,636 per QALY. The
impact of implementation of alternative testing strategies remained unclear.
There is also considerable uncertainty surrounding the true estimate of
effectiveness for the comparison between triplet regimens containing epirubicin
(ECX/ECF/EOX) and doublet CX/F regimens. Consequently, the view of the ERG was
that there is insufficient evidence on the efficacy of HCX/F compared with
current NHS standard therapy for an ICER to be determined with any degree of
certainty.
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