Lapatinib or trastuzumab in combination with an aromatase inhibitor for first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2
The Lancet Oncology - Volume 13, Issue 8 (August 2012) - Copyright © 2012 Elsevier -
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Lapatinib or trastuzumab in combination with an aromatase inhibitor for first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2
Sally Dossa
Janet Robertsona
Jane Adama
a National Institute for Health and Clinical Excellence, MidCity Place, London, UK
PII S1470-2045(12)70290-5
On 27 June, 2012, NICE published guidance which did not recommend lapatinib or trastuzumab in combination with an aromatase inhibitor for first-line treatment in postmenopausal women with metastatic hormone-receptor-positive breast cancer that overexpresses HER2.[1]
Lapatinib and trastuzumab in combination with aromatase inhibitors were appraised under the Multiple Technology Appraisal process, which is the original appraisal process that is now used mainly for reviews of existing appraisals or to appraise more than one technology for the same indication. An independent Assessment Group (Liverpool Reviews and Implementation Group) prepared a review of the clinical effectiveness and cost-effectiveness of lapatinib or trastuzumab in combination with an aromatase inhibitor based on a systematic review of the medical literature and a review of the submissions from the manufacturer of lapatinib (GlaxoSmithKline, Brentford, UK) and trastuzumab (Roche Products, Welwyn Garden City, UK).[2] Over the course of the appraisal, the Appraisal Committee met five times to develop the guidance.
The Assessment Group identified three randomised controlled trials: one that compared lapatinib in combination with letrozole with letrozole alone (EGF30008);[3] one comparing trastuzumab in combination with anastrozole with anastrozole alone (TAnDEM);[4] and one comparing trastuzumab in combination with letrozole with letrozole alone (eLEcTRA).[5] The eLEcTRA study was halted because of slow recruitment and so was not used to estimate effectiveness.
The evidence from the EGF30008 trial indicated that for patients with hormone-receptor-positive breast cancer that overexpresses HER2, median progression-free survival was 8·2 months for the lapatinib-plus-letrozole group and 3·0 months for the letrozole-alone group (hazard ratio [HR] for progression 0·71, 95% CI 0·53–0·96, p=0·019). Median overall survival for patients with hormone-receptor-positive breast cancer that overexpresses HER2 was 33·3 months in the lapatinib-plus-letrozole group and 32·3 months for the letrozole-alone group (HR for death 0·74, 95% CI 0·49–1·12, p=0·113). Evidence from the TAnDEM trial indicated that for the intention-to-treat (ITT) population, median progression-free survival was 4·8 months (95% CI 3·7–7·0) for the trastuzumab-plus-anastrozole group and 2·4 months (2·0–4·6) for the anastrozole-alone group (HR for progression 0·63, 95% CI 0·47–0·84, p=0·002). In the ITT population, median overall survival was 28·5 months (95% CI 22·8–42·4) in the trastuzumab-plus-anastrozole group and 23·9 months (18·2–37·4) in the anastrozole-alone group (HR for death 0·84, 95% CI 0·59–1.20, p=0·33).
The Assessment Group did not consider it appropriate to conduct an indirect comparison of trastuzumab and lapatinib because they considered that the populations in the TAnDEM and EGF30008 studies differed substantially and exchangeability of relative treatment effect between trials could not be assumed. Conversely, both manufacturers submitted analyses in which trastuzumab and lapatinib were indirectly compared.
Both manufacturers provided economic analyses to support their submissions in which the technologies under assessment were compared with each other and with letrozole and anastrozole as monotherapies. Because of their concerns about the validity of any indirect comparisons, the Assessment Group did two separate cost-effectiveness analyses. The incremental cost-effectiveness estimates (ICERs) for lapatinib plus an aromatase inhibitor versus the aromatase inhibitor alone ranged from GBP£74 000 per quality-adjusted life-year (QALY) gained as submitted by GlaxoSmitheKline to £229 000 per QALY gained as calculated by the Assessment Group. For trastuzumab plus an aromatase inhibitor, ICERs ranged from £51 000 per QALY gained as submitted by Roche to an estimate in excess of £70 000 per QALY gained as calculated by the Assessment Group. Most of the discrepancies between the estimated ICERs could be explained by differences in time spent in the progression-free and post-progression states.
In the Assessment Group models, estimates of additional post-progression survival with treatment with either lapatinib or trastuzumab plus an aromatase inhibitor were negative—ie, patients spent less time in the post-progression state than did those receiving aromatase inhibitor alone; all the benefits of treatment were experienced in the pre-progression state. Conversely, in both the manufacturers' models, the estimates of both pre-progression and post-progression survival were positive relative to aromatase inhibitor alone.
At the first Committee meeting, the clinical specialists stated that in present UK clinical practice, women with metastatic breast cancer that overexpresses HER2 are more likely to receive trastuzumab in combination with chemotherapy than either trastuzumab or lapatinib in combination with an aromatase inhibitor. The combination of lapatinib or trastuzumab plus an aromatase inhibitor is most likely to be used in women who, in consultation with their clinicians, considered that chemotherapy is not the best option for first-line treatment of metastatic disease. The Committee considered the clinical evidence and concluded that lapatinib plus an aromatase inhibitor offered a benefit in progression-free survival but only a small and uncertain overall survival gain. It also concluded that trastuzumab plus an aromatase inhibitor is associated with a significant increase in median progression-free survival, but that the evidence did not demonstrate a significant increase in overall survival.
The Committee considered the different ICERs presented for the two technologies. It concluded that the Assessment Group's estimates were probably an overestimate and that the most plausible ICER for lapatinib plus an aromatase inhibitor would be near to the manufacturer's estimate of £74 000 per QALY gained and the ICER for trastuzumab plus an aromatase inhibitor would be at least £51 000 per QALY gained. The Committee agreed that the cost-effectiveness estimates for both technologies were high and subject to uncertainties which would increase, rather than decrease, the manufacturers' ICERs.
The Committee considered the supplementary advice from NICE for the appraisal of treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses.[6] The Committee discussed whether lapatinib or trastuzumab plus an aromatase inhibitor met the criteria and concluded that they did not fulfil the three end-of-life criteria. Therefore, in June, 2011, a final appraisal determination was issued,[7] in which the Committee concluded that neither lapatinib nor trastuzumab would be a cost-effective use of NHS resources when combined with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2 compared with an aromatase inhibitor alone.
The final appraisal determination was appealed by one consultee (Roche) and an appeal hearing was held in September, 2011. The appeal points related to the considerations around the application of the end-of-life criteria. The Appeal Panel upheld points under Ground 1 (procedural unfairness) and also Ground 2 (NICE formulated guidance which cannot reasonably be justified in the light of the evidence submitted). The Appeal Panel suggested that the Committee should reconsider the application of the end-of-life policy and all its criteria. It also noted that the appellant and other consultees should have an opportunity to comment during that reconsideration. After the Appeal decision, the Committee discussed the end-of-life criteria at two Committee meetings in January, and March, 2012. The Committee again concluded that lapatinib or trastuzumab plus an aromatase inhibitor did not fulfil the criteria for special consideration under the supplementary advice from NICE. The Committee concluded that neither drug could be recommended as cost-effective. Furthermore, the Committee considered that even if the end-of-life criteria had been met, the ICERs were too high to consider either drug to be a cost-effective use of NHS resources in this indication.
We declare that we have no conflicts of interest.
REFERENCES:
1 NICE: Technology Appraisal guidance TA257. Lapatinib or trastuzumab in combination with an aromatase inhibitor for first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2. (accessed June 27, 2012).
http://nice.org.uk/TA257June, 2012
2 Fleeman N, Bagust A, Boland A, et al: Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor positive breast cancer which over-expresses HER2. (accessed June 15, 2012).
http://www.nice.org.uk/nicemedia/liv.../52179.pdfSept 15, 2010
3 Johnston S, Pippen , Jr , JrJ, Pivot X, et al: Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27. 5538-5546.2009; Abstract
4 Kaufman B, Mackey JR, Clemens MR, et al: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 27. 5529-5537.2009; Abstract
5 Huober J, Fasching P, Paepke S, et al: Letrozole in combination with trastuzumab is superior to letrozole monotherapy as first line treatment in patients with hormone-receptor-positive, HER2-positive metastatic breast cancer (MBC): results of the eLEcTRA Trial. Cancer Res 69. 4094.2009;
6 NICE: Appraising life-extending, end of life treatments. (accessed June 15, 2012).
http://www.nice.org.uk/media/E4A/79/...TACEoL.pdfJuly, 2009
7 NICE: Final appraisal determination: lapatinib or trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that ov
UK Govt agency (NICE--ha!)"AI+ lapatinib, AI+herceptin not cost-effective 4 Stage IV)
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