Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials

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• 作者：Keith T Flaherty ; MD^a ; Michael Hennig ; PhD^b ; Sandra J Lee ; PhD^c ; Paolo A Ascierto ; MD^d ; Prof Reinhard Dummer ; MD^e ; Prof Alexander M M Eggermont ; PhD^f ; Axel Hauschild ; MD^g ; Prof Richard Kefford ; PhD^h ; Prof John M Kirkwood ; MDⁱ ; Georgina V Long ; PhD^j ; Paul Lorigan ; MD^k ; Prof Andreas Mackensen ; MD^l ; Grant McArthur ; PhD^m ; Steven O'Day ; MDⁿ ; Poulam M Patel ; MD^o ; Caroline Robert ; PhD^p ; Prof Dirk Schadendorf ; MD^q ; ^{dirk.schadendorf@uk-essen.de" class="auth_mail}
• 刊名：Lancet Oncology
• 出版年：March, 2014
• 年：2014
• 卷：15
• 期：3
• 页码：297-304
• 全文大小：260 K

文摘

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Summary

Background

Recent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable surrogate for overall survival through a meta-analysis of randomised trials.

Methods

We systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR). We correlated HRs for overall survival and PFS, weighted by sample size or by precision of the HR estimate, assuming fixed and random effects. We did sensitivity analyses according to presence of crossover, trial size, and dacarbazine dose.

Findings

After screening 1649 reports and meeting abstracts published before Sept 8, 2013, we identified 12 eligible randomised trials that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, we noted a strong correlation between the treatment effects for PFS and overall survival, which seemed independent of treatment type. Pearson correlation coefficients were 0路71 (95% CI 0路29-0路90) with a random-effects assumption, 0路85 (0路59-0路95) with a fixed-effects assumption, and 0路89 (0路68-0路97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0路96 (0路81-0路99), which decreased to 0路93 (0路74-0路98) when two additional trials with less than 50% crossover were included. Inclusion of mature follow-up data after at least 50% crossover (in vemurafenib and dabrafenib phase 3 trials) weakened the PFS to overall survival correlation (0路55, 0路03-0路84). Inclusion of trials with no or little crossover with the random-effects assumption yielded a conservative statement of the PFS to overall survival correlation of 0路85 (0路51-0路96).

Interpretation

PFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomised trials of metastatic melanoma; we postulate that this association will hold as treatment standards evolve and are adopted as the control arm in future trials.

Funding

None.