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- February 7, 2014 at 5:07 pm
PFS as a Surrogate Endpoint for Survival in Metastatic Melanoma
Lancet Oncol 2014 Jan 31;[EPub Ahead of Print], KT Flaherty, M Hennig, SJ Lee, PA Ascierto, R Dummer, AMM Eggermont, A Hauschild, R Kefford, JM Kirkwood, GV Long, P Lorigan, A Mackensen, G McArthur, S O'Day, PM Patel, C Robert, D Schadendorf
Research · February 06, 2014TAKE-HOME MESSAGE
- In an effort to characterize survival, investigators performed a retrospective analysis using 12 clinical trials enrolling > 4400 patients with metastatic melanoma and demonstrated that PFS can serve as an accurate surrogate for overall survival.
- This demonstration has potential significant implications for future trial design and novel agent approval, especially if PFS is deemed an appropriate clinical endpoint.
– Chris Tully, MD
ABSTRACT
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 0·71 (95% CI 0·29—0·90) with a random-effects assumption, 0·85 (0·59—0·95) with a fixed-effects assumption, and 0·89 (0·68—0·97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0·96 (0·81—0·99), which decreased to 0·93 (0·74—0·98) 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 (0·55, 0·03—0·84). 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 0·85 (0·51—0·96).
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.
The Lancet OncologySurrogate Endpoints for Overall Survival in Metastatic Melanoma: A Meta-Analysis of Randomised Controlled Trials
Lancet Oncol 2014 Jan 31;[EPub Ahead of Print], KT Flaherty, M Hennig, SJ Lee, PA Ascierto, R Dummer, AMM Eggermont, A Hauschild, R Kefford, JM Kirkwood, GV Long, P Lorigan, A Mackensen, G McArthur, S O'Day, PM Patel, C Robert, D Schadendorf
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