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


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
None.
Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Keith T
KT
Flaherty
Biostatistics and Epidemiology, GlaxoSmithKline, Munich, Germany.
Michael
M
Hennig
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Sandra J
SJ
Lee
Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy-Istituto Nazionale Tumori Fondazione "G Pascale", Napoli, Italy.
Paolo A
PA
Ascierto
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Reinhard
R
Dummer
Gustave Roussy Cancer Campus, Paris-Sud University Grand Paris, Villejuif, France.
Alexander M M
AM
Eggermont
Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, University Hospital Kiel, Kiel, Germany.
Axel
A
Hauschild
Westmead Hospital and Melanoma Institute Australia, University of Sydney, NSW, Australia.
Richard
R
Kefford
Skin Cancer Program University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
John M
JM
Kirkwood
Melanoma Institute Australia and the University of Sydney, Sydney, NSW, Australia.
Georgina V
GV
Long
Institute of Cancer Sciences, Faculty of Medical & Human Sciences, University of Manchester, Manchester, UK.
Paul
P
Lorigan
Department of Internal Medicine 5-Hematology/Oncology, University of Erlangen, Erlangen, Germany.
Andreas
A
Mackensen
Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, VIC, Australia.
Grant
G
McArthur
Beverly Hills Cancer Center, Beverly Hills, CA, USA.
Steven
S
O'Day
Academic Unit of Oncology, University of Nottingham, Nottingham, UK.
Poulam M
PM
Patel
Dermatology and INSERM Unit 981 Gustave Roussy Cancer Campus and Paris-Sud University Grand Paris, Villejuif, France.
Caroline
C
Robert
Department of Dermatology, University Hospital Essen, Essen, Germany. Electronic address: dirk.schadendorf@uk-essen.de.
Dirk
D
Schadendorf
D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D015415:Biomarkers; D003606:Dacarbazine / Q000627:therapeutic use; D018572:Disease-Free Survival; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000401:mortality* / Q000556:secondary; D016032:Randomized Controlled Trials as Topic
D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D003606:Dacarbazine