59: Validating the Use of Surrogate Endpoints to Assess the Survival Outcomes of Melanoma Patients in Clinical Trials

Friday, March 24, 2023

10:44 AM – 10:54 AM

Location: Veterans Memorial Auditorium

Abstract Presenter(s)

Marc D. Moncrieff, MD FRCS(Plast.)

Professor of Plastic and Reconstructive Surgery
Norfolk & Norwich University Hospital
Norwich, United Kingdom

Disclosure(s): No financial relationships to disclose

First Author(s)

Marc D. Moncrieff, MD FRCS(Plast.)

Professor of Plastic and Reconstructive Surgery
Norfolk & Norwich University Hospital
Norwich, United Kingdom

Disclosure(s): No financial relationships to disclose

Author(s)

SL

Serigne Lo, MSc, PhD

A/prof
Melanoma Institute Australia; The University of Sydney, United States

Disclosure(s): No financial relationships to disclose
RS

Robyn Saw, MBBS, FRACS, MS

A/prof
Melanoma Institute Australia, Royal Prince Alfred Hospital, University of Sydney, United States

Disclosure information not submitted.
KS

Kerwin Shannon, MBBS, FRACS

Surgeon
Melanoma Institute of Australia, University of Sydney, Sydney, Australia, United States

Disclosure information not submitted.
AS

Andrew Spillane, MD FRACS BM BS

Professor
Melanoma Institute Australia,, United States

Disclosure information not submitted.
JS

Jonathan Stretch, D.Phil (Oxon) FRACS, AM

A/prof
Melanoma Institute Australia, Royal North Shore Hospital, United States

Disclosure information not submitted.
MH

Martin Heaton, MD FRCS(Plast.)

Consultant Plastic & Reconstructive Surgeon
Norfolk & Norwich University Hospital Foundation NHS Trust
Norwich, Norfolk, England, United Kingdom

Disclosure information not submitted.
AS

Andrew Snelling, FRCS(Plast.)

Consultant Plastic & Reconstructive Surgeon
Norfolk & Norwich University Hospitals NHS Trust, Norwich, UK
Norwich, England, United Kingdom

Disclosure information not submitted.
SC

Sydney Ch'ng, PhD, AFRCS

A/ Prof Plastic and Reconstructive Surgeon
Melanoma Institute Australia
Sydney, New South Wales, Australia

Disclosure information not submitted.
Omgo E. Nieweg, MD, PhD

Senior surgeon
Melanoma Institute Australia
North Sydney, New South Wales, Australia

Disclosure information not submitted.
John Thompson, MD

Emeritus Professor Melanoma and Surgical Oncology
Melanoma Institute Australia, The University of Sydney
North Sydney, New South Wales, Australia

Disclosure information not submitted.

Disclosure(s):

Marc D. Moncrieff, MD FRCS(Plast.): No financial relationships to disclose

Serigne Lo, MSc, PhD: No financial relationships to disclose

Introduction: Phase III clinical trials investigating the efficacy of adjuvant systemic therapy for high-risk, resected melanoma are ongoing, though it has already been approved as an international standard of care for AJCC stage IIB-IIC & III following sentinel node biopsy (SNB). These approvals were unusual, in that the median follow-up periods were relatively short and were based on improved disease-free survival (DFS) rather than the accepted gold standard endpoint overall survival (OS). The correlation between surrogate endpoints and OS has yet to be fully validated for melanoma.

Methods: 6269 primary melanoma patients staged with SNB at two large academic centres in Australia and the UK (2000-’20). Endpoints assessed included DFS, distant metastasis-free (DMFS), disease-specific (DSS) and OS.

Results: Median follow-up was 48 months (IQR: 23-86 months). The 5-yr DFS for SNB negative and SNB positive patients was 76.7% and 40.7%, respectively (HR=2.86, p< 0.001). The 5-yr DMFS for SNB negative and SNB positive patients was 83.8% and 58.7%, respectively (HR=2.91, p< 0.001). The 5-yr OS for SNB negative and SNB positive patients was 84.6% and 65.4%, respectively (HR=2.34, p< 0.001). The individual patient-level correlation coefficients of DFS with OS for the pooled dataset at 1,2,3, 5 and 10 years (0.30, 0.43, 0.50, 0.53 & 0.53, respectively), did not satisfy the accepted criteria for surrogacy of endpoints for cancer trials. Similar results were seen for DMFS and OS; and DFS with DSS. In contrast, there was very strong individual patient-level correlation between DFS and DMFS from 2 years onwards (coefficients >0.75 at 2,3,5 and 10 years). Trial-level validation of the surrogate endpoints was assessed by correlating log hazard ratios of the endpoints, stratified by centre, AJCC T-stage and SNB status. Trial-level correlations of DFS with OS and DSS were very high (R2=0.89, p=0.003 & R2=0.95, p< 0.001; respectively). Closely matching results were seen with DMFS and PFS, when compared to DFS, OS and DSS (figure 1).

Conclusions: The data suggest that DFS is a good surrogate endpoint for both OS and DSS when designing and interpreting clinical trials investigating adjuvant systemic therapy for cutaneous melanoma patients. However, our analysis suggested caution in the premature interpretation of the DFS endpoint, particularly before 5 years. DFS and DMFS are highly correlated beyond 2 years at the individual patient level which would suggest that systemic imaging should be used as a screening strategy for a minimum of three years when designing interventional clinical trials for high-risk melanoma.
Learning Objectives:
Define surrogate endpoints for survival in cancer trials
Assess the validity of disease free survival as a surrogate endpoint for distant metastasis-free and overall survival at the individual patient level for melanoma
Assess the validity of disease free, distant metastasis-free and progression-free survival as a surrogate endpoints for overall or specific survival at the trial level for melanoma