Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II–III Melanoma Adjuvant Therapy

Suciu, Stefan; Eggermont, Alexander M.M.; Lorigan, Paul; Kirkwood, John M.; Markovic, Svetomir N.; Garbe, Claus; Cameron, David; Kotapati, Srividya; Chen, Tai-Tsang; Wheatley, Keith; Ives, Natalie; Schaetzen, Gaetan de; Efendi, Achmad; Buyse, Marc

doi:10.1093/jnci/djx133

Cited by 74 publications

(51 citation statements)

References 52 publications

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“…The use of RFS to extrapolate long-term survival within the model aligns with recent evidence on the natural history of resected highrisk melanoma. In a meta-analysis of randomized controlled trials of adjuvant interferon, Suciu et al 75 found a high degree of correspondence between the HR for recurrence or death and the HR for death, and concluded that RFS appears to be a valid surrogate endpoint for OS. Five-year data from the EORTC 18071 trial similarly showed that relative reductions in recurrence or death with ipilimumab vs placebo (HR ¼ 0.76) closely aligned with relative reductions in death (HR ¼ 0.72) 18 .…”

Section: Discussionmentioning

confidence: 99%

Cost-effectiveness of pembrolizumab for the adjuvant treatment of resected high-risk stage III melanoma in the United States

Bensimon

Zhou

Jenkins

et al. 2019

Journal of Medical Economics

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Aims: To evaluate the cost-effectiveness of adjuvant pembrolizumab relative to observation alone following complete resection of high-risk stage III melanoma with lymph node involvement, from a US health system perspective. Materials and methods: A Markov cohort model with four health states (recurrence-free, locoregional recurrence, distant metastases, and death) was developed to estimate costs, life-years, and qualityadjusted life-years (QALYs) associated with pembrolizumab vs observation over a lifetime (46-year) horizon. Using a parametric multi-state modeling approach, transition probabilities starting from recurrence-free were estimated based on patient-level data from KEYNOTE-054 (NCT02362594), a direct head-to-head phase 3 trial. Post-recurrence transition probabilities were informed by real-world retrospective data and clinical trials in advanced melanoma. Health state utilities and adverse eventrelated disutility were derived from KEYNOTE-054 trial data and published literature. Costs of drug acquisition and administration, adverse events, disease management, and terminal care were estimated in 2018 US dollars. Deterministic and probabilistic sensitivity analyses were conducted to assess robustness. Results: Over a lifetime horizon, adjuvant pembrolizumab and observation were associated with total QALYs of 9.24 and 5.95, total life-years of 10.54 and 7.15, and total costs of $489,820 and $440,431, respectively. The resulting incremental cost-effectiveness ratios (ICERs) for pembrolizumab vs observation were $15,009/QALY and $14,550/life-year. Across the range of input values and assumptions tested in deterministic sensitivity analyses, pembrolizumab ranged from being a dominant strategy to having an ICER of $57,449/QALY vs observation. The ICER was below a willingness-to-pay threshold of $100,000/QALY in 90.2% of probabilistic simulations. Limitations: Long-term extrapolation of outcomes was based on interim results from KEYNOTE-054, with a median follow-up of 15 months. Conclusions: Based on common willingness-to-pay benchmarks, pembrolizumab is highly cost-effective compared with observation alone for the adjuvant treatment of completely resected stage III melanoma in the US. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Cost-effectiveness of pembrolizumab for the adjuvant treatment of resected high-risk stage III melanoma in the United States

Bensimon

Zhou

Jenkins

et al. 2019

Journal of Medical Economics

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“…In the adjuvant setting, RFS is a surrogate for OS for both adjuvant interferon and adjuvant ipilimumab. 8 Extrapolating from this, it is assumed that RFS is a surrogate for OS with adjuvant PD-1 inhibitor therapy; therefore, it is expected that -provided the HR is large -RFS is a surrogate for OS with adjuvant PD-1 inhibitor therapy. Based on this, it is expected that studies that have shown a significant improvement in RFS will translate into improvements in OS.…”

Section: Oncologymentioning

confidence: 99%

Current role of sentinel lymph node biopsy in the management of cutaneous melanoma: A UK consensus statement

Peach

Board

Cook

et al. 2020

Journal of Plastic, Reconstructive & Aesthetic Surgery

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“…The CGP method was used to adjust the final curve to apply to the model population that was consistent with the approved indication. The OS for nivolumab was estimated using a surrogacy relationship between the RFS HR and OS HR derived from previous adjuvant melanoma studies including two recent trials [15,[26][27][28]. We assumed the proportional hazards assumption is appropriate between nivolumab and observation because this was a reasonable assumption between nivolumab and ipilimumab for RFS and between ipilimumab and placebo for RFS and OS in CA184-029.…”

Section: Partitioned Survival Model: Surrogacy Modelmentioning

confidence: 99%

Modelling Survival of Patients Treated with Adjuvant Nivolumab Who Have Melanoma with Lymph Node Involvement or Metastatic Disease After Complete Resection

Batteson

Hart

Hemstock

et al. 2019

PharmacoEconomics Open

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Introduction Nivolumab demonstrated significant recurrence-free survival (RFS) gains versus ipilimumab in the Check-Mate-238 trial, whereas the CA184-029 trial showed superior RFS gains for ipilimumab versus placebo. No head-to-head trial data were available to compare the efficacy of nivolumab to that of observation, so indirect treatment comparisons were required. Additionally, overall survival (OS) data were not available from CheckMate-238, and the clinical pathway for melanoma has changed significantly over the last decade. Four modelling options were developed using different methods and evidence sources to estimate OS and the impact of nivolumab on predicted life-years in the adjuvant setting; however, this article focuses on two primary methods. Methods RFS for nivolumab and observation were informed by a patient-level data meta-regression. The first model was a partitioned survival model, where the parametric OS curve for observation was derived from CA184-029 and nivolumab OS was based on a surrogacy relationship between RFS and OS specific to adjuvant melanoma. The other option used a state-transition model to estimate post-recurrence survival using different data sources. Results The modelling options estimated different OS for both nivolumab and observation but demonstrated at least a 32% increase in life-years gained for nivolumab versus observation. Conclusion This analysis demonstrated the difficulties in modelling within the adjuvant setting. Each model produced different survival projections, showing the need to explore different techniques to address the extent of uncertainty. This also highlighted the importance of understanding the impact of RFS in the long term in a setting where the aim of treatment is to remain disease free.

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Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II–III Melanoma Adjuvant Therapy

Abstract: In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS.

Cited by 74 publications

References 52 publications

Cost-effectiveness of pembrolizumab for the adjuvant treatment of resected high-risk stage III melanoma in the United States

Cost-effectiveness of pembrolizumab for the adjuvant treatment of resected high-risk stage III melanoma in the United States

Current role of sentinel lymph node biopsy in the management of cutaneous melanoma: A UK consensus statement

Modelling Survival of Patients Treated with Adjuvant Nivolumab Who Have Melanoma with Lymph Node Involvement or Metastatic Disease After Complete Resection

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