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Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma?

ABSTRACT: BACKGROUND:In oncology clinical development, objective response rate, disease control rate and early tumor size changes are commonly used as efficacy metrics for early decision-making. However, for immunotherapy trials, it is unclear whether these early efficacy metrics are still predictive of long-term clinical benefit such as overall survival. The goal of this paper is to identify appropriate early efficacy metrics predictive of overall survival for immunotherapy trials. METHODS:Based on several checkpoint blockade based immunotherapy studies in metastatic melanoma, we evaluated the predictive value of early tumor size changes and RECIST-based efficacy metrics at various time points on overall survival. The cut-off values for tumor size changes to predict survival were explored via tree based recursive partitioning and validated by external data. Sensitivity analyses were performed for the cut-offs. RESULTS:The continuous tumor size change metric and RECIST-based trichotomized response metric at different landmark time points were found to be statistically significantly associated with overall survival. The predictive values were higher at Week 12 and 18 than those at Week 24. The percentage of tumor size changes appeared to have comparable or lower predictive values than the RECIST-based trichotomized metric, and a cut-off of approximately 10% tumor reduction appeared to be reasonable for predicting survival. CONCLUSIONS:An approximate 10% tumor reduction may be a reasonable cut-off for early decision-making while the RECIST-based efficacy metric remains the primary tool. Early landmark analysis is especially useful for decision making when accrual is fast. Composite response rate (utilizing different weights for PR/CR and SD) may be worth further investigation. TRIAL REGISTRATION:Clinical trials gov, NCT01295827 , Registered February 15, 2011; NCT01704287 , Registered October 11, 2012; NCT01866319 , Registered May 31, 2013.

SUBMITTER: Wang M

PROVIDER: S-EPMC6368769 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma?

Wang Meihua M Chen Cong C Jemielita Thomas T Anderson James J Li Xiaoyun Nicole XN Hu Chen C Kang S Peter SP Ibrahim Nageatte N Ebbinghaus Scot S

Journal for immunotherapy of cancer 20190208 1

<h4>Background</h4>In oncology clinical development, objective response rate, disease control rate and early tumor size changes are commonly used as efficacy metrics for early decision-making. However, for immunotherapy trials, it is unclear whether these early efficacy metrics are still predictive of long-term clinical benefit such as overall survival. The goal of this paper is to identify appropriate early efficacy metrics predictive of overall survival for immunotherapy trials.<h4>Methods</h4 ...[more]

PMID: 30736858

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Project description:Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan-Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. The median OS of the overall population was 16 months (95% CI 13.4-23.7) and the median PFS, 2.8 months (95% CI 2.5-3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.

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Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma?

Publications

Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma?

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