Dataset Information

Immunotherapy in advanced kidney cancer: an alternative meta-analytic method using reconstructed survival data in case of proportional hazard assumption violation.

ABSTRACT:

Background

With the advent of immuno-oncology compounds in randomized trials, we observe more and more survival curves crossing. From a statistical standpoint this corresponds to violation of the proportional hazard assumption. When this occurs, the hazard ratio from the Cox regression is not reliable as an estimate. Herein, we aimed to identify the most appropriate IO-based therapy for metastatic renal cell carcinoma applying an alternative method to overcome the issue of hazard assumption violation for meta-analyses.

Methods

Pubmed, EMBASE, Web of Science and Scopus databases were searched. Only phase III randomized clinical trials on IO-IO (nivo-ipi) or IO-TKI combinations were included. An algorithm to obtain survival data from published Kaplan-Meier curves was used to reconstruct data on overall survival (OS), progression-free survival (PFS) and duration of response (DoR). Differences in restricted mean survival time (RMST) were used for comparisons.

Results

individual survival data from 4,206 patients from five trials were reconciled. Patients who received nivo-ipi or IO-TKI had better OS, PFS and DoR relative to sunitinib (all p<0.001). Patients who received IO-TKI had similar OS and PFS relative to nivo-ipi, with a 36-month ΔRMST of -0.55 (95% CI: -1.71-0.60; p=0.3) and -1.5 (95% CI: -2.9-0.0; p=0.051) months, respectively. Regarding DoR, patients who received nivo-ipi had longer duration of response relative to IO-TKI, with a 24-month ΔRMST of 1.5 (95% CI: 0.2-2.8; p=0.02) months.

Conclusion

Despite overall similar OS and PFS for patients receiving nivo-ipi and IO-TKI combinations, DoR was more favorable in patients who received nivo-ipi compared to IO-TKI. A meta-analysis based on differences in RMST is a useful alternative whenever the proportional hazard assumption is violated. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021241421.

SUBMITTER: Nocera L

PROVIDER: S-EPMC9483094 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Immunotherapy in advanced kidney cancer: an alternative meta-analytic method using reconstructed survival data in case of proportional hazard assumption violation.

Nocera Luigi L Fallara Giuseppe G Raggi Daniele D Belladelli Federico F Robesti Daniele D Montorsi Francesco F Karakiewicz Pierre I PI Malavaud Bernard B Ploussard Guillaume G Necchi Andrea A Martini Alberto A

Frontiers in oncology 20220905

<h4>Background</h4>With the advent of immuno-oncology compounds in randomized trials, we observe more and more survival curves crossing. From a statistical standpoint this corresponds to violation of the proportional hazard assumption. When this occurs, the hazard ratio from the Cox regression is not reliable as an estimate. Herein, we aimed to identify the most appropriate IO-based therapy for metastatic renal cell carcinoma applying an alternative method to overcome the issue of hazard assumpt ...[more]

PMID: 36132135

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Project description:IntroductionNon-linear Mendelian randomization is an extension of conventional Mendelian randomization that performs separate instrumental variable analyses in strata of the study population with different average levels of the exposure. The approach estimates a localized average causal effect function, representing the average causal effect of the exposure on the outcome at different levels of the exposure. The commonly used residual method for dividing the population into strata works under the assumption that the effect of the genetic instrument on the exposure is linear and constant in the study population. However, this assumption may not hold in practice.MethodsWe use the recently developed doubly ranked method to re-analyse various datasets previously analysed using the residual method. In particular, we consider a genetic score for 25-hydroxyvitamin D (25[OH]D) used in a recent non-linear Mendelian randomization analysis to assess the potential effect of vitamin D supplementation on all-cause mortality.ResultsThe effect of the genetic score on 25(OH)D concentrations varies strongly, with a five-fold difference in the estimated genetic association with the exposure in the lowest and highest decile groups. Evidence for a protective causal effect of vitamin D supplementation on all-cause mortality in low vitamin D individuals is evident for the residual method but not for the doubly ranked method. We show that the constant genetic effect assumption is more reasonable for some exposures and less reasonable for others. If the doubly ranked method indicates that this assumption is violated, then estimates from both the residual and doubly ranked methods can be biased, although bias was smaller on average in the doubly ranked method.ConclusionAnalysts wanting to perform non-linear Mendelian randomization should compare results from both the residual and doubly ranked methods, as well as consider transforming the exposure for the residual method to reduce heterogeneity in the genetic effect on the exposure.

Dataset Information

Immunotherapy in advanced kidney cancer: an alternative meta-analytic method using reconstructed survival data in case of proportional hazard assumption violation.

Background

Methods

Results

Conclusion

Publications

Immunotherapy in advanced kidney cancer: an alternative meta-analytic method using reconstructed survival data in case of proportional hazard assumption violation.

Similar Datasets

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