Development and Evaluation of a Method to Correct Misinterpretation of Clinical Trial Results With Long-term Survival

Hsu, Chih Yuan; Lin, Emily; Shyr, Yu

doi:10.1001/jamaoncol.2021.0289

Cited by 11 publications

(7 citation statements)

References 15 publications

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“…For this reason, a secondary analysis was carried out in which the indirect comparisons of our first analysis were re‐assessed using the restricted mean survival time (RMST) instead of the HR estimated by Cox modeling. The RMST is not influenced by the presence of cured patients 18 …”

Section: Methodsmentioning

confidence: 87%

Immune checkpoint inhibitors as first line in advanced melanoma: Evaluating progression‐free survival based on reconstructed individual patient data

et al. 2022

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Background In patients with advanced melanoma, immune‐checkpoint inhibitors (ICIs) represent the mainstay for first line treatment. Recently, relatlimab+nivolumab was proposed as a new combination therapy. This review was aimed at summarizing the current data of effectiveness for ICIs. Progression‐free survival (PFS) was the endpoint of our analysis. Methods After a standard literature search, Phase II/III studies comparing different ICI regimens in previously untreated advanced melanoma patients were analyzed. Patient‐level data were reconstructed from Kaplan–Meier curves by application of the IPDfromKM method. These reconstructed datasets were used to perform indirect comparisons between treatments. Standard statistical testing was used, including hazard ratio and medians. A secondary analysis employed the restricted mean survival time. Results Six trials were included in our analysis. Information on PFS from these trials was pooled according to the following treatments: nivolumab or pembrolizumab as monotherapy, or in combination with ipilimumab, and relatlimab + nivolumab. Pembrolizumab+ipilimumab showed significantly better PFS compared with the other treatments; nivolumab+ipilimumab ranked second; the other treatments showed a similar survival pattern. Conclusions The picture of comparative effectiveness resulting from our analysis is complex. The IPDfromKM method is advantageous because it accounts for the length of follow‐up but loses the balance between treatment group and controls determined by randomization. Based on indirect comparisons, the combination of pembrolizumab+ipilimumab showed a particularly high efficacy, and so deserves further investigation. While the effect of between‐trial differences in inclusion criteria plays an important role, our results do not support the proposal of relatlimab+nivolumab as a new standard of care.

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Section: Methodsmentioning

confidence: 87%

Immune checkpoint inhibitors as first line in advanced melanoma: Evaluating progression‐free survival based on reconstructed individual patient data

et al. 2022

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“…Assessment of the benefit of ICIs raises several issues considering the unconventional pattern of radiological response. Novel tools assessing radiological response (i.e., immuneRECIST or radiomic tools) or innovative measures of net health benefit assessment may be able to capture the long-term benefit observed with ICIs [36]. According to ASCO statements [24], net health benefit is defined as the balance between clinical benefit and SAEs, and it is used to assess the difference between 2 different therapeutic strategies [37].…”

Section: Discussionmentioning

confidence: 99%

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2020

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Introduction: Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies. Methods: A Markov model was built to estimate the overall survival (OS) of sequential first-and sec-

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“…The Cox-TEL method was used to transform reported HRs for the ITT population in studies included for meta-analysis. 4 The Cox-TEL method links the Cox PH model and PH cure models through their mathematic association and provides an algorithm to transform Cox HR to the more appropriate treatment-effect estimates as obtained from the PH cure model. The method requires as inputs only the reported Cox HR with 95% CI and KM curves.…”

Section: Methodsmentioning

confidence: 99%

“…Cox PH–Taylor expansion adjustment for long-term survival data (Cox-TEL) is a novel adjustment method developed based on the mathematical association between Cox PH and PH cure models. The Cox-TEL disassembles the study population into subgroups with and without long-term survival, providing the difference in proportions of survival probability for long-term survivors (LT-DP) and adjusted HR for short-term survivors (ST-HR) . The only data required to perform the adjustment are Cox HR with 95% CIs and survival probabilities excerpted from KM curves, which are often made available in published studies.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Cancer Survival Associated With Immune Checkpoint Inhibitors After Statistical Adjustment

et al. 2022

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ImportanceAppropriate clinical decision-making relies on accurate data interpretation, which in turn relies on the use of suitable statistical models. Long tails and early crossover—2 features commonly observed in immune checkpoint inhibitor (ICI) survival curves—raise questions as to the suitability of Cox proportional hazards regression for ICI survival analysis. Cox proportional hazards–Taylor expansion adjustment for long-term survival data (Cox-TEL) adjustment may provide possible solutions in this setting.ObjectiveTo estimate overall survival and progression-free survival benefits of ICI therapy vs chemotherapy using Cox-TEL adjustment.Data SourcesA PubMed search was performed for all cataloged publications through May 22, 2022.Study SelectionThe search was restricted to randomized clinical trials with search terms for ICIs and lung cancer, melanoma, or urothelial carcinoma. The publications identified were further reviewed for inclusion.Data Extraction and SynthesisCox proportional hazards ratios (HRs) were transformed to Cox-TEL HRs for patients with short-term treatment response (ie, short-term survivor) (ST-HR) and difference in proportions for patients with long-term survival (LT-DP) by Cox-TEL. Meta-analyses were performed using a frequentist random-effects model.Main Outcomes and MeasuresOutcomes of interest were pooled overall survival (primary outcome) and progression-free survival (secondary outcome) HRs, ST-HRs, and LT-DPs. Subgroup analyses stratified by cancer type also were performed.ResultsA total of 1036 publications was identified. After 3 levels of review against inclusion criteria, 13 clinical trials (7 in non–small cell lung cancer, 3 in melanoma, and 3 in urothelial carcinoma) were selected for the meta-analysis. In the primary analysis, pooled findings were 0.75 (95% CI, 0.70-0.81) for HR, 0.86 (95% CI, 0.81-0.92) for ST-HR, and 0.08 (95% CI, 0.06-0.10) for LT-DP. In the secondary analysis, the pooled values for progression-free survival were 0.77 (95% CI, 0.64-0.91) for HR, 1.02 (95% CI, 0.84-1.24) for ST-HR, and 0.10 (95% CI, 0.06-0.14) for LT-DP.Conclusions and RelevanceThis systematic review and meta-analysis of ICI clinical trial results noted consistently larger ST-HRs vs Cox HRs for ICI therapy, with an LT-DP of approximately 10%. These results suggest that Cox HRs may not provide a full picture of survival outcomes when the risk reduction from treatment is not constant, which may aid in the decision-making process of oncologists and patients.

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Development and Evaluation of a Method to Correct Misinterpretation of Clinical Trial Results With Long-term Survival

Cited by 11 publications

References 15 publications

Immune checkpoint inhibitors as first line in advanced melanoma: Evaluating progression‐free survival based on reconstructed individual patient data

Immune checkpoint inhibitors as first line in advanced melanoma: Evaluating progression‐free survival based on reconstructed individual patient data

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Analysis of Cancer Survival Associated With Immune Checkpoint Inhibitors After Statistical Adjustment

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