Versatility of the clone-censor-weight approach: response to ‘trial emulation in the presence of immortal-time bias’

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p < 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values < 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

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Overall survival benefit from tebentafusp in patients with best response of progressive disease.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9509 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9509-9509

Author(s):

Anthony M. Joshua ◽

Jean-Francois Baurain ◽

Sophie Piperno-Neumann ◽

Paul Nathan ◽

Jessica Cecile Hassel ◽

...

Keyword(s):

Overall Survival ◽

Safety Profile ◽

Progressive Disease ◽

Analysis Data ◽

Cell Receptor ◽

Kaplan Meier ◽

Immortal Time Bias ◽

Best Response ◽

Overall Survival Benefit

9509 Background: Tebentafusp (tebe) is the first T cell receptor (TCR) therapeutic to demonstrate an overall survival (OS) benefit in a randomized Phase 3 (Ph3) study [ NCT03070392 ]. In Ph2, 42% of pts with best overall response (BOR) of progressive disease (PD) survived > 1 year (yr), suggesting RECIST-based radiographic assessments underestimate OS benefit of tebe. Here we analyzed OS in the Ph3 study in a cohort of pts with BOR of PD by comparing tebe to the control arm of investigator’s choice (IC). Methods: 378 pts were randomized in a 2:1 ratio to tebe vs. IC. BOR was assessed by investigators using RECIST v1.1. Treatment beyond first disease progression (TBP) was permitted for both arms. On the IC arm, only patients receiving pembrolizumab (pembro) continued with TBP and were included in the TBP-related analyses. No crossover to tebe was permitted; investigators were free to choose subsequent therapy. This analysis was conducted on the first interim analysis (data extracted Nov-2020). Kaplan-Meier estimates of OS were based on Day 100 landmark to eliminate immortal time bias and to capture majority of the PDs. Results: By Day 100, PD as BOR occurred in 52% (130/252) of tebe pts (PD-tebe) vs. 60% (76/126) of IC pts (PD-IC). Key baseline characteristics including lactate dehydrogenase, alkaline phosphatase, ECOG performance, age, and sex were similar between PD-tebe vs PD-IC. The proportion of pts with PD due to progression of target lesions (TL), non-TL, or new lesions were also similar between the two groups. More pts received TBP among PD-tebe 53% (69/130) vs PD-pembro 16% (10/61). Median duration of TBP was longer for PD-tebe (7 weeks) vs PD-Pembro (3 weeks). The safety profile of PD-tebe pts during TBP was similar to all tebe-treated pts. OS was superior for PD-tebe vs PD-IC, HR = 0.41 (95%CI 0.25-0.66), even when considering key baseline covariates. While some pts had regression of TL despite diagnosis of PD ( < 10% of pts), the OS benefit remained even when limited to pts with best change of tumor growth of TL, HR 0.46 (0.29, 0.73). 58% (75/130) PD-tebe and 52% (40/76) PD-IC pts received subsequent therapies. In a landmark OS analysis of these pts beginning on 1st day of subsequent therapy, prior tebe was associated with better OS vs. prior IC, HR 0.59 (95%CI 0.36-0.96). Conclusions: Tebe is the first TCR therapeutic to demonstrate an OS benefit in a solid tumor. Surprisingly, a strong OS benefit from tebe is observed even in pts with BOR of PD, suggesting that RECIST-based radiographic assessments do not capture the complete benefit from tebe. The safety profile of tebe during TBP was consistent with that for long-term tebe treatment. Clinical trial information: NCT03070392.

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Abstract WMP51: Risk and Timing of of Ischemic Stroke Following Acute Myocardial Infarction

Stroke ◽

10.1161/str.48.suppl_1.wmp51 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Alexander E Merkler ◽

Gino Gialdini ◽

Santosh Murthy ◽

Shadi Yaghi ◽

Babak Navi ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Ischemic Stroke ◽

Stroke Risk ◽

Absolute Risk ◽

Absolute Increase ◽

Risk Increase ◽

Immortal Time Bias ◽

Acute Mi ◽

The Absolute

Background: Acute myocardial infarction (MI) has long been reported as a risk factor for ischemic stroke, but the magnitude and duration of risk remains uncertain. Methods: We performed a crossover-cohort study using inpatient and outpatient claims data from a nationally representative 5% sample of Medicare beneficiaries from 2008 through 2014. We identified all patients ≥66 years of age with a first-recorded hospitalization for acute MI. The primary outcome was ischemic stroke. All predictors and outcomes were defined using previously validated ICD-9-CM codes. To exclude stroke that may have been due to percutaneous coronary intervention, we included only cases of ischemic stroke that occurred after discharge from the MI hospitalization. We compared the risk of ischemic stroke in successive 4-week periods during the 12 weeks after MI versus the corresponding 4-week periods 1 year later. To avoid immortal time bias, we limited our cohort to patients who remained alive and insured throughout the 15 month study period. Odds ratios (OR) and absolute risk differences were calculated using the Mantel-Haenszel estimator for matched data. Results: We identified 22,798 patients with an acute MI in whom the mean age was 77.4 (±7.9) years and 50.3% were women. In the 12 weeks after discharge, 216 patients (0.95%) developed a stroke, as compared to 21 (0.09%) patients in the corresponding 12-week period 1 year later. The absolute increase in stroke risk was 0.45% (95% confidence interval [CI], 0.36-0.55%) in the first 4 weeks after acute MI compared to the 4-week time period 1 year later, corresponding to an OR of 18.2 (95% CI, 8.1-50.6). The absolute risk increase was 0.24% (95% CI, 0.16-0.31%) during weeks 5-8 (OR, 8.7; 95% CI, 4.0-22.6) and 0.17% (95% CI, 0.10-0.23%) during weeks 9-12 (OR, 5.8; 95% CI, 2.7-14.1). Conclusions: Acute MI is associated with a substantially elevated short-term risk of ischemic stroke. This risk was independent of periprocedural stroke risk in the setting of coronary reperfusion therapies.

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Attention to Immortal Time Bias in Critical Care Research

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.202008-3238cp ◽

2021 ◽

Author(s):

Emily A. Vail ◽

Hayley B Gershengorn ◽

Hannah Wunsch ◽

Allan J Walkey

Keyword(s):

Critical Care ◽

Care Research ◽

Immortal Time Bias

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Multidisciplinary care and immortal time bias

Kidney International ◽

10.1038/ki.2013.257 ◽

2013 ◽

Vol 84 (5) ◽

pp. 1052 ◽

Cited By ~ 2

Author(s):

Brenda R. Hemmelgarn ◽

Jianguo Zhang ◽

Braden J. Manns ◽

Marcello Tonelli

Keyword(s):

Multidisciplinary Care ◽

Immortal Time Bias

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Immortal time bias or sorafenib effect in elderly patients with HCC?

Hepatology ◽

10.1002/hep.29250 ◽

2017 ◽

Vol 66 (2) ◽

pp. 678-679

Author(s):

Hanna K. Sanoff ◽

YunKyung Chang ◽

Jennifer L. Lund ◽

Bert H. O'Neil ◽

Stacie B. Dusetzina

Keyword(s):

Elderly Patients ◽

Immortal Time Bias

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Immortal Time Bias in the Study of Stillbirth Risk Factors

Epidemiology ◽

10.1097/ede.0000000000000216 ◽

2015 ◽

Vol 26 (1) ◽

pp. e13

Author(s):

&NA;

Keyword(s):

Risk Factors ◽

Immortal Time Bias

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Effect of delays in concordant antibiotic treatment on mortality in patients with hospital-acquired Acinetobacter spp. bacteremia: a 13-year retrospective cohort

10.1101/2020.04.27.20081513 ◽

2020 ◽

Author(s):

Cherry Lim ◽

Mo Yin ◽

Prapit Teparrukkul ◽

Maliwan Hongsuwan ◽

Nicholas P.J. Day ◽

...

Keyword(s):

Medical Research ◽

Antibiotic Treatment ◽

Research Council ◽

Medical Research Council ◽

Research Training ◽

Absolute Increase ◽

Immortal Time Bias ◽

Training Fellowship ◽

Hospital Acquired ◽

The Impact

AbstractBackgroundTherapeutic options for multidrug-resistant Acinetobacter spp. are limited, and resistance to last resort antibiotics in hospitals is increasing globally. Quantifying the impact of delays in concordant antibiotic treatment on patient mortality is important for designing hospital antibiotic policies.MethodsWe included patients with Acinetobacter spp. hospital-acquired bacteremia (HAB) in a hospital in Thailand over a 13-year period. For each day of stay following the first positive blood culture we considered antibiotic treatment to be concordant if the isolated organism was susceptible to at least one antibiotic given. We used marginal structural models with inverse-probability weightings to determine the association between delays in concordant treatment and 30-day mortality.ResultsBetween January 2003 and December 2015, 1,203 patients had HAB with Acinetobacter spp., of which 682 patients (56.7%) had one or more days of delay in concordant treatment. These delays were associated with an absolute increase in 30-day mortality of 6.6% (95% CI 0.2%-13.0%), from 33.8% to 40.4%. Crude 30-day mortality was substantially lower in patients with three or more days of delays in concordant treatment compared to those with one to two days of delays. Accounting for confounders and immortal time bias resolved this paradox, and showed similar 30-day mortality for one, two and three or more days of delays.ConclusionsDelays in concordant antibiotic treatment were associated with a 6.6% absolute increase in mortality among patients with hospital-acquired Acinetobacter spp. bacteremia. If this association is causal, switching fifteen patients from discordant to concordant initial treatment would be expected to prevent one death.FundingThe Mahidol Oxford Tropical Medicine Research Unit (MORU) is funded by the Wellcome Trust [grant number 106698/Z14/Z]. CL is funded by a Wellcome Trust Research Training Fellowship [grant number 206736/Z/17/Z]. MY is supported by a Singapore National Medical Research Council Research Fellowship [grant number NMRC/Fellowship/0051/2017]. BSC is funded by the UK Medical Research Council and Department for International Development [grant number MR/K006924/1]. DL is funded by a Wellcome Trust Intermediate Training Fellowship [grant number 101103]. The funder has no role in the design and conduct of the study, data collection, or in the analysis and interpretation of the data.

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