Lead Investigator: Zhengfei Zhu, Fudan University Shanghai Cancer Center
Title of Proposal Research: Clinical value and optimal candidate of cranial radiotherapy in atezolizumab-treated advanced non-small cell lung cancer with baseline brain metastasis
Vivli Data Request: 7322
Funding Source: STCSM funding (Grant No. 20Y11913500)
Potential Conflicts of Interest: None
Summary of the Proposed Research:
While cancer burden is expected to grow globally in recent years, lung cancer remains the leading cause of cancer-related death. Approximately 10%-30% of newly diagnosed patients with advanced non-small cell lung cancer (NSCLC) have brain metastases. Patients with brain metastases have complex symptom experiences, limited life expectancy and worsening quality of life. And that’s why there is a high unmet need to identify a more efficient treatment strategy for brain lesions. Given the importance of radiotherapy as the mainstay of local treatment for patients with brain metastases for advanced NSCLC, the relative roles of cranial radiotherapy and immunotherapy like anti-PD-(L)1(Programmed Death-Ligand 1) therapy are of considerable clinical interest for defining the optimal treatment strategy for advanced NSCLC with brain metastasis.
For most of the studies, patients with asymptomatic baseline brain metastases are usually eligible but subgroup analysis for brain metastases is difficult to conduct due to small number of patients in a single study.
This individual level data pooled analysis from atezolizumab trials aims to offer insights into the clinical value of treatment strategy, e.g. optimal timing, potential candidate and treatment-related toxicities of cranial radiotherapy in relation to atezolizumab administration, focusing particularly on subgroups of patients stratified by the status of baseline brain metastases (number, size).
Statistical Analysis Plan:
The between-trial heterogeneity of treatment effects will be evaluated by Cochran test and I2, to be accounted by a random-effects (RE) model. For tests of heterogeneity and interaction, a P value less than 0.10 would be considered significant. Of note, The Peto method (reference: Lueza B, Rotolo F, Bonastre J, Pignon J-P, Michiels S. Bias and precision of methods for estimating the difference in restricted mean survival time from an individual patient data meta-analysis. BMC Med ResMethodol. 2016;16:37) will be used to estimate the stratified survival curves comparing the upfront cranial radiotherapy with non upfront cranial radiotherapy arms.
Moreover, subgroup analyses stratified by the treatment lines (first-line vs ≥2 lines), treatment regimens (Atezolizumab monotherapy vs combinational therapy containing Atezolizumab), number of brain metastases and largest size of brain metastases, will be performed by means of an interaction test. Treatment-related adverse events will be compared using the Mantel-Haenszel λ2 test stratified by trial for combining 2*2 tables. Individualized patient data multivariable analyses will also be performed using Cox models that included the trial as a random variable.
Patients’ clinical and treatment characteristics were compared using the χ2 test or Fisher’s exact test for categorical variables, and unpaired Student’s t test or Mann–Whitney U test for continuous variables, as appropriate. The Kaplan–Meier method was adopted to estimate PFS, iPFS, and OS, and survival curves were compared using log-rank testing. Cox proportional-hazards regression was used to estimate univariate and multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for PFS and OS. Variables were selected for the multivariate analysis on the basis of their statistical significance (P <0.10) by univariate analysis. Time to intracranial progression was measured from the start of anti-PD-1/PD-L1 therapy to radiologically confirmed intracranial progression (event of interest). Competing risk methodology was adopted to perform actuarial univariate and multivariate analyses of factors potentially associated with time to intracranial progression, in which death without the event was defined as a competing risk. A two-sided P value <0.05 was considered statistically significant. All statistical analyses were performed with R.
Requested Studies:
A Phase III, Open-Label, Multicenter, Randomized Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Paclitaxel or Atezolizumab in Combination With Carboplatin+Nab-Paclitaxel Versus Carboplatin+Nab-Paclitaxel in Chemotherapy-Naive Patients With Stage IV Squamous Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02367794
Sponsor ID: GO29437
A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02367781
Sponsor ID: GO29537
A Phase III, Open-Label, Randomized Study of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Paclitaxel With or Without Bevacizumab Compared With Carboplatin + Paclitaxel + Bevacizumab in Chemotherapy-Naïve Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02366143
Sponsor ID: GO29436
A Phase II, Multicenter, Single-Arm Study OF Atezolizumab In Patients With PD-L1-Positive Locally Advanced Or Metastatic Non-Small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT02031458
Sponsor ID: GO28754
A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared With Docetaxel in Patients With Non-Small Cell Lung Cancer After Failure With Platinum Containing Chemotherapy
Data Contributor: Roche
Study ID: NCT02008227
Sponsor ID: GO28915
A Phase II, Open-label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of MPDL3280A (Anti−PD-L1 Antibody) Compared With Docetaxel in Patients With Non−Small Cell Lung Cancer After Platinum Failure
Data Contributor: Roche
Study ID: NCT01903993
Sponsor ID: GO28753
A Phase II, Multicenter, Single-arm Study of MPDL3280A in Patients With PD-L1-Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer
Data Contributor: Roche
Study ID: NCT01846416
Sponsor ID: GO28625
Public Disclosures:
- Guo, T., Zhou, Y., Liang, F., Wang, Z., Bourbonne, V., Käsmann, L., Sundahl, N., Wu, A.J.C., Ni, J. and Zhu, Z., 2024. Potential synergistic effects of cranial radiotherapy and atezolizumab in non-small cell lung cancer: an analysis of individual patient data from seven prospective trials. Translational Lung Cancer Research, 13(1), p.126. Doi : 10.21037/tlcr-23-792
- Zhou, Y., Guo, T., Liang, F., Wang, Z., Zhang, J., Ni, J. and Zhu, Z., 2024. Cumulative incidence and risk factors of brain metastases in metastatic non–small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from IMpower130, IMpower131, and IMpower150. Cancer. Doi : 10.1002/cncr.35242
- Guo, T., Zhou, Y., Liang, F., Wang, Z., Bourbonne, V., Käsmann, L., Sundahl, N., Wu, A.J.C., Ni, J. and Zhu, Z., 2024. Association of previously irradiated stable brain metastases with outcomes of atezolizumab‐treated non‐small cell lung cancer: A pooled analysis of individual patient data from three randomized trials. Cancer Communications, 44(2), p.278. Doi : 10.1002/cac2.12512
- Zhou, Y., Ni, J., Zhu, Z. and Zhang, Z., 2023. Risk of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from three randomized clinical trials involving first-line atezolizumab treatment. Doi : 10.1200/JCO.2023.41.16_suppl.2032