Antiangiogenic Second line Lung cancer Meta-Analysis (ANSELMA) - A meta-analysis on antiangiogenic agents in advanced non-small cell lung cancer patients who failed first-line chemotherapy.

Proposal
1847

Title of Proposed Research

Lead Researcher

Benjamin Besse

Affiliation

University Paris-Sud and Gustave Roussy, Department of Medicine 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, FrancePhone: +33 (0)1 42 11 43 22 Fax: +33 (0)1 42 11 52 19

Funding Source

This is an independent and academic meta-analysis and funding will be from the academic center. The meta-analysis platform is supported by the French League against Cancer, a charity. A grant from ARC, a charity, has been requested.

Potential Conflicts of Interest

No personal financial disclosures.
Institutional grants for clinical and translational research:
AstraZeneca, BMS, Boehringer-Ingelheim, Lilly, Pfizer, Roche-Genentech, Sanofi-Aventis, Clovis, GSK, Servier, EOS, Onxeo, OncoMed, Inivata, OSE Pharma.No personal financial disclosures.
Institutional grants for clinical and translational research:
unrestricted research grant in 2015 from Bayer for a meta-analysis of radionuclide in prostate cancer.

Data Sharing Agreement Date

21 August 2017

Lay Summary

After failure of the initial treatment, only 20% of patients with advanced non-small cell lung cancer (NSCLC) appear to benefit from immune checkpoint inhibitors as second treatment. Those inhibitors allow the immune system to be unleashed on cancer cells. Creation of new blood vessels (process called angiogenesis) by the tumor is critical for tumor growth. Antiangiogenic agents, are used in combination with chemotherapy as a therapeutic strategy as first treatment in advanced NSCLC patients.Several randomized studies have tested the efficacy antiangiogenic agents in combination with chemotherapy or erlotinib (another drug) with inconsistent benefit, limiting its acceptance in daily clinical practice. Then, this treatment may be proposed to the 80% of patients who do not benefit from immune checkpoint inhibitors.A synthesis (or meta-analysis) of these studies using individual patient data (i.e. data of each patient included in these studies with preservation of their anonymity) instead of information available in articles will allow to study the variation of treatment effects and toxicities according to patients' factors such as age or sex, and biological factors such as mutation of the Epidermal Growth Factor (a protein known to be involved in many cancers) or the time from the start of the first treatment until tumor re-growth. Results of this meta-analysis may allow to identify patients who will benefit from antiangiogenic treatment after failure of their first treatment. Those results will have important implications for clinical practice. In order to have valid and reliable results, all randomized studies testing antiangiogenic agents will be included in the meta-analysis.

Study Data Provided

[{ "PostingID": 4770, "Title": "SANOFI-D4200C00036", "Description": "A Phase III, Randomized, Double-blinded, Parallel Group, Multi-centre Study to Assess the Efficacy and Safety of ZD6474 (ZACTIMA™) in Combination With Pemetrexed (Alimta®) Versus Pemetrexed Alone in Patients With Locally-Advanced or Metastatic NSCLC" },{ "PostingID": 4771, "Title": "SANOFI-D4200C00006", "Description": "A Randomized, Double-blind, Multicenter, Phase II Study to Assess the Safety, Tolerability, and Efficacy of ZD6474 in Combination With Docetaxel (TAXOTERE™) in Subjects With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) After Failure of Prior Platinum-based Chemotherapy." },{ "PostingID": 4772, "Title": "SANOFI-D4200C00032", "Description": "A Phase III, Randomized, Double-Blinded, Multi-Center, Study to Assess the Efficacy of Docetaxel (TAXOTERE™) in Combination With ZD6474 (ZACTIMA™) Versus Docetaxel (TAXOTERE™) With Placebo in Subjects With Locally Advanced or Metastatic NSCLC" }]

Statistical Analysis Plan

Trial characteristics will be reported in tabular form, information will include patient numbers, population description, treatment details, number of patients lost to follow-up and median follow-up. Median follow-up will be computed using the reverse Kaplan-Meier method.The ultimate aim will be to obtain and analyse data from all randomized patients included in all relevant randomized trials on an intention-to-treat basis. With around 5 000 patients (or 2750 deaths) it would be possible to detect, with a power of 90%, an absolute improvement in survival from 40 % to 45 % at 1-years (two-sided log-rank test, type I error = 5%).The main analysis will be performed on the endpoint of overall survival. Additional analyses will be performed on objective response rate, progression-free survival, if sufficient data are available. Compliance and severe acute toxicity rates will be also studied.All analyses will include all randomized patients and will be carried out on an intention-to-treat basis that is patients will be analysed according to the treatment allocated, irrespective of whether they received that treatment. Survival analyses will be stratified by trial, and the log-rank expected number of deaths and variance would be used to calculate individual and overall pooled hazard ratios by the fixed-effect model. Thus, the time to death for individual patients will be used within trials to calculate the hazard ratio, representing the overall risk of death for patients who were allocated standard treatment plus antiangiogenic compared with those who were allocated standard treatment. For comparing toxicity rates, overall pooled odds ratio stratified by trials will be calculated by a fixed-effect model.The X2 heterogeneity tests will be used to test for gross statistical heterogeneity, the I2 statistic will be used as a measure of consistency among trials. Random effect will be used in case of unexplained heterogeneity. Stratified survival curves will be estimated for control and experimental groups using annual death rates and hazard ratios. They will be used to calculate absolute benefit at 6-months, and 12-months with their 95% confidence intervals. All p-values will be two-sided.

Publication Citation

Remon J, Lacas B, Herbst R, Reck M, Garon EB, Scagliotti GV, Ramlau R, Hanna N, Vansteenkiste J, Yoh K, Groen HJM, Heymach JV, Mandrekar SJ, Okamoto I, Neal JW, Heist RS, Planchard D, Pignon JP, Besse B; ANSELMA collaborative group.
ANtiangiogenic Second-line Lung cancer Meta-Analysis on individual patient data in non-small cell lung cancer: ANSELMA. Eur J Cancer. 2022 Mar 11;166:112-125.
https://doi.org/10.1016/j.ejca.2022.02.002
PMID: 35286903