Lead Investigator: Alessio Cortellini, Imperial College London
Title of Proposal Research: The predictive role of inflammation indices in patients treated with immunotherapy or chemotherapy for advanced non-small cell lung cancer.
Vivli Data Request: 7126
Funding Source: None
Potential Conflicts of Interest: Professor Borghaei is an investigator in several land mark studies of immune checkpoint inhibitors in NSCLC. These potential conflict of interest will be managed by declaring them in any subsequent publications.
Summary of the Proposed Research:
Lung cancer is by far the leading cause of cancer death among both men and women, making up almost 25% of all cancer deaths, and non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses. Overall, the chance that a man will develop lung cancer in his lifetime is about 1 in 15; for a woman, the risk is about 1 in 17.
Unfortunately, patients with advanced NSCLC are not deemed suitable for radical/curative treatments, however they can currently benefit from several immunotherapy options with immune checkpoint inhibitors (ICIs). The mechanism of action of ICIs is based on the dis-inhibition of patient’s own immune systems, to make it able to recognize the tumour and control its growth as if it was an external threat. This has been shown to extend patients’ life-expectancy as compared to standard chemotherapy in different treatment settings. To further improve the benefit from ICIs, recent clinical trials have confirmed that the combination of a chemotherapy backbone with a single agent ICI can lead to even greater improved outcomes.
However, against this background of increasing treatment options, there is still a need for additional and reliable information that could help improving the decision-making process when planning a therapeutic strategy. Among the alleged prediction tools in clinical practice, blood immune-inflammatory indices computed from routinary available full blood count values are one of the most investigated, because they are easily accessible and reproducible. These indices include the neutrophil-to-lymphocyte ratio (NLR), which consists of the ratio between the absolute neutrophil count and the absolute lymphocyte count. The NLR has been also combined with other routinely available bloods tests, including the serum lactate dehydrogenase (LDH) and the absolute plates count, to form other indices, such as the Systemic Inflammation Index (SII).
OAK is a randomised, open-label, international phase 3 study which enrolled patients with advanced NSCLC to receive either atezolizumab (immunotherapy, programmed death ligand-1/PD-L1 inhibitor) or docetaxel (chemotherapy), confirming a survival benefit for immunotherapy over chemotherapy. Our aim is to access to the OAK study dataset and analyse patients’ clinical outcomes across both the cohorts according to the baseline NLR and other blood immune-inflammatory indices. We will be able to evaluate their differential prognostic ability between two prospectively randomized cohorts, eventually confirming the differential impact on clinical outcomes for patients treated with atezolizumab and docetaxel.
The overarching goal of this analysis is to provide an easily accessible tool that might assist clinicians in their decision-making process and identify patients more (or less) likely to benefit from immunotherapy, as compared to chemotherapy.
Statistical Analysis Plan
The minimum sample size was estimated only for patients who received atezolizumab, on the basis of the expected number of patients with NLR ≥ 4. On the basis of literature data, we hypothesized a 40% prevalence of patients with a baseline NLR ≥ 4. We assumed a possible survival benefit for patients with a baseline NLR < 4 with a reduction of the risk of death by 40%. With a probability of type I error of 0.05 and type II error of 0.20, a minimum of 148 death events was necessary, and at least 330 patients had to be included. All baseline clinic-pathologic information will be reported by descriptive statistics. The descriptive analysis will be carried out using percentages for the binary variables, mean and median for the continuous variables.
The cut-offs for the LDH and SII will be explored and confirmed by receiver operating characteristic (ROC) curves on the risk of progression and death. OS and PFS will be estimated using the Kaplan–Meier method and reported as medians with 95% confidence interval (CIs). The prognostic role of NLR (and the indices) on OS and PFS will be assessed by the two-sided log-rank test across the atezolizumab and docetaxel cohorts. Similarly, the correlation between NLR (and other indices) and the ORR will be explored by the Chi-square tests. Cox regression will be used for multivariable analyses and to report hazard ratios (HR) with 95% Cis for risk of death (OS) and disease progression (PFS). In the case of a significant prognostication for PFS and OS in both the cohorts, the HR for PFS and OS will be compared. Subsequently, a pooled multivariable analysis of the two cohorts will be performed, using all the clinically meaningful characteristics already investigated within the OAK trial as covariates (gender, age, EOCG-PS, number of previous treatments, smoking status, histology, liver, central nervous system and bone metastasis – categorized as previously described). An initial multivariable model without interactions will be presented and then the interaction term between the treatment modality (atezolizumab vs docetaxel) and the variable of interest (e.g. the NLR and other indices) will be tested in separate models to eventually determine the differential impact on clinical outcomes. The alpha level for all analyses was set to p<0.05.
MedCalc® Statistical Software version 20 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2021) will be used for statistical analyses.
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
Differential prognostic effect of systemic inflammation in patients with NSCLC treated with immunotherapy or chemotherapy: A post hoc analysis of the phase III OAK trial. Alessio Cortellini, Biagio Ricciuti, Hossein Borghaei, Abdul Rafeh Naqash, Antonio D’Alessio, Claudia A.M. Fulgenzi, Alfredo Addeo, Giuseppe Luigi L. Banna, and David J. James Pinato. Journal of Clinical Oncology 2022 40:16_suppl, 9056-9056. doi:10.1200/JCO.2022.40.16_suppl.9056