To Define an Easy and Feasible Panel Which May be Routinely Applied to Select Patients for Immunotherapy Avoiding More Complex and Expensive Methods Clinical Trial
Official title:
Integration of Programmed Cell Death Ligand 1 and Neutrophil to Lymphocyte Ratio to Predict Response to Nivolumab in Non-Small Cell Lung Cancer
This retrospective study explores the combination of Programmed cell death ligand 1 (PD-L1) expression and Neutrophil to Lymphocyte Ratio (NLR) as an easy feasible panel to predict benefit to nivolumab.
We will retrospectively analyze patients with advanced NSCLC who have received at least one
cycle of nivolumab (3mg/kg intravenously every 2 weeks) within the early access program (EAP)
or after the drug approval. All patients have been treated with immunotherapy, in second or
further line, in two Italian Institution (the S. Maria delle Croci Hospital in Ravenna and
the S. Maria della Misericordia Hospital in Perugia) between February 2015 and May 2017.
Patient data and laboratory values will be recorded in an electronic anonymized database and
personally collected by one of the investigators (C.B.). PD-L1 expression will be assessed by
immunoistochemistry (IHC) on available archival tissue samples with clone E1L3N (monoclonal
rabbit; Cell Signaling technology, Danverd, MA) or SP263 (monoclonal rabbit; Ventana Medical
System, Tucson, AZ), in a Ventana automated stainer according to the manufacturer's protocol
and using proprietary reagents. Since a specific PD-L1 level is not mandatory for prescribing
immunotherapy in second or further lines, except for pembrolizumab, we established the PD-L1
positivity as expression on ≥ 1% of tumor cells. To calculate NLR, the absolute neutrophil
count will be divided by the lymphocytes value measured in peripheral blood within 4 weeks
prior to the first infusion of nivolumab. Patients will be dichotomized according to a
pre-specified cutoff value as high (NLR ≥ 3) or low (NLR < 3), since a ratio greater than 3
has been associated with poor outcome in many types of cancer. Patients will be divided in
two cohorts according to combined PD-L1/NLR value: cohort1 with PD-L1 positive and low NLR
and cohort 2 with PD-L1 negative and high NLR. Primary end point will be ORR, calculated as
the percentage of responses among all treated patients. Response to treatment will be
assessed by computed tomography and classified according to RECIST 1.1 criteria [15 Eisenauer
Cancer 2009]. The influence of the combined PD-L1/NLR on overall response rates (ORR), will
be analyzed with univariable logistic regression. Secondary outcome will be OS and PFS,
calculated from the start of nivolumab treatment to death and radiographic or clinical
progression, respectively, with deterioration of performance status classified as disease
progression. We will also examine whether PD-L1, NRL, or combined PD-L1/NRL contribute to the
prediction of OS or PFS, through multi-variable analyses. Since data collected included many
variables, we will perform multivariable models to examine the dependence of OS and PFS on
known prognostic factors: Eastern Cooperative Oncology Group Performance Status (ECOG PS)
(0-1 vs. ≥2) and brain involvement at time of initiating nivolumab, smoking history [never
(<100 cigarettes per lifetime) vs. former/current smokers], histology (squamous vs.
non-squamous), molecular profiling for epidermal growth factor receptor (EGFR), Kirsten rat
sarcoma viral oncogene homolog (K-RAS) and anaplastic lymphoma kinase (ALK) when available.
Patients with squamous-cell cancers will be counted as wild type for targetable mutation,
which are considered to be infrequent in this population. The study was approved by the local
Research Ethics Committee.
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