Virtual Library
Start Your Search
Jean-David Fumet
Author of
-
+
EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
-
+
EP1.01-25 - An Interactive Interface for Prediction of Anti-PD-1 Efficacy in Lung Cancer Patients (ID 2460)
08:00 - 18:00 | Author(s): Jean-David Fumet
- Abstract
Background
The past decade has seen a new field of promising treatments for non-small cell lung cancer patients (NSCLC) with immune checkpoint inhibitors (ICI). Medicine community embarks on a biomarker race to identify the one-quarter of responders and potential hyper-progressors. The assessment of PD-L1 tumor expression by IHC is used to select responder patients and is considered as the gold standard biomarker in many studies but it does not predict the absence of anti-PD-1 efficacy. Recent review from Keenan TE et al. summaries all potential studied markers in literature as intratumoral T cell infiltration, tumor neoantigens or else mismatch repair deficiency. Despite this abundance of potential markers, recommendations only rely on high PD-L1 expression and more recently on high tumor mutational burden (TMB). In this study, we propose estimations of response probability based on the different data that may be available for clinicians according their molecular biology and material means.
Method
Based on a cohort of 100 patients with advanced NSCLC treated with nivolumab in second line of treatment, we developed an algorithm enabling the calculation of the probability of survival without progression at 6 or 12 months when treated with ICI. Using Cox proportional hazards multiple regression, we adjusted these three stages of information to estimate the probability of response of a patient based on the type of available data: only clinical data and/or exome analysis and/or RNA sequencing. Stability and predictive ability of these models where evaluated internally and externally through bootstrap procedure.
Result
Among the 100 patients, 90 had both somatic and constitutional exome sequencings available and 50 had an RNA sequencing. We built a main model based on clinical and pathological data easily available for clinicians. As mandatory criteria, the age, sex, performance status, tumor histology, routine mutational status and PD-L1 immunohistochimical expression were first included in the predictive model. In addition, RECIST response to previous chemotherapy line and antibiotics usage were added into the initial model as they were described significantly associated with respectively good and poor survival to ICI in previous publications. Additional criterion were obtained thanks to extensive DNA tumor analysis such as TMB, mutations in DNA repair pathways, the number of large deletions and intratumoral TCR clones. A third stage of data was added with CD8A and CD274 RNA expressions obtained by RNA sequencing. Thus, several models are available for clinicians to estimate the probability of survival without progression at 6 or 12 months for their patients according to the type of available data. An interactive on-line interface based on R Shiny enables the questioning of all these models for further predictions.
Conclusion
Altogether, these data provide validated and more complex biomarkers according to the type of available data to predict probability of survival without progression to anti-PD-1 in patients with advanced NLCSC. Further predictions can be obtained thanks to a shiny R free and interactive interface available on-line.
-
+
P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
-
+
P1.01-116 - Early Immune-Related Adverse Events Under PD-1/PD-L1 Inhibitors Predict Better Progression-Free Survival in NSCLC (ID 1932)
09:45 - 18:00 | Author(s): Jean-David Fumet
- Abstract
Background
Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis improve survival in patients with advanced non-small-cell lung cancer (NSCLC) without oncogenic addiction; however, they are also responsible for immune-related adverse events (irAE) sometimes leading to treatment discontinuation. Despite a clear association with response to ICB in melanoma, the predictive significance of a better outcome for irAE in NSCLC is unclear.
Method
We retrospectively collected clinical and basic biological data from 160 stage IV NSCLC patients who received nivolumab, pembrolizumab or atezolizumab as second-line single agent in two cancer centers in France between January 2015 and December 2017. All irAE were collected using the Common Terminology Criteria for Adverse Events v5.0 ; general symptoms (e.g. fatigue) and cancer-related symptoms were discarded. We used two different statistical approaches to evaluate whether early irAE (≤ 12 weeks) were correlated to a better progression-free survival: i- a 12-week landmark method, including a multivariate Cox proportional hazards model (with ECOG PS and PD-L1 as covariates), ii- a propensity score matching (PSM) method, using PD-L1 level as the matching variable, followed by a Cox proportional hazards model. Finally, we investigated whether grade and number of early irAE were associated with improved PFS.
Result
Most patients were male (n=107; 66.3%), smokers (n=146; 91.3%) and ECOG PS 0-1 (n=121; 75.7%) and received ICB as second (n=96; 60%), third line (n=38; 23.8%) or more (n=22; 13.8%). Nivolumab was the most used ICB (n=145; 90.6%). Within the first 12 weeks of treatment, 46 irAE occurred in 30 patients (18.8%), including 3 grade 3 irAE (1 pneumonitis, 1 myocarditis, 1 renal failure). Musculoskeletal (8.8%) and skin toxicity (5%) were the most frequent irAE. Clinical baseline characteristics were comparable between patients displaying early irAE (irAE+) and those who did not (irAE-), except for ECOG status (71.5% of PS 0-1 patients in irAE- group versus 93.3% in irAE+, p = 0.023) and PD-L1 level (PD-L1 ≥ 50% in 13.1% of patients in irAE- group versus 30.0% of patients in the irAE+ group, p = 0.016). The 12-week landmark analysis included 80 patients; 23/80 (28.8%) of them experienced at least 1 early irAE. PFS was improved in the irAE+ group in both univariate (HR = 0.24 [0.11-0.53], p < 0.001), and multivariate Cox models (HR = 0.33 [0.14-0.76] p = 0.009). After matching irAE+ and irAE- patients on PD-L1 level, early irAE were still associated with prolonged PFS (HR = 0.29 [0.15-0.57], p = 0.001). In the 12-week landmark population, grade ≥2 irAE were associated with even longer PFS (HR = 0.43 [0.26-0.71], p = 0.0009), and so were multiple co-occurring early irAE (HR = 0.30 [0.15-0.60], p = 0.0007).
Conclusion
Early occurrence of irAE before 12 weeks appears to be associated with prolonged response to ICBs, independently of PD-L1 baseline expression in advanced NSCLC.
-
+
P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.01-97 - Angiotensin-Converting Enzyme Inhibitor Is Associated with Decreased Survival in NSCLC Patients Treated with PD-1 Checkpoint Blockers (ID 2389)
10:15 - 18:15 | Author(s): Jean-David Fumet
- Abstract
Background
Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension and congestive heart failure. Preclinical evidence shows that ACE plays a role on both innate and adaptive immune responses by promoting macrophages and neutrophils function and the stimulation of antigen presentation, thus suggesting the possibility of anti-tumor immunity through an ACE inhibitor-mediated mechanism. Interactions between ACE inhibitors and immune checkpoint blockers (ICB) have not been currently investigated in cancer patients (pts). Our study evaluated the effect of ACE inhibitors on non-small cell lung cancer (NSCLC) pts treated with PD-1/PD-L1 inhibitors.
Method
We conducted a retrospective multicohort retrospective analysis of pts treated with PD-1/PD-L1 inhibitors for NSCLC at Dijon Cancer Center, and at the University of Montreal Hospital. Clinical data and co-medications were collected. Groups were defined as pts treated with ACE inhibitor or not with at the time of ICB initiation. PFS and OS were compared between both groups. Statistical analyses were performed using the Kaplan-Meier method. Cox regression analyses were performed separately to adjust for standard prognostic factors. RNA sequencing of several tumors were performed and analyzed using CIBERSORT to determine immune cells infiltration.
Result
Among 283 pts included (177 pts from Dijon, and 106 pts from Montreal), 27 (10%) received ACE inhibitors. Baseline characteristics were equally balanced in both groups. However, the ACE inhibitor group was more frequently treated with statins, beta blockers and metformin. The ACE inhibitor group had shorter median PFS compared to the control group: 2.5 vs. 3.8 months, p= 0.02 (HR=1.7 CI95% 1.1-2.5). The negative impact of ACE inhibitor group was maintained after multivariate analyses adjusting for known risk factors (HR=1.9 CI95% 1.1-3.5 p=0.02 for PFS and HR=2.3 CI95% 1.2-4.4 p=0.01 for OS). RNA sequencing suggested that ACE inhibitor group tumors had lower M1 macrophages, activated mast cells, NK cells and memory activated T cells thus suggesting an immunosuppressed state.
Conclusion
ACE inhibitor prescription concomitant to the PD-1/PD-L1 inhibitors treatment is associated with impaired outcome in pts with advanced NSCLC pts. This reduction is independent of standard prognostic factors. Biological correlative analyses suggest a tumor immunosuppressed state in ACE inhibitor group. These results should be validated in larger prospective cohorts.
