Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial
Laurent Greillier
(1)
,
Florence Monville
(2)
,
Vanina Leca
(2)
,
Frédéric Vely
(3, 4)
,
Stephane Garcia
(3)
,
Joseph Ciccolini
(4, 3, 5)
,
Florence Sabatier
(3, 4)
,
Gilbert Ferrani
(4)
,
Nawel Boudai
(4)
,
Lamia Ghezali
(2)
,
Marcellin Landri
(2)
,
Clémence Marin
(3)
,
Mourad Hamimed
(5, 6)
,
Laurent Arnaud
(4)
,
Melanie Karlsen
(5)
,
Kevin Atsou
(5)
,
Sivan Bokobza
(7)
,
Nicolas Cloarec
(8)
,
Pauline Fleury
(5)
,
Arnaud Boyer
(9)
,
Clarisse Audigier-Valette
(10)
,
Stéphanie Martinez
(11)
,
Hervé Pegliasco
(12)
,
Patrice Ray
(13)
,
Lionel Falchero
(14)
,
Antoine Serre
(15)
,
Louisiane Lebas
(16)
,
Stephane Hominal
(17)
,
Patricia Barre
(18)
,
Sarah Zahi
(19)
,
Ahmed Frikha
(20)
,
Pierre Bory
(21)
,
Maryannick Le Ray
(4)
,
Lilian Laborde
(22)
,
Virginie Martin
(22)
,
Richard Malkoun
(4)
,
Fabrice Barlesi
(23, 24)
,
Marie Roumieux
(3)
,
Julien Mazieres
(25)
,
Maurice Perol
(26)
,
Eric Vivier
(3, 4, 7)
,
Sébastien Benzekry
(5)
,
Jacques Fieschi
(2)
1
Service d'oncologie multidisciplinaire innovations thérapeutiques [Hôpital Nord - APHM]
2 Veracyte SAS
3 AMU - Aix Marseille Université
4 APHM - Assistance Publique - Hôpitaux de Marseille
5 COMPO - Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique
6 SMARTc - Simulation and Modeling of Adaptive Response for Therapeutics in Cancer
7 Innate Pharma
8 Centre Hospitalier Henri Duffaut (Avignon)
9 Hôpital Saint-Joseph [Marseille]
10 Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse
11 CHIAP - Centre Hospitalier d'Aix en Provence [Aix-en-Provence]
12 Hôpital Européen [Fondation Ambroise Paré - Marseille]
13 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
14 Hôpital Nord-Ouest [Villefranche sur Saône]
15 Instit Cancéro - GARD - Institut de Cancérologie du GARD ICG - CHU Nîmes
16 Centre Hospitalier du Val d'Ariège
17 Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois]
18 Centre hospitalier Jean Rougier
19 CH Montauban - Centre hospitalier de Montauban
20 Polyclinique Maymard
21 Centre Hospitalier de Bastia
22 IPC - Institut Paoli-Calmettes
23 IGR - Institut Gustave Roussy
24 Université Paris-Saclay
25 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
26 Centre Léon Bérard [Lyon]
2 Veracyte SAS
3 AMU - Aix Marseille Université
4 APHM - Assistance Publique - Hôpitaux de Marseille
5 COMPO - Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique
6 SMARTc - Simulation and Modeling of Adaptive Response for Therapeutics in Cancer
7 Innate Pharma
8 Centre Hospitalier Henri Duffaut (Avignon)
9 Hôpital Saint-Joseph [Marseille]
10 Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse
11 CHIAP - Centre Hospitalier d'Aix en Provence [Aix-en-Provence]
12 Hôpital Européen [Fondation Ambroise Paré - Marseille]
13 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
14 Hôpital Nord-Ouest [Villefranche sur Saône]
15 Instit Cancéro - GARD - Institut de Cancérologie du GARD ICG - CHU Nîmes
16 Centre Hospitalier du Val d'Ariège
17 Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois]
18 Centre hospitalier Jean Rougier
19 CH Montauban - Centre hospitalier de Montauban
20 Polyclinique Maymard
21 Centre Hospitalier de Bastia
22 IPC - Institut Paoli-Calmettes
23 IGR - Institut Gustave Roussy
24 Université Paris-Saclay
25 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
26 Centre Léon Bérard [Lyon]
Laurent Greillier
- Function : Author
- PersonId : 777166
- ORCID : 0000-0002-5807-9503
- IdRef : 116390867
Frédéric Vely
- Function : Author
Mourad Hamimed
- Function : Author
- PersonId : 749888
- IdHAL : mourad-hamimed
Fabrice Barlesi
- Function : Author
- PersonId : 1357222
- ORCID : 0000-0001-5793-3539
- IdRef : 087602997
Julien Mazieres
- Function : Author
- PersonId : 1033301
- ORCID : 0000-0002-5921-7613
Sébastien Benzekry
- Function : Author
- PersonId : 12116
- IdHAL : sebastien-benzekry
- ORCID : 0000-0002-3749-8637
- IdRef : 159344212
Abstract
Abstract Background: Resistance to PD1/L1 immune checkpoint inhibitors (ICIs) in advanced NSCLC patients is observed in about 80% of individuals with no robust predictive biomarker yet. The PIONeeR trial (NCT03493581) aims to predict such resistances through a comprehensive multiparametric biomarkers analysis.
Methodology: Among the >300 advanced NSCLC patients (pts) recruited in PIONeeR, we focused on the first 137 ≥2nd line ECOG PS0-1 pts treated with single-agent nivolumab, pembrolizumab or atezolizumab. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout the 24 weeks post C1D1. Response to PD1/L1 ICIs was assessed by RECIST 1.1 every 6 weeks. Immune contexture was characterized in tumor & blood of each pt through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC/digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma dosage, leading to 331 measured biomarkers in addition to routine clinical parameters. Multivariable (MV) logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histological type & PDL1+ Tumor Cells) with the risk of Early Progression (EP), i.e. within 3.5 months of treatment. Multivariable Cox regression analysis was conducted for association with PFS and OS.
Results: Overall, the 137 pts were mainly male (64%), smokers (92%) and <70yrs (68%). Tumors were mainly non-squamous (79%) with >1% PDL1+ TC in 36% of the cases, and 21% of pts were still on treatment at data cut-off. Archived samples were available for 80% of pts at inclusion and re-biopsy was available in 52.9% of these cases. The median follow up was 19.8 months, 22.5% of pts did not progress at data cut-off while 62% presented EP. Tumor Cytotoxic T-cells density, especially PD1+ were lower in EP (MV OR=0.45, p=0.022); conversely, higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in EP (MV OR=3.8, p<0.001). Among other biomarkers, Tregs (MV OR=0.44, p=0.018), NK cell subsets (MV OR≤0.44, p<0.05), albumin (MV OR=0.4, p<0.01) and PDL1 TC % (MV OR=0.27, p<0.01) were decreased whereas alkaline phosphatase was increased (OR=3, p=0.018). >65% inter-pt variability was observed in plasma exposures for all ICIs, with 8-10% of pts displaying trough levels below the target engagement threshold. Data will be presented through unsupervised clustering algorithms & multi-modal supervised learning methods. Changes after 6 weeks of treatment will be analyzed to further investigate drugs mechanisms of action. Conclusion: The PIONeeR trial provides with the 1st comprehensive biomarkers’ analysis to establish predictive models of resistance in advanced NSCLC pts treated with PD1/L1 ICIs and highlights how tumor and circulating biomarkers are complementary.
