PIONeeR aims to predict response/resistance to PD1/L1 ICIs in advanced NSCLC pts through comprehensive agnostic multiparametric and longitudinal biomarkers assessment. These ICIs significantly improve long-term outcome in 20% of advanced NSCLC pts but to date, no robust biomarker predicts primary or secondary resistance.
Advanced NSCLC pts with available archived tumor tissue treated with either nivolumab, pembrolizumab or atezolizumab, alone (2nd line min) or combined with chemotherapy (1st line), were systematically re-biopsied and blood-sampled at 6wks (V2) of treatment. ORR was assessed by RECIST 1.1 every 6wks. Quantification of circulating and tumor infiltrating immune cells and PD-L1 mediated inhibition (Immunoscore® IC) were performed by FACS and multiplex IHC coupled to digital pathology respectively. Endothelial activation, blood soluble factors, PK and TMB through WES were also assessed.
The first 100 pts are mainly male (64%), smokers (91-8%), <65yrs (55%), with an ECOG PS0/1 (97%), treated in 2nd line setting (86%). Tumors were mainly ADC (57%) with ≥1% PDL1 expression in 38% of the cases. 21% were still on treatment at data cut-off. V2 biopsy was available in 46% of cases; 33 pts progressed before the 6wks milestone, and 13 pts were considered as responders. Median PFS was 2.99 months (mo) [95%CI: 2.43 – 4.83] and median OS was 11.01 mo [95%CI: 8.21 - NA]. At baseline (VS), PD-L1 tumor cell percentage was significantly higher in responders, as well as tumor infiltration by cytotoxic lymphocytes (cTILs) (median: 160 vs 410 cells/mm2). Five non-responders presented high cTILs densities (up to 1800 cells/mm2), associated either to no PDL1 expression, high infiltration of Treg cells in the tumor or weak PD1 expression on cTILs. High immune cell densities at the periphery and in the tumor were associated with survival. Immune cell infiltration and PD-L1+ cell density increased from VS to V2, as well as proximity between these cells. Massive PK variability among patients was found.
Immune cells quantification and characterization add value to clinical factors to predict advanced NSCLC response/resistance to ICIs.
NCT03493581, Release date: February 2018.
Assistance Publique Hôpitaux de Marseille (AP-HM).
French National Research Agency (ANR-17-RHUS-0007).
F. Barlesi: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): ACEA; Research grant/Funding (institution): Amgen; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Boehringer-Ingelheim; Research grant/Funding (institution): Eisai; Honoraria (self), Research grant/Funding (institution): Eli Lilly Oncology; Honoraria (self), Research grant/Funding (institution): F. Hoffmann-La Roche Ltd.; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Innate Pharma; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): MedImmune; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Merck; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Pierre Fabre; Honoraria (self), Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Sanofi-Aventis; Honoraria (self), Research grant/Funding (institution): Takeda. F. Monville: Full/Part-time employment: HalioDx. J. le treut: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Boehringer; Honoraria (self): Roche. C. Audigier-Valette: Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: Lilly; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (institution), Advisory/Consultancy: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: AbbVie; Advisory/Consultancy: FoundationOne; Advisory/Consultancy: Takeda. S. Garcia: Travel/Accommodation/Expenses: MSD. J. Ciccolini: Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): Institut Roche; Honoraria (self): Pierre Fabre; Honoraria (self): BMS; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Ipsen. P. Outters: Full/Part-time employment: HalioDx. J. Mazieres: Honoraria (self), Research grant/Funding (self): Roche; Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self), Research grant/Funding (self): Pierre Fabre; Honoraria (self): Takeda; Honoraria (self), Research grant/Funding (self): BMS; Honoraria (self): MSD; Honoraria (self): Hengrui; Honoraria (self): Blueprint; Honoraria (self): Daiichi; Honoraria (self): Novartis. M. Pérol: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Speaker Bureau/Expert testimony: Amgen; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Takeda; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Chugai. E. Vivier: Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Innate Pharma. J. Fieschi: Officer/Board of Directors: HalioDx. All other authors have declared no conflicts of interest.