Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study

Manuela Tiako Meyo; Anne Jouinot; Etienne Giroux-Leprieur; Elizabeth Fabre; Marie Wislez; Marco Alifano; Karen Leroy; Pascaline Boudou-Rouquette; Camille Tlemsani; Nihel Khoudour; Jennifer Arrondeau; Audrey Thomas-Schoemann; Hélène Blons; Audrey Mansuet-Lupo; Diane Damotte; Michel Vidal; François Goldwasser; Jérôme Alexandre; Benoit Blanchet

doi:10.3390/cancers12020473

Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study

Cancers (Basel). 2020 Feb 18;12(2):473. doi: 10.3390/cancers12020473.

Authors

Manuela Tiako Meyo^{1

2

3}, Anne Jouinot^{3

4}, Etienne Giroux-Leprieur⁵, Elizabeth Fabre⁶, Marie Wislez⁷, Marco Alifano⁸, Karen Leroy⁹, Pascaline Boudou-Rouquette³, Camille Tlemsani³, Nihel Khoudour¹, Jennifer Arrondeau³, Audrey Thomas-Schoemann^{2

3}, Hélène Blons¹⁰, Audrey Mansuet-Lupo⁹, Diane Damotte⁹, Michel Vidal^{1

2}, François Goldwasser^{3

11}, Jérôme Alexandre^{3

4

11}, Benoit Blanchet^{1

2}

Affiliations

¹ Drug Biology-Toxicology, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France.
² UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, Paris Descartes University, PRES Sorbonne Paris Cité, 75006 Paris, France.
³ Department of Medical Oncology, Cochin Hospital, AP-HP, Paris Descartes University, CARPEM, 75014 Paris, France.
⁴ Institut Cochin, INSERM U1016, 75014 Paris, France.
⁵ Department of Respiratory Diseases and Thoracic Oncology, APHP-AmbroiseParé Hospital and EA 4340 University Versailles-Saint Quentin en Yvelines, 92100 Boulogne, France.
⁶ Department of Thoracic Oncology, Georges Pompidou European Hospital, AP-HP, 75015 Paris, France.
⁷ Department of Pneumology, Cochin Hospital, APHP, 75014 Paris, France.
⁸ Department of Thoracic Surgery, Cochin Hospital, APHP, 75014 Paris, France.
⁹ Department of Cyto-pathology, Cochin Hospital, AP-HP, 75014 Paris, France.
¹⁰ Department of Cyto-pathology, Georges Pompidou European Hospital, AP-HP, 75015 Paris, France.
¹¹ Institut Cordeliers, INSERM U1147, 75006 Paris, France.

Abstract

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55-109) vs. 658 days (222-not reached); HR: 4.12 (1.95-8.71), p = 0.0002) and OS (HR: 3.99(1.63-9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17-6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30-0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21-0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.

Keywords: Immune checkpoint inhibitors; NSCLC; PD-1; biomarkers; nivolumab.