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378 Efficacy, safety and ancillary analyses of pembrolizumab in combination with nintedanib for the treatment of patients with relapsed advanced mesothelioma
  1. Francois-Xavier Danlos1,
  2. Capucine Baldini1,
  3. Matthieu Texier1,
  4. Andreea Varga1,
  5. Severine Mouraud2,
  6. Bastien Job1,
  7. Diane Letourneur3,
  8. Lydie Cassard1,
  9. Delphine Bredel2,
  10. Salim Laghouati1,
  11. Julien Adam4,
  12. Nathalie Droin1,
  13. Aurelien Parpaleix1,
  14. Nathalie Chaput-Gras5,
  15. Audrey Rabeau6,
  16. Gerard Zalcman7,
  17. David Planchard1,
  18. Christophe Massard1,
  19. Jean-Charles Soria1 and
  20. Aurelien Marabelle1
  1. 1Gustave Roussy, VILLEJUIF, France
  2. 2Gustave Roussy, INSERM, CLAMART, France
  3. 3Gustave Roussy, ENS Lyon, Villejuif, France
  4. 4Hopital Paris Saint-Joseph, Villejuif, France
  5. 5Gustave Roussy, Université Paris Saclay, Villejuif, France
  6. 6Institut Universitaire Oncologie, Toulouse, France
  7. 7CHU Bichat, APHP, Paris, France


Background We report the results from the advanced malignant mesothelioma (aMM) expansion cohort of the PEMBIB Phase Ib trial (NCT02856425) evaluating the safety, efficacy & biomarkers of an antiangiogenic tyrosine kinase inhibitor (nintedanib) with an anti-PD1 immunotherapy (pembrolizumab).

Methods Patients with aMM relapsing after at least one line of platinum doublet chemotherapy and not previously pre-exposed to IO were treated with a combination of oral nintedanib (150mg BID) & IV pembrolizumab (200mg Q3W) with a 7 days nintedanib lead-in preceding pembrolizumab initiation. Baseline and on-treatment (cycle D2, day 1 [C2D1]) fresh tumor & blood samples were prospectively phenotyped by flow cytometry (FC). RNAseq was run on tumor samples. Immune factors were titrated on tumor secretome and plasma.

Results 30 aMM patients were treated and 29 evaluable for response. Median age was 68 years old (38–85) and 86% of aMM were epithelioid. The most frequent adverse events (AE) (grades 1–3) related to the combination were liver enzymes increase, fatigue, nausea, and diarrhea. 4 (13.3%) patients developed grade 3–5 immune- related AE. Patients died of cancer progression (n=14, 46.7%), myocarditis with thrombo-embolic event (n=1, 3.3%) and COVID-19 (n=1, 3.3%). Median follow-up was 14.8 months (95%CI [9.70–18.2]). Best Overall Response Rates (BORR) per RECISTv1.1 were Partial Response (PR, n=7/29; 24.1%), Stable Disease (SD, n=17/29; 58.6%) and Progressive Disease (n=5/29; 17.2%). Disease Control Rate (DCR) (defined as PR + SD) was 46.6% at 6 months. Patients with DCR at 6 months had significantly higher percentage of PDL1 expression on tumor cells (by Immuno-Histo-Chemistry, antibody clone SP263) and higher CD8+ T cells infiltrate in tumor biopsies (by FC) at screening. Upon treatment, soluble plasma rate of CXCL9 and CXCL13 increased in all patients, as well as tumor immune infiltrates estimated by deconvolution of tumor biopsies RNA-seq. But deconvoluted estimates of NK cells, T cells and myeloid dendritic cells infiltrates on baseline tumors and C2D1 biopsies were higher in patients with DCR at 6 months. Pre & on-treatment IL6 and IL8 rates in tumor secretome & plasma were higher in patients without DCR. Gene Set Enrichment Analyses on RNA-seq from screening biopsies highlighted an enrichment in E2F, MYC and KRAS gene pathways and lower expression of type 1 interferon signature in patients without DCR than those with DCR at 6 months.

Conclusions With a BORR of 24% and a DCR of 47% at 6 months, pembrolizumab and nintedanib combination provided valuable therapeutic benefits for patients with aMM.

ClinicalTrials gov, NCT02856425. Registered August 4, 2016 — Prospectively registered,

Ethics Approval The protocol was first approved by the Agence Nationale de Sécurité du Médicament (ANSM) on June 24th 2016 (Ref #160371A-12). The protocol was also approved by the Ethical Committee (Comité de Protection des Personnes Ile de France 1) on Jul 12th 2016 (Ref #2016-mai-14236ND).

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