Pembrolizumab and nintedanib for patients with advanced mesothelioma

ABSTRACT

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 TKI (nintedanib = [N]) with an anti-PD1 immunotherapy (pembrolizumab = [P]). Methods: Patients (Pts) with aMM that relapsed after at least one line of platinum-based combination were treated with a combination of oral [N] (150mg BID) & IV [P] (200mg Q3W) with 7 days [N] lead-in preceded [P] initiation. Baseline and on-treatment fresh tumor & blood samples were prospectively phenotyped immune cells by flow cytometry (FC). RNAseq was run on tumor samples. Immune factors were titrated by multiplex ELISA on tumor secretome and plasma. Results: 30 aMM Pts 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%) Pts developed grade 3-5 immune- related AE. Patients died of cancer progression (n=14), myocarditis with thrombo-embolic event (n=1) and COVID-19 (n=1). Median follow-up was 14.8 months (95%CI [9.70-18.2]). Best Overall Response Rates (BORR) were Partial Response (PR;n=7), Stable Disease (SD;n=17) and Progressive Disease (PD;n=5). Disease Control Rate (DCR) (defined as PR + SD) was 68.4% and 46.6% at 3 and 6 months, respectively. Analyses on fresh tumor biopsies showed that all patients increased their CD3+ T-cells and circulating levels of soluble PD1 and CXCL9 under treatment. Pts developing PR had significantly higher CD45+ and CD3+ tumor infiltrative cells at baseline compared to Pts with SD & PD as BORR. Pts with DCR at 6 months had significantly higher expression of integrins on circulating effector memory CD4+ & CD8+ T cells by FC, and higher NK, T, and myeloid dendritic cells infiltrates on baseline tumor RNAseq. Pre & on-treatment IL6 and IL8 levels in tumor secretome & plasma were higher among Pts with PD. Conclusions: With a BORR of 23% and a DCR of 47% at 6 months, [P]+[N] combination provided valuable therapeutic benefits for Pts with aMM. Flow cytometry and secretome on fresh baseline tumor biopsies are simple techniques which could be used to predict treatment efficacy in aMM Pts. Clinical trial identification NCT02856425. Legal entity responsible for the study Gustave Roussy. Funding: Funding: Boehringer Ingelheim;Drug supply Boehringer Ingelheim & MSD;Sponsor Gustave Roussy. Disclosure C. Baldini Financial Interests, Personal, Invited Speaker Sanofi;Financial Interests, Personal, Invited Speaker BMS;Financial Interests, Personal, Invited Speaker AstraZeneca;Financial Interests, Institutional, Research Grant Seattle Genetics;Financial Interests, Institutional, Research Grant Iteos;Financial Interests, Institutional, Invited Speaker Tahio;Financial Interests, Institutional, Research Grant BMS. N. Chaput Financial Interests, Institutional, Research Grant AstraZeneca;Financial Interests, Institutional, Research Grant BMS;Financial Interests, Institutional, Research Grant GSK;Financial Interests, Institutional, Research Grant Roche;Financial Interests, Institutional, Research Grant Sanofi;Financial Interests, Institutional, Research Grant Cytune Pharma. G. Zalcman Financial Interests, Personal, Invited Speaker, outside the submitted work BMS;Financial Interests, Personal, Invited Speaker, outside the submitted work MSD;Financial Interests, Personal, Invited Speaker, outside the submitted work AstraZeneca;Financial Interests, Personal, Invited Speaker, outside the submitted work Boehringer Ingelheim;Non-Financial Interests, Personal, Advisory Board, outside the submitted work Roche;Non-Financial Interests, Personal, Advisory Board, outside the submitted work Takeda;Non-Financial Interests, Personal, Advisory Board, outside the submitted work AstraZeneca;Non-Financial Interests, Personal, Advisory Board, outside the submitted work AbbVie. C. Massard Non-Financial Interests, Personal, Advisory Role Amgen;Non-Financial Interests, Personal, Advisory Role Astellas Pharma;Non-Financial Interests, Personal, Advisory Role AstraZeneca;Non-Financial Interests, Personal, Advisory Role Bayer;Non-Financial Interests, Personal, Advisory Role BeiGene;Non-Financial Interests, Personal, Advisory Role BMS;Non-Financial Interests, Personal, Advisory Role Celgene;Non-Financial Interests, Personal, Advisory Role Debiopharm Group;Non-Financial Interests, Personal, Advisory Role Genentech/Roche;Non-Financial Interests, Personal, Advisory Role Ipsen;Non-Financial Interests, Personal, Advisory Role Janssen;Non-Financial Interests, Personal, Advisory Role Lilly;Non-Financial Interests, Personal, Advisory Role MSD;Non-Financial Interests, Personal, Advisory Role Novartis;Non-Financial Interests, Personal, Advisory Role Pfizer;Non-Financial Interests, Personal, Advisory Role Sanofi;Non-Financial Interests, Personal, Advisory Role Orion;Non-Financial Interests, Personal, Advisory Role Taiho Pharmaceuticals;Non-Financial Interests, Personal, Advisory Role Blueprint Medicinces;Non-Financial Interests, Personal, Advisory Role Innate Pharma;Non-Financial Interests, Personal, Advisory Role PharmaMar;Non-Financial Interests, Personal, Advisory Role Faron Pharmaceuticals. J-C. Soria Financial Interests, Personal, Stocks/Shares AstraZeneca;Financial Interests, Personal, Stocks/Shares Gritstone Oncology;Financial Interests, Personal, Stocks/Shares Relay Therapeutics;Financial Interests, Personal, Member of the Board of Directors Hookipa Pharmaceuticals;Financial Interests, Personal, Full or part-time Employment, sept 2017 to dec 2019 AstraZeneca. A. Marabelle Financial Interests, Personal, Invited Speaker Roche/Genentech;Financial Interests, Personal, Invited Speaker BMS;Financial Interests, Personal, Invited Speaker Merck Serono;Financial Interests, Personal, Invited Speaker AstraZeneca;Financial Interests, Personal, Invited Speaker Amgen;Financial Interests, Personal, Invited Speaker Sanofi;Financial Interests, Personal, Invited Speaker Servier;Non-Financial Interests, Personal, Principal Investigator Roche/Genentech;Non-Financial Interests, Personal, Principal Investigator BMS;Non-Financial Interests, Personal, Principal Investigator MSD;Non-Financial Interests, Personal, Principal Investigator Pfizer;Non-Financial Interests, Personal, Principal Investigator Lytix Pharma;Non-Financial Interests, Personal, Principal Investigator Eisai;Non-Financial Interests, Personal, Principal Investigator AstraZeneca;Non-Financial Interests, Personal, Principal Investigator Tesaro;Non-Financial Interests, Personal, Principal Investigator Chugai;Non-Financial Interests, Personal, Principal Investigator Ose Immunotherapeutics;Non-Financial Interests, Personal, Principal Investigator Sotio;Non-Financial Interests, Personal, Principal Investigator Molecular Partners;Non-Financial Interests, Personal, Principal Investigator IMCheck;Non-Financial Interests, Personal, Principal Investigator Pierre Fabre;Non-Financial Interests, Personal, Principal Investigator Adlai Nortye;Financial Interests, Personal, Stocks/Shares Pegascy SAS;Financial Interests, Personal, Stocks/Shares Centessa Pharmaceuticals;Financial Interests, Personal, Stocks/Shares HiFiBio;Financial Interests, Personal, Stocks/Shares Shattuck Labs;Financial Interests, Institutional, Research Grant Merus;Financial Interests, Institutional, Research Grant BMS;Financial Interests, Institutional, Research Grant Boehringer Ingelheim;Financial Interests, Institutional, Research Grant Transgene;Financial Interests, Institutional, Research Grant Fondation MSD Avenir;Financial Interests, Institutional, Research Grant Sanofi. All other authors have declared no conflicts of interest.