Pembrolizumab and nintedanib for patients with advanced mesothelioma

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.

Sustained cancer clinical trial activity during the COVID-19 pandemic

Background: The COVID-19 pandemic deeply threatens the rigorous conduct of clinical trials, notably by delaying site initiation visits, patient enrolment, treatment administration, trial-associated procedures, and data monitoring. Unlike most other medical specialties, clinical trials are an integral part of patient care in oncology. Limiting access to clinical trials therefore results in a loss of chance for patients. Methods: In this retrospective single-center study, we collected clinical trial-specific items (including patient-related or trial management-related items) during the first pandemic wave (March– June 2020) and lockdown (March 17th-May 11th) at Gustave Roussy, and compared them to those of the same period in 2019. Results: In March 2020, 84 phase I (P1) and 210 phase II/III (P2/3) trials were open. During the first pandemic wave, 21 (25%) P1 and 20 (9%) P2/3 trials were temporarily halted, following a unilateral sponsor decision in virtually all cases;all but one were industry-sponsored. Despite this, all important metrics of the P1/2 trial activity remained similar to those of 2019, including the number of patients referred for inclusion (599 vs 620), inclusion consultations (215 vs 247), patients starting treatment (130 vs 130), Internal Review Board (IRB) submissions (14 vs 16), and site initiation visits (11 vs 15), all in 2020 vs 2019, respectively. The impact of the first lock-down was more marked on P2/3, with 152 patient inclusions (vs 346 in 2019), 125 randomizations (vs 278), 43 IRB submissions (vs 50) and 34 site initiation visits (vs 40). However, in parallel, 475 patients were included in three “COVID and cancer” trials. Among the 443 P1 and 2851 P2/3 patients, 198 and 628 COVID-19 PCR were performed internally, and five and 15 (2.5%) were positive, respectively. One patient with a community-based COVID-19 died after transfer in intensive care. Conclusions: Cancer clinical trials can, and must be maintained despite challenges brought by COVID-19. Sharing experiences and retrospectively evaluating the impact on patients’ safety and cancer-related outcomes will be critical to durably improve the clinical trials conduct and to anticipate at best challenges brought by future similar crises. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.