Abstract 984P
Background
We aimed to determine the safety and efficacy of nintedanib ([N]), an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab ([P]), an anti-PD1 immunotherapy in patients (Pts) with advanced solid tumors (NCT02856425).
Methods
In this monocentric cohort phase Ib dose escalation cohort, we evaluated escalating doses of [N] (Dose level 1 (DL1) = 150 mg BID; DL2 = 200 mg BID) in combination with IV flat dose of [P] (200 mg Q3W). Patients received a week lead-in dose of [N] monotherapy prior starting [P]. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to determine the recommended phase II dose (RP2D), to assess the anti-tumor efficacy and identify associated biomarkers. Baseline & on-treatment tumor & blood samples prospectively phenotyped by flow cytometry (FC) & IHC. Cytokines were dosed by multiplex ELISA on plasma.
Results
A total of 12/13 patients enrolled were evaluable for DLT (1 consent withdrawn prior to [P]). Three patients at 200mg BID experienced a DLT (grade 3 liver enzymes increase). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55-40.5). Three patients developed a partial response (PR)(ORR=25%) and five patients had clinical benefit (CB) defined as PR or stable disease ≥ 6 months (DCR at 6 months=42%). At baseline, patients having higher IHC tumor infiltrates with DCLAMP+ dendritic cells, CD3+ T-cells, and FOXP3+ T-cells developed PR. Higher baseline plasma levels of Tie2, CXCL10 and CCL22 and higher circulating eosinophils and CD4+ PD1+ OX40+ were associated with CB. For Pts who eventually developed CB, the [N] lead-in monotherapy resulted in higher blood CCL3, Tregs & CXCR5- CCR4+ CXCR3+ CD4 T-cells. After the first [P] infusion, Pts with CB showed higher CCL22 and lower IL6, IL8 & IL27 plasma rates.
Conclusions
[N] 150mg BID is the RP2D for combination with [P] in multiple expansion cohorts and is being currently investigated. Early tumor and circulating immune biomarkers were associated with cancer outcome under [N]+[P] therapy.
Clinical trial identification
NCT02856425.
Editorial acknowledgement
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: BMS; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Institutional, Research Grant: Iteos; Financial Interests, Institutional, Research Grant: Tahio. N. Chaput: Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal and Institutional, Research Grant: GSK; Financial Interests, Personal and Institutional, Research Grant: Roche; Financial Interests, Personal and Institutional, Research Grant: Sanofi; Financial Interests, Personal and Institutional, Research Grant: Cytune Pharma. 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. C. Massard: Non-Financial Interests, Personal and Institutional, Advisory Role: Amgen; Non-Financial Interests, Personal and Institutional, Advisory Role: Astellas Pharma; Non-Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca; Non-Financial Interests, Personal and Institutional, Advisory Role: Bayer; Non-Financial Interests, Personal and Institutional, Advisory Role: BeiGene; Non-Financial Interests, Personal and Institutional, Advisory Role: BMS; Non-Financial Interests, Personal and Institutional, Advisory Role: Celgene; Non-Financial Interests, Personal and Institutional, Advisory Role: Debiopharm Group; Non-Financial Interests, Personal and Institutional, Advisory Role: Genentech/Roche; Non-Financial Interests, Personal and Institutional, Advisory Role: Ipsen; Non-Financial Interests, Personal and Institutional, Advisory Role: Janssen; Non-Financial Interests, Personal and Institutional, Advisory Role: Lilly; Non-Financial Interests, Personal and Institutional, Advisory Role: MSD; Non-Financial Interests, Personal and Institutional, Advisory Role: Novartis; Non-Financial Interests, Personal and Institutional, Advisory Role: Pfizer; Non-Financial Interests, Personal and Institutional, Advisory Role: Sanofi; Non-Financial Interests, Personal and Institutional, Advisory Role: Orion; Non-Financial Interests, Personal and Institutional, Advisory Role: Taiho Pharmaceuticals; Non-Financial Interests, Personal and Institutional, Advisory Role: Blueprint Medicinces; Non-Financial Interests, Personal and Institutional, Advisory Role: Innate Pharma; Non-Financial Interests, Personal and Institutional, Advisory Role: PharmaMar; Non-Financial Interests, Personal and Institutional, Advisory Role: Faron Pharmaceuticals. A. Marabelle: Financial Interests, Personal, Invited Speaker: Roche/Genentech; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; 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, Advisory Board: Merck Serono; Non-Financial Interests, Personal, Advisory Board: eTheRNA; Non-Financial Interests, Personal, Advisory Board: Lytix pharma; Non-Financial Interests, Personal, Advisory Board: Kyowa Kirin Pharma; Non-Financial Interests, Personal, Advisory Board: Novartis; Non-Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: AstraZeneca; 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.