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ePoster Display

984P - Phase I dose escalation trial of nintedanib in combination with pembrolizumab in patients with advanced solid tumors (PEMBIB trial)

Date

16 Sep 2021

Session

ePoster Display

Topics

Immunotherapy

Tumour Site

Presenters

Capucine Baldini

Citation

Annals of Oncology (2021) 32 (suppl_5): S829-S866. 10.1016/annonc/annonc705

Authors

C. Baldini1, F. Danlos2, A. Varga1, H. Halse3, S. Mouraud4, L. Cassard5, D. Bredel4, G. Escriou4, A. Parpaleix6, S. Rafie1, A.E. Abbassi1, S. Laghouati7, S. Farhane1, L. Tselikas8, M. Texier9, J. Adam10, N. Chaput11, J. Soria12, C. Massard13, A. Marabelle14

Author affiliations

  • 1 Drug Development Department, Gustave Roussy, 94805 - Villejuif/FR
  • 2 Inserm Umr1015 - Drug Development Department, Gustave Roussy, 94805 - Villejuif/FR
  • 3 Inserm U1163, Gustave Roussy - Imagine institut, 94800 - Villejuif/FR
  • 4 Inserm Umr1015, Gustave Roussy, 94800 - Villejuif/FR
  • 5 Laboratory Of Immunomonitoring In Oncology, Cnrs-ums 3655 And Inserm-us23, Paris Saclay University, Gustave Roussy, 94805 - Villejuif, Cedex/FR
  • 6 Sponsor Clinical Project Coordinator, Gustave Roussy, 94800 - Villejuif/FR
  • 7 Pharmacovigilance Department, Gustave Roussy, 94800 - Villejuif/FR
  • 8 Interventional Radiology, Gustave Roussy - Cancer Campus, 94805 - Villejuif/FR
  • 9 Biostatistics, Gustave Roussy, 94805 - Villejuif/FR
  • 10 Pathology Dept., Groupe Hospitalier Paris Saint Joseph, 75014 - Paris/FR
  • 11 Laboratory Of Immunomonitoring In Oncology, Umr9019 - Cnrs, Genome Integrity And Cancers, Equipe Labellisée Ligue Nationale Contre Le Cancer, Université Paris-Saclay, Gustave Roussy, 94805 - Villejuif/FR
  • 12 General Director, Institut Gustave Roussy, 94805 - Villejuif/FR
  • 13 Drug Development Department (ditep), Gustave Roussy, 94800 - Villejuif/FR
  • 14 Drug Development Department - Inserm Umr1015, Institut Gustave Roussy, 94805 - Villejuif/FR

Resources

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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.

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