Safety, recommended dose, efficacy and immune correlates for nintedanib in combination with pembrolizumab in patients with advanced cancers
Authors: Baldini Capucine , Danlos Francois-Xavier , Varga Andreea , Texier Matthieu , Halse Heloise , Mouraud Severine , Cassard Lydie , Champiat Stéphane , Signolle Nicolas , Vuagnat Perrine , Martin-Romano Patricia , Michot Jean-Marie , Bahleda Rastislav , Gazzah Anas , Boselli Lisa , Bredel Delphine , Grivel Jonathan , Mohamed-Djalim Chifaou , Escriou Guillaume , Grynszpan Laetitia , Bigorgne Amelie , Rafie Saloomeh , Abbassi Alae , Ribrag Vincent , Postel-Vinay Sophie , Hollebecque Antoine , Susini Sandrine , Farhane Siham , Lacroix Ludovic , Parpaleix Aurelien , Laghouati Salim , Zitvogel Laurence , Adam Julien , Chaput Nathalie , Soria Jean-Charles , Massard Christophe , Marabelle Aurelien 
Published: July 2022

Abstract
Background
We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425).

Methods
In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. 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 assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy.

Results
A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1–2 immune related adverse events (irAE). 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 (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5− memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels.

Conclusion
Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy.

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