Abstract CT141: Safety and efficacy results from a phase I dose-escalation trial of Nintedanib in combination with Pembrolizumab in patients with advanced solid tumors (PEMBIB trial)
Authors: Varga Andreea , Baldini Capucine , Martin-Romano Patricia , Hollebecque Antoine , Gazzah Anas , Bahleda Rastislav , Menis Jessica , Champiat Stephane , El-Dakdouki Yolla , Paoletti Xavier , Ribrag Vincent , Michot Jean-Marie , Rafie Saloomeh , Planchard David , Besse Benjamin , Massard Christophe , Soria Jean-Charles , Marabelle Aurelien 
Published: August 2018

Abstract
Background: Antiangiogenic drugs can synergize with immunotherapy in preclinical models. However some molecules have shown unacceptable levels of toxicity when combined with anti-PD-1. We aimed to determine the safety and activity of the nintedanib+pembrolizumab combination. Nintedanib is an oral angiokinase inhibitor aiming the vascular endothelial growth factor receptors 1,2,3, platelet-derived growth factor receptors α,β, fibroblast growth factor receptors 1,2,3 as well as RET. Pembrolizumab is a highly selective, humanized monoclonal IgG4-kappa isotype antibody against PD-1 designed to block the negative immune regulatory signaling of the PD-1 receptor expressed by T cells.
Methods: PEMBIB is a monocentric phase Ib trial which evaluated escalating doses of continuous oral intake of nintedanib (Dose level 1 (DL1) = 150 mg BID; DL2 =200 mg BID) in combination with intravenous flat dose of pembrolizumab at 200 mg every 21 days in patients with advanced solid tumors using the rolling 6 design. A lead-in monotherapy of nintedanib was performed 7 days prior starting the C1D1 of pembrolizumab with the aim of modifying the tumor microenvironment. The primary objective was to establish the MTD of nintedanib in combination with pembrolizumab based on the assessment of DLT occurrence during the first 4 weeks (28 days since C1D1) and to determine the recommended phase II dose (RP2D). Secondary objectives included antitumor activity assessed by both RECIST v1.1 and irRECIST. The clinical activity of the combination is being further evaluated in the expansion part of this trial.
Results: As of November 24, 2016, 13 patients (12 evaluable for DLT) have been enrolled in the escalation part with the following pathology: 2 squamous cervical carcinoma, 1 MSI colorectal cancer, 1 triple negative breast cancer, 2 thymic carcinoma, 1 malignant pleural mesothelioma, 1 peritoneal mesothelioma, 1 gastric adenocarcinoma, 1 clear cell renal carcinoma, 1 neuroendocrine tumor, 1 nasopharyngeal cancer. 50% patients were male, ECOG 0 (83%) or 1. There were no grade 4-5 toxicities. The most frequent adverse events reported for more than 2 patients were alanine & aspartate aminotransferase increase, fatigue, decreased appetite, diarrhea, nausea, vomiting, hypothyroidism. Three dose-limiting toxicities of liver enzymes elevation were observed in 200 mg BID nintedanib thus recommending 150 mg BID nintedanib for the phase II part. One nasopharyngeal carcinoma, 1 squamous cervical carcinoma and 1 thymic carcinoma developed an objective RECIST partial response (ORR=25%).
Conclusions: Toxicity was consistent with the drugs profile and no unexpected events have been seen with the combination. Nintedanib at 150 mg BID with 200 mg flat dose of Pembrolizumab was well tolerated. Additional data for safety and efficacy is further evaluated in the expansion part.
Citation Format: Andreea Varga, Capucine Baldini, Patricia Martin-Romano, Antoine Hollebecque, Anas Gazzah, Rastislav Bahleda, Jessica Menis, Stephane Champiat, Yolla El-Dakdouki, Xavier Paoletti, Vincent Ribrag, Jean-Marie Michot, Saloomeh Rafie, David Planchard, Benjamin Besse, Christophe Massard, Jean-Charles Soria, Aurelien Marabelle. Safety and efficacy results from a phase I dose-escalation trial of Nintedanib in combination with Pembrolizumab in patients with advanced solid tumors (PEMBIB trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT141.