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617 A Phase I study of a tumor-targeted, fibroblast activation protein (FAP)-CD40 agonist (RO7300490) in patients with advanced solid tumors
  1. Ignacio Melero1,
  2. Maria Lostes Baradji2,
  3. Iben Spanggaard3,
  4. Dae Lee4,
  5. James Spicer5,
  6. Fiona C Thistlethwaite6,
  7. Stefan Symeonides7,
  8. Do-Youn Oh8,
  9. Antoine Hollebecque9,
  10. Corinne Rusterholz10,
  11. Olivera Cirovic11,
  12. Yvonne Zhao12,
  13. Nicole Kratochwil13,
  14. Bernhard Reis11,
  15. Alexandra Epp14,
  16. Georgios Kazantzidis15 and
  17. Victor Moreno16
  1. 1Clinica Universidad de Navarra. CIMA, Pamplona, Spain
  2. 2Vall d’Hebron Institute of Oncology, Barcelona, Spain
  3. 3Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
  4. 4University of Ulsan College of Medicine, Seoul, Republic of Korea
  5. 5King’s College London, Guy’s Hospital, London, UK
  6. 6The Christie NHS Foundation Trust and University of Manchester, Manchester, UK
  7. 7Edinburgh Cancer Centre, NHS Lothian and Edinburgh Experimental Cancer Medicine Centre, University of Edinburgh, Edinburgh, UK
  8. 8Seoul National University Hospital, Seoul, Republic of Korea
  9. 9Gustave Roussy, Villejuif, France
  10. 10Roche Pharma Research and Early Development, Early Clinical Development, Roche Innovation Center Basel, Basel, Switzerland
  11. 11Roche Pharma Research and Early Development, Early Development Oncology, Roche Innovation Center Basel, Basel, Switzerland
  12. 12Roche Product Development Safety, Roche (China) Holding Ltd, Shanghai, China
  13. 13Roche Pharma Research and Early Development, Pharmaceutical Science, Basel, Switzerland
  14. 14Roche Pharma Research and Early Development, Early Development Oncology, Roche Innovation Center Munich, Munich, Germany
  15. 15Roche Data Science and Statistics, Biostatistics Oncology, Basel, Switzerland
  16. 16START Madrid-FJD, Hospital Fundacion Jimenez Diaz, Madrid, Spain
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background FAP-CD40 is a second-generation, bispecific, FAP-targeted CD40 agonist antibody, which was developed to overcome systemic toxicities and the narrow therapeutic index of conventional anti-CD40 therapeutics.

FAP-CD40 was designed to specifically activate antigen-presenting cells when CD40 is crosslinked by FAP-positive cells in the tumor.

Methods This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of FAP-CD40 in adult patients with solid tumors considered to express FAP.

Patients diagnosed with locally advanced and/or metastatic solid tumor types that were not amenable to standard therapy, and with adequate bone marrow and organ function were eligible. FAP-CD40 was administered intravenously every 2 weeks until disease progression, unacceptable toxicity or other discontinuation criteria were met. A Bayesian model-based approach guided dose escalation.

Results Twenty-nine patients received FAP-CD40 in 6 cohorts at doses ranging from 16mg to 1100mg. Discontinuations were mainly due to progressive disease or symptomatic deterioration (79.3%).

No DLT was reported. Most adverse events (AE) were mild to moderate and non-serious. The most common treatment-related (TR) AE was low-grade arthralgia (31%). No Grade 4–5 TRAE was reported. Grade 3 TRAEs were reported in 2 patients. One single case of Grade 1 cytokine-release syndrome occurred. Three AEs led to treatment withdrawal, 2 of which were assessed related to FAP-CD40. There was no evidence of dose-related AE incidence or severity.

The best overall response was stable disease, which was achieved in 14/26 patients.

At lower doses, FAP-CD40 showed non-linear PK, which can be attributed to the saturation of peripheral CD40 binding sites, with a trend for linear PK at the higher doses. Persistent and full occupancy of CD40 receptors on circulating B cells was reached at the higher doses. A dose-dependent reduction of circulating B cells was also observed. There was no detectable effect of FAP-CD40 on peripheral cytokines and chemokines.

Conclusions FAP-CD40 was well tolerated up to the highest dose tested and the maximum tolerated dose was not reached. Toxicities were as anticipated and manageable. No objective response was achieved.

FAP-CD40 demonstrated target-mediated drug disposition with a sustained exposure at higher doses. Target engagement and peripheral PD effects aligned with expectations for a tumor-targeted mode of action.

In summary, targeting CD40 agonism to the tumor has led to a favorable safety profile at doses with strong and sustained target engagement, and supports further studies in combination with other anti-cancer therapies.

The patients and their families The study investigators and members of the clinical study teams. F. Hoffmann- La Roche, Ltd, the study sponsor.

Trial Registration NCT04857138

Ethics Approval The study was approved by all relevant IRB/EC (CEIC de Navarra: EC_2021/2; HRA & HCRW: 21/FT/0031; De VK Region Hovedstaden: H-21017757; SNUH IRB: H-2104–078-1211; ASM IRB S2021–0747-0001); CPP Ile de France I: CPPIDF1–2022-DI21-cat.1)

Study participants gave informed consent prior enrollment.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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