RO is a bispecific antibody-like fusion protein based on a trimeric 4-1BB ligand and a targeting Fab moiety recognizing fibroblast activation protein-α (FAP) abundantly expressed by cancer-associated fibroblasts in many tumors. Upon TCR/CD3 engagement, simultaneous binding of FAP and 4-1BB results in clustering and activation of T- and NK- cells at the tumor site, thereby leading to potent anti-tumor activity in a panel of preclinical models.
This is a 3-part FIH study: Part A and B explored the safety, PK, PD and anti-tumor activity to establish the recommended dose for expansion (RDE) into Part C of RO as single agent (SA) and in combination with ATZ, respectively. Part C assesses the efficacy and safety of the combination in selected, FAP positive tumors. Preliminary results of Part A/B are presented here, where patients (pts) were treated with RO weekly (QW) at escalated dose levels (DLs).
Part A: 62 pts were treated at 13 DLs, range 5 – 2000 mg IV. Part B (plus ATZ 1200 mg Q3W): 39 pts at 8 DLs, 45 – 2000 mg IV. Serum exposure (Cmax; AUC) increased dose dependently, with evidence of non-linearity in elimination at lower doses, suggestive of target-mediated drug disposition (TMDD). In blood, expression of 4-1BB and release of soluble 4-1BB indicated T-cell activation and 4-1BB targeting. Paired tumor biopsies revealed strong accumulation of CD8+Ki67+ T-cells. Adverse events (AEs) were generally mild to moderate (i.e., G1-2) across both parts. Most common AEs ≥ G3 in Part A were asthenia (6.5%), AST elevation and pneumonia (each 4.8%), whereas pneumonia, pneumonitis (each 10.3%), neutro- and lymphocytopenia (each 7.7%) were most frequent in Part B. DLTs were febrile neutropenia G3 (45 mg), CRS G3 (130 mg) and pneumonitis G3 (500 mg plus ATZ); a MTD was not reached. Objective response rates were 3.6% (A) and 18.4% (B).
RO demonstrated an acceptable safety profile as SA and in combination with ATZ. PK and PD- effects were favorable and consistent with the antibody-like format and the postulated MoA, respectively. Preliminary anti-tumor activity supports further exploration of the combination in tumor-specific indications.
EUDRACT Number: 2017-003961-83; Protocol Number: BP40087.
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
I. Melero: Advisory/Consultancy, Non-remunerated activity/ies: AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): BMS; Advisory/Consultancy: Bioncotech; Advisory/Consultancy, Research grant/Funding (self): Alligator; Advisory/Consultancy: Numab; Advisory/Consultancy: F-Star; Advisory/Consultancy: Roche; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (self): Merck Serono; Advisory/Consultancy: MSD; Advisory/Consultancy: Boston Pharmaceuticals; Advisory/Consultancy: Servier; Research grant/Funding (self): Palo Biopharma; Non-remunerated activity/ies: Roche ImCore. M.F. Sanmamed: Research grant/Funding (self): Roche. E. Calvo: Research grant/Funding (self), Research grant/Funding (institution): AstraZeneca; Research grant/Funding (self), Research grant/Funding (institution): Novartis; Research grant/Funding (self): Beigne; Advisory/Consultancy, Research grant/Funding (institution): Abbvie; Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Boehringer; Advisory/Consultancy, Research grant/Funding (institution): BMS; Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): Janssen Onc; Research grant/Funding (institution): Hospira; Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Merck; Research grant/Funding (institution): Millenium; Research grant/Funding (institution): Merus; Advisory/Consultancy, Research grant/Funding (institution): Nanobiotix; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): OncoMed; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): PharmaMed; Advisory/Consultancy, Research grant/Funding (institution): PisOxus; Research grant/Funding (institution): Puma; Research grant/Funding (institution): Regeneron; Advisory/Consultancy, Research grant/Funding (institution): Roche; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Spectrum; Research grant/Funding (institution): ACEA Bio; Research grant/Funding (institution): Cytomx. I. Moreno: Speaker Bureau/Expert testimony: BMS. V. Moreno: Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Beigene; Research grant/Funding (institution): Boehringer; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): E-Therapeutics; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Menarini; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Nonobiotix; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): Psioxus; Research grant/Funding (institution): Puma; Research grant/Funding (institution): Regneron; Advisory/Consultancy: Pieris; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: Pieris; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Beigene; Research grant/Funding (institution): Boehringer; Advisory/Consultancy: Pieris; Advisory/Consultancy, Research grant/Funding (institution): BMS; Research grant/Funding (institution): Celgene; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Beigene; Research grant/Funding (institution): Boehringer; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): E-Therapeutics; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Menarini; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Nonobiotix; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): E-Therapeutics; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): Psioxus; Research grant/Funding (institution): Puma; Research grant/Funding (institution): Regneron; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Menarini. M. Martinez-Garcia: Leadership role, Board Member: GENIO; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Clinical Trial: Roche; Research grant/Funding (institution), Travel/Accommodation/Expenses, Clinical Trial: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Speaker Bureau/Expert testimony: Pierre Fabre; Research grant/Funding (institution), Clinical Trial: Array Biopharma; Research grant/Funding (institution), Clinical Trial: Astellas; Research grant/Funding (institution), Clinical Trial: Immunomedics; Research grant/Funding (institution), Clinical Trial: Macrogenics; Research grant/Funding (institution), Clinical Trial: MSD; Research grant/Funding (institution), Clinical Trial: Sanofi; Research grant/Funding (institution), Clinical Trial: Novartis. A. Rodriguez-Vida: Research grant/Funding (self): MSD; Research grant/Funding (self): Takeda; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy: Astellas; Advisory/Consultancy: Janssen; Advisory/Consultancy: Bayer; Advisory/Consultancy: Clovis; Advisory/Consultancy: Roche; Advisory/Consultancy: BMS; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Elisa Pharma. J. Tabernero: Advisory/Consultancy: Array; Advisory/Consultancy: AstraZeneca; Speaker Bureau/Expert testimony: Bayer; Advisory/Consultancy: Beigene; Advisory/Consultancy: Boehringer; Advisory/Consultancy: Chugai; Advisory/Consultancy: Genentech; Advisory/Consultancy: Genmab; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Imugene; Advisory/Consultancy: Inflection Biosciences; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Kura; Advisory/Consultancy: Lilly; Advisory/Consultancy: MSD; Advisory/Consultancy: Menarini; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Merus; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Agendia; Research grant/Funding (institution): Debiopharm; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Mologen; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Symphogen. A.B. Azaro Pedrazzoli: Advisory/Consultancy: Orion Pharma; Advisory/Consultancy, Research grant/Funding (self): Amcure GmbH. I. Spanggaard: Research grant/Funding (institution): Puma Biotech; Leadership role, Board Member: Danish Society of Clin Oncol. K.S. Rohrberg: Research grant/Funding (institution): Puma; Research grant/Funding (institution), Clinical Trial: Roche; Research grant/Funding (institution), Clinical Trial: BMS; Research grant/Funding (institution), Clinical Trial: Genentech; Research grant/Funding (institution), Clinical Trial: Orion; Research grant/Funding (institution), Clinical Trial: Catargia; Research grant/Funding (institution), Clinical Trial: Pfizer; Research grant/Funding (institution), Clinical Trial: Cellgen; Research grant/Funding (institution), Clinical Trial: Loxo; Research grant/Funding (institution), Clinical Trial: Eli Lilly; Research grant/Funding (institution), Clinical Trial: Symphogen; Research grant/Funding (institution), Clinical Trial: Alligator Bioscience; Research grant/Funding (institution), Clinical Trial: Genmab; Research grant/Funding (institution), Clinical Trial: Incyte; Research grant/Funding (institution), Clinical Trial: Novartis; Research grant/Funding (institution), Clinical Trial: Amgen; Research grant/Funding (institution), Clinical Trial: Bayer. E. Guarin, M. Ceppi, U. Sweere, C. McIntyre: Full/Part-time employment: Roche. E. Nueesch, E. Chesne, O. Krieter: Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche. F.S. Lichtenegger: Speaker Bureau/Expert testimony, Speaker honoraria while in academia: Novartis; Shareholder/Stockholder/Stock options, Full/Part-time employment: Roche; Research grant/Funding (institution), Clinical trial funding while in academia: BMS; Research grant/Funding (institution), Research funding while in academia: Miltenyi. All other authors have declared no conflicts of interest.