Reference Detail

Ref Type

PMID

Authors

I. Melero M.F. Sanmamed E. Calvo I. Moreno V. Moreno T.C. Hernandez Guerrero M. Martinez-Garcia A. Rodriguez-Vida J. Tabernero A.B. Azaro Pedrazzoli I. Spanggaard K.S. Rohrberg E. Guarin E. Nueesch E. Chesne M. Ceppi U. Sweere C. McIntyre F.S. Lichtenegger O. Krieter

Title

1025MO First-in-human (FIH) phase I study of RO7122290 (RO), a novel FAP-targeted 4-1BB agonist, administered as single agent and in combination with atezolizumab (ATZ) to patients with advanced solid tumours

Journal	Vol	Issue	Date	Pages	Journal Short Title
Ann Oncol	31	Suppl 4	Sep 2020

URL

https://www.annalsofoncology.org/article/S0923-7534(20)41141-X/fulltext

Abstract Text

Background 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. Methods 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). Results 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). Conclusions 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
RO7122290	RO7122290	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
RO7122290		RO 7122290\|RO-7122290		RO7122290 is a fusion protein consisting of a ligand of TNFRS9 fused to a Fab fragment targeting FAP, which may lead to activation of anti-tumor immune response against FAP-expressing tumor cells (Ann Oncol Sep 2020, 31 (Suppl 4), S707).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References