Melero and Tanos et al. report phase 1 results for RO7122290, a bispecific fusion protein carrying a 4-1BB (CD137) ligand and a fibroblast activation protein α binding site that co-stimulates T cells as a single agent or in combination with atezolizumab in patients with advanced or metastatic solid tumors. RO7122290 demonstrated an acceptable safety profile and the postulated mechanism of action. Treatment-induced increases in intratumoral and peripheral proliferating and activated T cells were accompanied by associated gene expression changes in both arms. Clinical activity was most strongly observed in combination with atezolizumab (2 CRs and 9 PRs), mostly in CPI naive patients.
Contributed by Shishir Pant
ABSTRACT: This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein _ (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent (n = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks (n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8(+) and Ki67(+)CD8(+) T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.
Author Info: (1) Department of Immunology and Immunotherapy, Clinica Universidad de Navarra and CIMA, 31008 Pamplona, Spain. CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain. (2) Ro
Author Info: (1) Department of Immunology and Immunotherapy, Clinica Universidad de Navarra and CIMA, 31008 Pamplona, Spain. CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain. (2) Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. (3) Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. (4) Department of Immunology and Immunotherapy, Clinica Universidad de Navarra and CIMA, 31008 Pamplona, Spain. CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain. Department of Medical Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain. (5) START Madrid-CIOCC, Centro Integral Oncolgico Clara Campal, 28050 Madrid, Spain. (6) START Madrid-CIOCC, Centro Integral Oncolgico Clara Campal, 28050 Madrid, Spain. (7) START Madrid-FJD, Hospital Fundacin Jimnez Daz, 28040 Madrid, Spain. (8) START Madrid-FJD, Hospital Fundacin Jimnez Daz, 28040 Madrid, Spain. (9) Department of Medical Oncology, Hospital del Mar-CIBERONC, 08003 Barcelona, Spain. (10) Department of Medical Oncology, Hospital del Mar-CIBERONC, 08003 Barcelona, Spain. (11) CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain. Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain. (12) Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain. (13) CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain. Department of Medical Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain. (14) Department of Oncology, Rigshospitalet University Hospital of Copenhagen, 2100 Copenhagen, Denmark. (15) Department of Oncology, Rigshospitalet University Hospital of Copenhagen, 2100 Copenhagen, Denmark. (16) Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. (17) Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. (18) Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. (19) Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. (20) Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. (21) Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. (22) Roche Pharma Research and Early Development, Roche Innovation Center Welwyn, AL7 1TW Welwyn Garden City, UK. (23) Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland. (24) Roche Pharma Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany. (25) Roche Pharma Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany.
