781TiP AGADIR: A basket multicenter open-label phase II study evaluating the first in class TLR7/8 agonist BDB001 in combination with atezolizumab and stereotactic body radiation therapy in patients with advanced solid tumors

Monotherapy response rates to PD1/PDL1 monoclonal antibodies remain low, and additional therapies are required to fully exploit their potential. In this regard, strategies that target tumor-resident innate immune cells and induce local tumor proinflammatory responses, which recruit CD8+ TILs, represent a promising approach. One strategy to turn an immunologically cold tumor hot is to promote activation of antigen presenting cells (APC) by targeting the endosomal TLRs TLR3, TLR7, TLR8, TLR9. The first in class TLR7/8 agonist BDB001 can activate both myeloid dendritic cell mDC (which express TLR8) and plasmacytoid dendritic cell pDC (which express TLR7 and TLR9). Targeting both TLR7 and TLR8 allows for a more potent activation signal capable of overriding other inhibitory mechanisms, including turning a « cold » tumor into a « hot » tumor. Stereotactic body radiation therapy (SBRT) can also promote an antitumor systemic response (“abscopal effect”) through T cell-mediated activation of the adaptive immune system. AGADIR is a multi-cohort single-arm phase 2, multicenter, open-label study investigating BDB001 with atezolizumab in patients with advanced cancers: pancreatic adenocarcinoma (pop 1), virus-associated tumors (pop 2), previously exposed to PD1/PDL1 antibodies non-small cell lung cancer (pop 3) and bladder cancer (pop 5), soft-tissue sarcomas (pop 4), triple-negative breast cancer (pop 6). This study will enroll ∼247 patients with no standard treatment options available and ECOG 0–1. BDB0001 is given IV on days 1, 8, and 15 of cycles 1 to 3 and on day 1 every 3 weeks therafter. Atezolizumab is given on day 1 every 3 weeks. SBRT of metastatic lesion will start at least one week after the first dose of atezolizumab. The primary endpoints are disease control rate within 24 weeks of treatment in populations 1, 2, 3, 5 and 6 and progression-free rate at 6 months for population 4 (RECIST 1.1). Secondary endpoints include toxicity, overall and progression-free survival. Pharmacodynamic and other biomarkers will be explored. The first patient received study drug on June 2022. NCT03915678, 16 April 2019. Institut Bergonié, Bordeaux, France. INCa Fondation ARC.