Phase 1/2a clinical trial of BI-1206, an anti-CD32b (FcγRIIB) antibody, in combination with pembrolizumab in subjects with advanced solid tumors previously treated with anti-PD-1/PD-L1.

2593 Background: PD-1 blockade has demonstrated positive anti-tumor activity across multiple tumor types. While the anti-tumoral response can be substantial and even curative, response rates remain low in many cancer types. Long-lasting responses are only observed in a minority of patients, and additional immunotherapeutic alternatives remain limited for patients who fail to respond or initially respond but subsequently experience progression. Combining anti-PD-1 with other immunotherapies may improve the durability and depth of anti-tumoral immune responses. Non-clinical data suggest anti-PD-1 interactions with macrophage Fc gamma receptors (FcγRs) compromise therapeutic activity by several mechanisms including the rapid removal of anti-PD-1 from its target on CD8+ T-cells and phagocytosis of anti-PD-1 coated CD8+ T cells. Accordingly, we and others have shown that blockade of Fc/FcγR interactions with immunocompetent antibodies to the inhibitory FcγRIIB, a receptor highly upregulated in the tumor microenvironment, overcomes these resistance mechanisms and enhances anti-PD-1 efficacy in vitro and in vivo. BI-1206 is a fully human IgG1 targeting CD32b (FcγRIIB). Methods: This is a Ph1/2a trial in patients with advanced solid tumors who received previous lines of treatment with anti-PD 1/PD-L1 agents to evaluate safety, tolerability and PK/PD of BI-1206 at ascending IV and SC doses after coadministration with pembrolizumab Q3W using a mTPI-2 design. Results: Dose escalation with BI-1206 IV has been completed with no formal MTD defined. The most frequent related adverse events were infusion-related reactions, thrombocytopenia and elevated liver enzymes. All were transient without any clinical consequences, and adequate pre-medication with corticosteroids or split dose administration reduced the risk and/or intensity of these events. Out of 15 evaluable patients, 5 patients showed SD, including one lasting >24 months in a metastatic melanoma patient. Furthermore, long-lasting PR (>24 months) was observed in a uveal melanoma patient, and CR was observed in a metastatic melanoma patient who previously received three prior anti-PD-1 containing treatments (one including anti-CTLA4). Enrollment to BI-1206 SC dose escalation began Nov2023. Dose level and administration route to be further explored in Phase 2a will be determined after an integrated review of PK, PD and safety. The Ph2a consists of 3 expansion cohorts at the RP2D, each comprising a specific subset of subjects with advanced solid tumors (e.g., NSCLC, MM, and other tumors responsive to PD-1/PD-L1 inhibition). More than one dose level may be evaluated if warranted. Conclusions: Coadministration of BI-1206 with pembrolizumab was well tolerated in a heavily pretreated population, with promising hints of responses to be further explored in Ph2. Clinical trial information: NCT04219254 .