Safety, pharmacokinetics, efficacy, and preliminary biomarker data of first-in-class BI 765063, a selective SIRPα inhibitor: Results of monotherapy dose escalation in phase 1 study in patients with advanced solid tumors.
Authors: Champiat Stéphane , Cassier Philippe A. , Kotecki Nuria , Korakis Iphigenie , Vinceneux Armelle , Jungels Christiane , Blatchford Jon , Elgadi Mabrouk M. , Clarke Nicole , Fromond Claudia , Poirier Nicolas , Vasseur Berangere , Marabelle Aurelien , Delord Jean-Pierre 
Published: June 2021

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Background: BI 765063 is a humanized IgG4 monoclonal antibody antagonist of SIRPα (Signal Regulatory Protein α), which blocks the “don't eat me” signal of the SIRPα/CD47 axis, a critical innate immune checkpoint. SIRPα is expressed on myeloid cells. BI 765063 binds to the V1 SIRPα allele with high affinity and to the V2 SIRPα allele with low affinity. BI 765063 lacks SIRPγ binding to preserve T-cell activation. We report results of the completed BI 765063 monotherapy dose escalation in patients with advanced solid tumors. Methods: This study involves a step 1 dose escalation to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD), then a step 2 dose-confirmation expansion at recommended phase 2 dose. In Step 1, BI 765063 ascending doses, given IV every 3 weeks, were tested using a Bayesian Logistic Regression Model (BLRM) approach with overdose control. The endpoints were safety, pharmacokinetics, receptor occupancy (RO) in peripheral CD14+ monocytes and efficacy (RECIST 1.1). Results: Fifty patients (26 V1/V1, 24 V1/V2) received at least one dose of BI 765063. The most frequent tumors were ovarian (9), colorectal (8), lung (5), breast (4), melanoma (3), and kidney (3). No DLTs were reported up to the highest dose tested. MTD was not reached. The most frequent related adverse events were infusion related reaction (IRR) (46%), fatigue (12%), headache (10%), arthralgia and diarrhea (8% each). All related adverse events were mild to moderate, except one case of IRR Grade 3. No related anemia nor thrombocytopenia were observed. BI 765063 showed dose proportional exposure and full RO saturation in Cycle 1 after the fourth dose level. Clinical benefit was observed in 21/47 (45%) patients evaluable per RECIST 1.1. One patient with hepatocellular carcinoma (HCC) with liver and lung metastases and 7 prior lines of therapy showed a durable partial response maintained for 27 weeks treatment (ongoing). The baseline tumor biopsy of this patient showed high CD8 T-cell and macrophage infiltration. There was an increase in CD8 T-cell infiltration and activation on treatment. An increase in PD-L1 expression on tumor cells 2 weeks after first dosing was also observed. Analysis of paired tumor biopsies in other patients is ongoing. Conclusions: The first-in-class SIRPα inhibitor BI 765063 was well-tolerated, showed monotherapy activity, and sustained RO saturation. A durable partial response was observed in an advanced HCC patient. The on-treatment biopsy of the responder showed an increase in CD8 T-cell infiltration and activation. PD-L1 expression on tumor cells also increased. BI 765063 dose escalation in combination with ezabenlimab (anti-PD1 antibody) is ongoing. Clinical trial information: NCT03990233.