Phase 2 dose expansion study of DSP107, a first-in-class bi-specific 4-1BB T-cell engager, with and without atezolizumab in metastatic MSS colorectal cancer patients.

3517 Background: DSP107 is a bi-specific fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BBL. The SIRPα arm selectively targets CD47 overexpressed on tumor cells, while simultaneously anchoring trimeric 4-1BBL to the tumor, to engage and co-stimulate 4-1BB on activated immune cells in the tumor microenvironment. This results in tumor-localized, conditional activation of innate and adaptive immune responses. Phase 1 data demonstrated an excellent safety profile with no RBC binding and no hematological, hepatic or other dose limiting toxicities (DLTs). Here we describe safety and efficacy data from a Phase 2 microsatellite stable (MSS) colorectal (CRC) expansion cohort in which patients were treated with DSP107 alone or with atezolizumab (NCT04440735). Methods: Metastatic/unresectable MSS CRC patients who progressed following 2 lines of therapy including standard chemotherapy ± targeted antibodies (n = 50), were randomized to receive weekly IV DSP107 infusions (10 mg/kg/dose) alone or with atezolizumab (1200 mg) Q3W during 3-week treatment cycles. The majority (76%) had liver metastases. Study objectives were safety, tolerability and preliminary efficacy. Restaging imaging was performed every 2 months and evaluated by RECIST v1.1 criteria. Results: DSP107 monotherapy and with atezolizumab was well tolerated with no DLTs. The most frequent TRAEs were infusion-related reactions (IRR; 38% Grade 1 or 2, 4% Grade 3), fatigue (12% Grade 1 or 2, 4% Grade 3), Grade 1 or 2 nausea (14%) and Grade 1 or 2 anemia (10%). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. The median OS from the efficacy-evaluable patients who received DSP107 monotherapy (n = 19) and combination therapy with atezolizumab (n = 21) has not been reached but currently (Dec 2024 cutoff) stands at 7.6 and 14.6 months, respectively. Disease control was demonstrated in 26% (monotherapy) and 62% (combination) of evaluable patients including a patient who achieved complete response ( > 2.5 years) and a patient with a deep (86% target lesion reduction) and durable ( > 16 months) confirmed partial response and disappearance of pulmonary and hepatic metastases. Immunofluorescence analysis of baseline tumor biopsies (n = 16) demonstrated moderate to high levels of CD47 expression in 15/16 biopsies ( > 120 H-Score), and very high levels of CD47 expression ( > 170 H-Score) in all 7 samples collected from liver metastases. Conclusions: These data suggest that the combination of DSP107 with PD(L)1 blockade has anti-tumor activity and provides clinical benefit in third line metastatic MSS CRC including in patients with liver metastases. Updated survival data will be presented at the conference. A Phase 2 randomized controlled study is currently in planning to confirm this preliminary efficacy signal. Clinical trial information: NCT04440735 .