Evorpacept

Overview

Evorpacept (ALX148) is an investigational CD47-blocking fusion protein designed to enhance antitumor phagocytosis with an “Fc‑silent” backbone to minimize on‑target hematologic toxicity seen with some CD47 agents. It has been evaluated across solid tumors and hematologic malignancies, mainly in combination with anticancer antibodies or checkpoint inhibitors. A randomized phase 2 trial in previously treated HER2‑positive gastric/GEJ cancer reported improved response rates with evorpacept added to trastuzumab/ramucirumab/paclitaxel, while two phase 2 studies in first‑line head and neck squamous cell carcinoma (HNSCC) combining evorpacept with pembrolizumab did not meet their primary endpoints. (thelancet.com)

Mechanism of action

• Target: CD47, a “don’t‑eat‑me” signal on tumor cells that inhibits phagocytosis via SIRPα on myeloid cells. Evorpacept binds CD47 with high affinity, blocking CD47–SIRPα while carrying an inactivated Fc region that avoids Fcγ receptor engagement and complement binding. In combinations, the partner antibody (for example, trastuzumab or rituximab) provides the active Fc to drive antibody‑dependent cellular phagocytosis. Preclinical work and early clinical pharmacodynamics show near‑complete target occupancy and enhanced myeloid and downstream adaptive responses. (pmc.ncbi.nlm.nih.gov)

Efficacy

• HER2‑positive gastric/GEJ cancer (previously treated): In the randomized phase 2 portion of ASPEN‑06, evorpacept + trastuzumab/ramucirumab/paclitaxel achieved a confirmed objective response rate (ORR) of 40.3%–41.3% vs 26.6% with the control regimen; median duration of response was 15.7 months with evorpacept vs 9.1 months with control. Benefit appeared greater in a biomarker‑defined subset with confirmed HER2 positivity (ORR ~49%). Overall survival was immature at the December 2, 2024 data cut presented in January 2025. (ascopubs.org)

• Head and neck squamous cell carcinoma (1L): The phase 2 ASPEN‑03 (evorpacept + pembrolizumab vs pembrolizumab) and ASPEN‑04 (evorpacept + pembrolizumab + chemotherapy vs pembrolizumab + chemotherapy) did not meet primary endpoints based on ORR vs historical controls; the sponsor discontinued further development of these combinations in HNSCC. (globenewswire.com)

• Relapsed/refractory B‑cell non‑Hodgkin lymphoma: Phase 1 ASPEN‑01 (evorpacept + rituximab) reported an ORR of 50.0% (95% CI, 33.1–69.8%) among response‑evaluable patients (n=32). (pmc.ncbi.nlm.nih.gov)

• Microsatellite‑stable metastatic colorectal cancer: An investigator‑initiated phase 2 study of evorpacept + cetuximab + pembrolizumab is ongoing; the 2024 ASCO abstract details design and rationale but does not provide mature efficacy outcomes in the abstract text. (ascopubs.org)

Safety

• Across first‑in‑human/early combination cohorts (ASPEN‑01), evorpacept with pembrolizumab or trastuzumab was generally well tolerated with mostly low‑grade adverse events; common treatment‑related events included fatigue, transaminase increases, and decreased platelets, consistent with the Fc‑silent design to mitigate anemia/thrombocytopenia typical of some CD47 agents. No maximum tolerated dose was reached. (thelancet.com)

• In ASPEN‑06 (gastric/GEJ), the addition of evorpacept showed a safety profile generally consistent with the control regimen (trastuzumab/ramucirumab/paclitaxel). (ir.alxoncology.com)

• In relapsed/refractory NHL (ASPEN‑01), evorpacept + rituximab was well tolerated with no dose‑limiting toxicities; most treatment‑related events were grade 1–2 (for example, rash 24.2%, fatigue 15.2%). (pmc.ncbi.nlm.nih.gov)

• Early hematologic malignancy studies combining evorpacept with azacitidine (MDS) reported no dose‑limiting toxicities in phase 1 and a safety profile consistent with underlying disease and background therapy. (ashpublications.org)

Further reading

• Lakhani NJ, et al. Evorpacept alone and in combination with pembrolizumab or trastuzumab (ASPEN‑01), Lancet Oncology 2021. (thelancet.com)
• Kauder SE, et al. ALX148 blocks CD47 and enhances antitumor immunity (preclinical rationale). (pmc.ncbi.nlm.nih.gov)
• ASPEN‑06 randomized phase 2 (HER2+ gastric/GEJ): ASCO GI 2025 abstract and company summary of updated results. (ascopubs.org)
• ASPEN‑03/04 phase 2 HNSCC topline results (press release). (globenewswire.com)
• ASPEN‑01 phase 1 in NHL: Haematologica 2025 (peer‑reviewed). (haematologica.org)
• ASPEN‑02 phase 1/2 in MDS (ASH abstract). (ashpublications.org)

Notes: This summary reflects data available through January–April 2025 for the cited trials and presentations; overall survival for ASPEN‑06 was not mature at the December 2, 2024 cutoff summarized at ASCO GI 2025. (ir.alxoncology.com)

Last updated: Oct 2025