Evorpacept

Summary

Evorpacept (ALX148) is an investigational CD47‑blocking fusion protein that links a high‑affinity SIRPα domain to an inactive IgG Fc. It is being tested intravenously in cancer, most often combined with other agents such as cetuximab, pembrolizumab, rituximab, lenalidomide, or trastuzumab. Early‑phase trials have shown tumor‑growth inhibition in pre‑clinical models and clinical activity in B‑cell non‑Hodgkin lymphoma and solid tumours, but safety concerns, including severe immune‑related events, have limited its development.

Mechanism of Action

CD47 on tumour cells engages SIRPα on macrophages to transmit a "don't‑eat‑me" signal that suppresses phagocytosis. Evorpacept provides a soluble, high‑affinity SIRPα decoy that competitively blocks CD47, preventing the inhibitory signal. Because its Fc region is engineered to be inactive, it does not trigger Fc‑mediated effector functions, focusing its activity on disrupting CD47‑SIRPα interaction and thereby enhancing innate macrophage‑mediated clearance and promoting downstream adaptive immune activation.

What the Research Shows

Pre‑clinical HIS‑PDX models of microsatellite‑stable colorectal cancer showed that evorpacept combined with cetuximab and pembrolizumab reduced tumour growth and increased CD8+ T‑cell infiltration. A first‑in‑human phase I study in solid tumours (n=110) found no maximum tolerated dose up to 10 mg/kg weekly, with thrombocytopenia and neutropenia as common grade ≥ 3 events. In B‑cell non‑Hodgkin lymphoma (phase I, n=20), evorpacept plus rituximab and lenalidomide produced an 80% complete response rate and 69% two‑year progression‑free survival, with increased tumour‑infiltrating T cells and macrophages. A phase II trial in refractory MSS colorectal cancer (n=16) reported a 6.3% objective response rate but was halted after grade 5 hemophagocytic lymphohistiocytosis and cytokine‑release syndrome. Review articles note a 50% objective response in NHL when paired with rituximab, but also describe recent discontinuations of CD47 programs in myelodysplastic syndromes.

Reported Benefits

Clinical data suggest evorpacept can potentiate anti‑tumour immunity, achieving high complete‑response rates in B‑cell NHL and modest activity in solid tumours. Pre‑clinical studies demonstrate enhanced tumour control and CD8+ T‑cell infiltration when combined with other targeted agents. The inactive Fc design may reduce Fc‑mediated toxicity compared with earlier CD47 antibodies, and combination regimens appear to remodel the tumour microenvironment toward an immunostimulatory phenotype.

Limitations of the Evidence

Evidence of efficacy is limited to early‑phase trials and pre‑clinical models; no late‑stage or regulatory‑approved data exist. Safety signals—including severe cytokine‑release syndrome, hemophagocytic lymphohistiocytosis, thrombocytopenia, and neutropenia—have led to trial halts and program discontinuations. The modest response in MSS colorectal cancer and the need for combination partners raise questions about optimal patient selection and dosing. Long‑term outcomes and comparative effectiveness remain unknown.

Safety Considerations

Common treatment‑related adverse events are grade 3‑4 thrombocytopenia, neutropenia, and infections. In the colorectal cancer study, two treatment‑related grade 5 events (hemophagocytic lymphohistiocytosis and cytokine‑release syndrome) prompted early termination. Phase I solid‑tumour cohorts reported dose‑limiting neutropenia with infection and thrombocytopenia with bleeding. Overall, the safety profile aligns with expectations for CD47 blockade but underscores a need for vigilant monitoring of immune‑mediated toxicities.

How It Is Administered

Evorpacept is administered by intravenous infusion. Early trials explored weekly dosing from 0.3 mg/kg up to 10 mg/kg and a 30 mg/kg every‑other‑week schedule. It has been given as monotherapy or in combination with pembrolizumab, trastuzumab, cetuximab, rituximab, lenalidomide, or azacitidine, typically in 21‑ or 28‑day cycles until disease progression or unacceptable toxicity.

Routes of Administration

Goals & Uses

• Breast cancer treatmentOncologyLow
• Gastric/Gastroesophageal Junction Cancer TreatmentOncologyModerate
• Acute Myeloid Leukemia (AML) TreatmentHematology/OncologyModerate
• Head and neck squamous cell carcinoma treatmentOncologyModerate
• Myelodysplastic Syndromes (MDS) TreatmentHematology/OncologyModerate

Contraindications

• Severe uncontrolled autoimmune diseaseAutoimmuneModerate
• Known severe hypersensitivity to evorpacept or its componentsAllergy/ImmunologyHigh

Adverse Effects

• ThrombocytopeniaHematologicUncommonLow platelet count
• AnemiaHematologicCommonLow red blood cell count or hemoglobin
• NeutropeniaHematologicUncommonLow neutrophil count
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• FatigueGeneralCommonLow energy or tiredness
• Infusion-related reactionsHypersensitivityCommon

Drug Interactions

• AzacitidineLow
• TrastuzumabLow
• PembrolizumabLow

Population Constraints

• Severe renal or hepatic impairmentOrgan FunctionRelative
• PregnancyReproductive SafetyRelative
• Pediatric patientsAgeRelative

Regulatory Status

• European UnionInvestigationalUnder clinical investigation; no EMA approval as of 2024.
• United StatesInvestigationalFDA Fast Track Designation granted for select indications. Multiple ongoing Phase 2/3 trials (e.g., MOUNTAINEER-03). IND active.
• United KingdomInvestigationalNo MHRA approval; part of international clinical trial programs.

Not yet approved by FDA, EMA, or other major regulatory agencies. Received Fast Track Designation from the FDA for certain oncology indications. Investigated under multiple INDs in the US and internationally.

Evidence & Sources

• Phase II Clinical Trial and Preclinical Evaluation of a Novel CD47 Blockade Combination in Refractory Microsatellite-Stable Metastatic Colorectal Cancer
  Journal ArticleModerateLentz RW, et al.2025-01-01T00:00:00.000000Z
• Beyond immune checkpoint blockade: T cell engagers and antibody-drug conjugates in cancer and autoimmune disease
  Journal ArticleModerateAbdelaziz AM, Shokr MM2026-01-01T00:00:00.000000Z
• A Phase I Trial of Evorpacept, Lenalidomide, and Rituximab for Patients with B-Cell Non-Hodgkin Lymphoma
  Journal ArticleModerateStrati P, et al.2025-01-01T00:00:00.000000Z
• Targeting the CD47/SIRPα pathway in malignancies: recent progress, difficulties and future perspectives
  Journal ArticleModerateJiang C, et al.2024-01-01T00:00:00.000000Z
• State of the art and upcoming trends in HER2-directed therapies in gastrointestinal malignancies
  Journal ArticleModerateLee J, Ku G2024-01-01T00:00:00.000000Z
• Evorpacept alone and in combination with pembrolizumab or trastuzumab in patients with advanced solid tumours (ASPEN-01): a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study
  Journal ArticleModerateLakhani NJ, et al.2021-01-01T00:00:00.000000Z

Frequently Asked Questions