Evorpacept as single-agent or combination pembrolizumab or trastuzumab shows promise in the treatment of advanced solid tumours

1. This is the first human clinical trial of evorpacept, a CD47 inhibitor, and the results suggest an acceptable safety profile to proceed with further investigations

2. Patients receiving single-agent evorpacept experienced adverse events such as fatigue, headache, thrombocytopenia and neutropenia.

Evidence Rating Level: 2 (Good)

Study Rundown: CD47 is an immune-suppressing protein that is overexpressed in patients with hematological and solid tumours. In addition, tumour cells may utilize the CD47-SIRPα interaction to compromise immune surveillance by inhibiting phagocytosis of apoptotic/abnormal cells. Evorpacept is a high-affinity CD47-blocking protein with an inactive IgG Fc region, which has been shown to minimize the risk of hematological toxicity. This study aimed to evaluate the pharmacokinetics, pharmacodynamics, efficacy and safety of evorpacept in patients with solid tumours. The study was divided into 3 phases: 3+3 dose-escalation, safety lead-in, and dose expansion phases. The median follow-up time was 29.1 months (single agent evorpacept), 27.0 months (evorpacept plus pembrolizumab) and 27.0 months (evorpacept plus trastuzumab). The median follow-up for the single-agent evorpacept cohort was 29.1 months. For the evorpacept plus pembrolizumab cohort and the evorpacept plus trastuzumab cohort, the median follow-up was 27.0 months and 32.7 months, respectively. No maximum tolerated dose for evorpacept was reached. Commonly reported adverse events in patients receiving evorpacept single agent included fatigue, headache, thrombocytopenia and neutropenia of which the most common grade 3 events were thrombocytopenia and neutropenia. Limitations to the study include having a low number of patients in each cohort, lack of randomization in the dose-expansion cohort, and the short duration of follow-up. Overall, this study provides preliminary findings of the therapeutic use of evorpacept in advanced solid tumours. Further investigation will be necessary to better understand the efficacy and the safety of the evorpacept in combination with other anti-cancer medications.

Click to read the study in The Lancet Oncology

Relevant Reading: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors.

In-Depth [randomized controlled trial]: This was an open-label, phase 1 study of 110 patients in 9 hospitals and 1 clinic in the United States and Korea. The study was divided into 3 phases: 3+3 dose-escalation, safety lead-in, and dose expansion phases. Patients were eligible if were 18 years or older and if they had a diagnosis of advanced/metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Initially, patients received single agent evorpacept intravenously or in combination with pembrolizumab or trastuzumab either 0.3, 1, 3, or 10 mg/kg once per week in 21-day cycles or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients received the maximum tolerated dose of evorpacept from the dose-escalation phase and intravenous pembrolizumab, or trastuzumab. Once patients reached the maximum tolerated dose or maximum administered dose of the study agents, patients with head and neck squamous cell carcinoma (HNSCC) and non-small-cell lung cancer (NSCLC), HER2-positive gastric or gastroesophageal junction cancer were subsequently enrolled into three parallel dose-expansion cohorts until disease progression or voluntary withdrawal from the patient. For this phase of the study, NSCLC or HNSCC patients received the maximum tolerated dose of evorpacept and intravenous pembrolizumab for up to 24 months. Patients with HER2-positive gastric or gastroesophageal junction cancer received the maximum tolerated dose of evorpacept and intravenous trastuzumab. The primary end point was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab. No maximum tolerated dose for evorpacet was reached. In the dose-expansion cohort, the overall response for each cohort was stable disease in 4 out of 20 patients (95% CI: 5.7-43.7) in the HNSCC cohort, 1 out of 20 patients (95% CI: 5.7- 43.7) in the NSCLC cohort and 4 out of 19 patients (95% CI: 6.1-45.6) in the HER2-positive gastric or gastroesophageal junction cancer cohort.

Image: PD

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