In the phase I ASPEN-01 study reported in The Lancet Oncology, Nehal Lakhani, MD, and colleagues found evidence of activity of the CD47-blocking protein evorpacept in combination with pembrolizumab or trastuzumab for the treatment of advanced solid tumors.

As stated by the investigators, “Both innate and adaptive immune responses are important components of anticancer immunity. The CD47–SIRPα interaction could represent an important pathway used by tumor cells to evade immune surveillance. We aimed to evaluate the safety … and anticancer activity of evorpacept, a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumors.”

Nehal Lakhani, MD

Study Details

In the first-in-human trial, a total of 110 patients enrolled between March 2017 and February 2019 from sites in the United States and Korea received single-agent evorpacept (n = 28), evorpacept plus pembrolizumab (n = 52), or evorpacept plus trastuzumab (n = 30), and were included in the safety analysis. In the dose-escalation phase, 28 patients received intravenous evorpacept at 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 dose-expansion phase, additional patients were enrolled into three cohorts consisting of  those with head and neck squamous cell carcinoma and those with non–small cell lung cancer (NSCLC), who were to receive the maximum tolerated dose of evorpacept plus pembrolizumab at 200 mg every 3 weeks, and those with HER2-positive gastric or gastroesophageal junction cancer, who were to receive the maximum tolerated dose of evorpacept plus trastuzumab at an 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks. Treatment continued until disease progression, voluntary withdrawal, or unacceptable toxicity.

Toxicity

During dose-escalation, dose-limiting toxicities in the first cycle of single-agent evorpacept occurred in two patients (7%), consisting of neutropenia with associated infection in one patient at 3 mg/kg once per week and thrombocytopenia with associated bleeding in one patient at 30 mg/kg once every other week. No evorpacept maximum tolerated dose was reached. The 10 mg/kg once per week dose was used in the expansion cohorts in combination with pembrolizumab or trastuzumab.

The most common grade ≥ 3 treatment-related adverse events were thrombocytopenia with single-agent evorpacept during dose escalation (2 patients, 7%) and with evorpacept plus pembrolizumab (2 patients, 4%), and thrombocytopenia (2 patients, 7%) and neutropenia (2 patients, 7%) with evorpacept plus trastuzumab. Serious evorpacept-related adverse events occurred in four patients treated with single-agent evorpacept (neutropenia, thrombocytopenia, pancreatitis, and death), four treated with evorpacept plus pembrolizumab (autoimmune hemolytic anemia and pancytopenia, febrile neutropenia, neutropenia, and peripheral neuropathy), and one treated with evorpacept plus trastuzumab (febrile neutropenia).  

Responses

Among 15 response-evaluable patients receiving single-agent evorpacept once per week in the dose-escalation phase, 4 (27%) had best overall response of stable disease (2 at 0.3 mg/kg, 1 at 3 mg/kg, and 1 at 10 mg/kg). Among 11 who received single-agent evorpacept at 30 mg/kg once every other week, 2 (18%) had stable disease.

Among response-evaluable patients in the dose-expansion cohort, objective response was observed in 4 (20.0%, 95% confidence interval [CI] = 5.7%–43.7%) of 20 patients with head and neck cancer receiving evorpacept plus pembrolizumab, 1 (5.0%, 95% CI =  0.1%–24.9%) of 20 with NSCLC receiving evorpacept plus pembrolizumab, and 4 (21.1%, 95% CI = 6.1%–45.6%) of 19 with gastric or gastroesophageal junction cancer receiving evorpacept plus trastuzumab. Disease control rates in the three groups were 30.0%, 40.0%, and 26.3%.

The investigators concluded, “The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumors. Preliminary antitumor activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with head and neck squamous cell carcinoma, gastric or gastroesophageal junction cancer, and NSCLC.”

Sophia S. Randolph, MD, of ALX Oncology, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by ALX Oncology. For full disclosures of the study authors, visit thelancet.com.