Evorpacept alone and in combination with pembrolizumab or trastuzumab in patients with advanced solid tumors (ASPEN-01): a first human, open-label, multicenter, phase 1 study with dose escalation and dose expansion


Background

Innate and adaptive immune responses are important components of cancer immunity. The CD47-SIRPα interaction could represent an important pathway used by tumor cells to evade immune surveillance. Our objective was to assess the safety, pharmacokinetics, pharmacodynamics and anticancer activity of evorpacept (also known as ALX148), a high affinity CD47 blocking protein with an inactive IgG Fc region in patients with solid tumors.

Methods

We conducted a first human, open-label, multicenter, phase 1 dose escalation and dose escalation study in nine hospitals and one clinic in the United States and Korea. Patients eligible for the dose escalation and safety introduction phases were 18 years of age or older with a histologic or cytologic diagnosis of advanced or metastatic solid tumors with no available standard treatment, measurable or non-measurable disease depending on the response endpoints in solid tumor version 1.1, and an Eastern Cooperative Oncology Group performance index score of 0 or 1. In the dose escalation phase, which used a design 3 + 3, patients received intravenous evorpacept at 0.3, 1, 3 or 10 mg / kg once a week in 21-day cycles, or 30 mg / kg once every two weeks in cycles 28 days. During the Safety Introduction phase, patients received the maximum tolerable dose of evorpacept from the dose escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (loading dose of 8 mg / kg followed by 6 mg / kg once every 3 weeks). During the dose extension phase, additional patients aged 18 years or older with second-line or last-line advanced malignancies were included in three parallel cohorts: those with squamous cell carcinoma of the head and neck (HNSCC) and those with non-small cell cancer. lung cancer (NSCLC) received the maximum tolerated dose of evorpacept plus pembrolizumab intravenously (200 mg given once every 3 weeks), and patients with cancer of the stomach or gastrointestinal junction HER2-positive esophagus received the maximum tolerated dose of evorpacept plus trastuzumab intravenously (8 mg / kg loading dose followed by 6 mg / kg once every 3 weeks) until disease progression, voluntary withdrawal of study or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept given as monotherapy and in combination with pembrolizumab or trastuzumab, measured by the occurrence of dose-limiting toxicities in the first cycle, and was evaluated in all patients. who have received at least one dose. evorpacept. Secondary outcomes included the safety, tolerability, and antitumor activity of evorpacept, alone or in combination with pembrolizumab or trastuzumab. Primary efficacy endpoint, safety and tolerability were assessed in all patients who received at least one dose of evorpacept, and antitumor activity was assessed in those who received at least one dose of the treatment. study and underwent at least one post-inclusion tumor assessment. This trial is registered with ClinicalTrials.gov, NCT03013218.

Results

Between March 6, 2017 and February 21, 2019, 110 patients received evorpacept monotherapy (n = 28), evorpacept plus pembrolizumab (n = 52) or evorpacept plus trastuzumab (n = 30), and were included in the study. of security. analysis. The median follow-up was 29.1 months (95% CI not calculable [NC]–NC) in the monotherapy cohort, 27.0 months (25.1–28.8) in the evorpacept plus pembrolizumab cohort and 32.7 months (27.0–32.7) in the evorpacept plus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle were reported in patients who received evorpacept monotherapy; neutropenia with associated infection in a patient with gastroesophageal junction cancer who received 3 mg / kg once weekly, and thrombocytopenia with associated bleeding in a patient with pancreatic cancer who received 30 mg / kg once every two weeks. No maximum tolerated dose has been reached; the maximum doses administered were 10 mg / kg once a week or 30 mg / kg once every two weeks. The once weekly dose of 10 mg / kg has been used in extension cohorts in combination with pembrolizumab or trastuzumab. The most common grade 3 or worse treatment-related adverse events were thrombocytopenia with evorpacept monotherapy (two [7%] patients) and evorpacept plus pembrolizumab (two [4%]) and thrombocytopenia (two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patients who received evorpacept monotherapy, four serious treatment-related adverse events were reported. Five treatment-related serious adverse events with evorpacept plus pembrolizumab were reported, and one serious adverse event with evorpacept plus trastuzumab was reported. In patients with evaluable response in the dose escalation phase (n = 15) receiving evorpacept monotherapy once weekly, four (27%) had a better overall disease response stable (two had received 0.3 mg / kg, one received 3 mg / kg and one received 10 mg / kg); of the 11 patients who received evorpacept monotherapy at the highest dose of 30 mg / kg once every two weeks, two (18%) experienced stable disease. In the dose extension cohort, overall responses were recorded in four (20.0%; 95% CI 5.7–43.7) of 20 patients with HNSCC who received evorpacept plus pembrolizumab , in only one (5.0%; 0 · 1–24 · 9) of 20 NSCLC patients who received evorpacept plus pembrolizumab, and in four (21.1%; 6 · 1–45 6) of 19 patients with gastric or gastroesophageal junction cancer who received evorpacept plus trastuzumab.

Interpretation

The safety results support the use of evorpacept in combination with pembrolizumab or trastuzumab in patients with advanced solid tumors. Preliminary results of antitumor activity support future studies of evorpacept in combination with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC.

Funding

ALX Oncology.


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