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

Background : Both innate and adaptive immune responses are important components of anticancer immunity.The CD47–SIRP

α interaction could represent an important pathway used by tumour cellsto evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics,and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blockingprotein with an inactive IgG Fc region in patients with solid tumours. Methods

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We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansionstudy at nine hospitals and one clinic in the USA and Korea. Eligible patients forthe dose-escalation and safety lead-in phases were aged 18 years or older with histologicalor cytological diagnosis of advanced or metastatic solid tumours with no availablestandard therapy, measurable or unmeasurable disease according to the Response EvaluationCriteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performancestatus score of 0 or 1. In the dose-escalation phase, which used a 3

 + 3 design, patientsreceived intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-inphase, patients were given the maximum tolerable dose of evorpacept from the dose-escalationphase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks)or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3weeks). In the dose-expansion phase, additional patients aged 18 years or older withsecond-line or later-line advanced malignancies were enrolled into three parallelcohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-celllung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenouspembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positivegastric or gastroesophageal junction cancer were given the maximum tolerated doseof evorpacept plus intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kgonce every 3 weeks) until disease progression, voluntary withdrawal from the study,or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab,measured by the occurrence of dose-limiting toxicities during the first cycle, andwas assessed in all patients who had received at least one dose of evorpacept. Secondaryoutcomes included the safety, tolerability, and antitumour activity of evorpacept,alone or in combination with pembrolizumab or trastuzumab. The primary outcome, safety,and tolerability were assessed in all patients who had received at least one doseof evorpacept, and antitumour activity was assessed in those who recieved at leastone dose of study treatment and underwent at least one post-baseline tumor assessment.This trial is registered with ClinicalTrials.gov, NCT03013218. Findings : Between March 6, 2017, and Feb 21, 2019, 110 patients received single-agent evorpacept(n=28), evorpacept plus pembrolizumab (n=52), or evorpacept plus trastuzumab (n=30),and were included in the safety analysis. Median follow-up was 29·1 months (95% CInot calculable [NC]–NC) in the single-agent cohort, 27·0 months (25·1–28·8) in theevorpacept plus pembrolizumab cohort, and 32·7 months (27·0–32·7) in the evorpaceptplus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle werereported in patients who received single-agent evorpacept; neutropenia with an associatedinfection in one patient with gastroesophageal junction cancer who received 3 mg/kgonce per week, and thrombocytopenia with associated bleeding in one patient with pancreaticcancer who received 30 mg/kg once every other week. No maximum tolerated dose wasreached; the maximum administered doses were 10 mg/kg once per week or 30 mg/kg onceevery other week. The 10 mg/kg once per week dose was used in the expansion cohortsin combination with pembrolizumab or trastuzumab. The most common grade 3 or worsetreatment-related adverse events were thrombocytopenia with single-agent evorpacept(two [7%] patients) and evorpacept plus pembrolizumab (two [4%]), and thrombocytopenia(two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patientswho received single-agent evorpacept, four treatment-related serious adverse eventswere reported. Five serious treatment-related adverse events related to evorpaceptplus pembrolizumab were reported, and one serious adverse event related to evorpaceptplus trastuzumab was reported. In response-evaluable patients in the dose-escalationphase (n=15) receiving single-agent evorpacept once per week, four (27%) had a bestoverall response of stable disease (two received 0·3 mg/kg, one received 3 mg/kg,and one received 10 mg/kg); in the 11 patients who received single-agent evorpaceptat the highest dose of 30 mg/kg once every other week, two (18%) had stable disease.In the dose-expansion 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 one (5·0%; 0·1–24·9) of 20 patients with NSCLC who received evorpacept plus pembrolizumab,and in four (21·1%; 6·1–45·6) of 19 patients with gastric or gastroesophageal junctioncancer who received evorpacept plus trastuzumab. Interpretation : The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activityresults support future investigation of evorpacept combined with pembrolizumab ortrastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, andNSCLC.

The Lancet Oncology 2021

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