ASPEN-06: Evorpacept Plus TRP Lifts ORR to 40.3% in Pretreated HER2-Positive Gastric Cancer
核心洞察
In the randomized phase 2 ASPEN-06 study, evorpacept plus trastuzumab, ramucirumab and paclitaxel produced a 40.3% investigator-assessed objective response rate versus 26.6% for the triplet alone.
The 13.7% intent-to-treat ORR difference exceeded the prespecified 8% threshold, but the comparison against the 30% historical benchmark missed the one-sided alpha of 0.025.
Post hoc analyses identified CD47 (搜索) expression as a potential predictive biomarker, with 63.6% versus 23.1% ORR in patients who had retained HER2 (搜索) positivity and high CD47 staining.
Evorpacept added to trastuzumab, ramucirumab and paclitaxel (TRP) produced an investigator-assessed objective response rate (ORR) of 40.3% versus 26.6% for TRP alone in patients with pretreated, HER2 (搜索)-overexpressing advanced gastric or gastroesophageal junction (GEJ) cancer, according to the phase 2 portion of the randomized ASPEN-06 study published in Nature Medicine.
The 127-patient trial, conducted at 49 academic and community institutions across ten countries, met one of its two primary objectives. The ORR difference between arms was 13.7% in the intent-to-treat (ITT) population and 31.7% in the fresh biopsy HER2 (搜索)-positive subgroup (54.8% versus 23.1%), both exceeding the prespecified thresholds of 8% and 9.7%, respectively. However, the second primary objective, which compared ORR against an assumed historical benchmark of 30% for ramucirumab plus paclitaxel, was not met: the ITT ORR of 40.3% yielded a one-sided P = 0.0949 and the fresh biopsy subgroup ORR of 54.8% yielded a one-sided P = 0.030, neither satisfying the prespecified one-sided alpha of 0.025.
Trial Design and Patient Population
ASPEN-06 (NCT05002127) is an international, multicenter, randomized phase 2/3 study. In the open-label phase 2 portion reported here, patients were randomized 1:1 to evorpacept plus TRP (n = 63) or TRP alone (n = 64), with a one-arm, two-stage Simon design adopted in the evorpacept arm. Randomization used stochastic minimization based on the variance method, balancing prior trastuzumab deruxtecan use, line of therapy, geographic region, cancer type and HER2 (搜索) overexpression status.
Eligible patients were adults with HER2 (搜索)-positive advanced or metastatic gastric/GEJ adenocarcinoma that had progressed on or after a prior HER2-directed agent and/or fluoropyrimidine- or platinum-containing chemotherapy. Patients with prior ramucirumab or any anti-CD47 (搜索) or anti-SIRPα agent were excluded. Median age was 64 years, 81.1% of patients were male, and 73.2% received study treatment in the second line. All patients had received trastuzumab or another HER2-directed therapy; 14.2% had prior trastuzumab deruxtecan and 21.3% had prior anti-PD-1 therapy.
Dosing comprised evorpacept 30 mg kg⁻¹, trastuzumab (6 mg kg⁻¹ loading, then 4 mg kg⁻¹) and ramucirumab 8 mg kg⁻¹ every two weeks, with paclitaxel 80 mg m⁻² weekly for the first three weeks of each 28-day cycle, all given intravenously in the outpatient setting. The primary analysis used a data cutoff of 24 May 2024 with a median follow-up of 7.8 months; updated efficacy, safety and biomarker analyses used a cutoff of 15 May 2025.
Durability and Survival Signals
Median duration of response (DOR) by investigator assessment was 15.7 months with evorpacept plus TRP versus 7.6 months with TRP alone in both the ITT population and the fresh biopsy HER2 (搜索)-positive subgroup. Median progression-free survival (PFS) was 7.5 versus 7.4 months in the ITT population and 9.0 versus 7.4 months in the fresh biopsy subgroup. Overall survival data were not mature at the primary analysis; in the updated analysis, OS was similar between arms (ITT hazard ratio 1.07, 95% CI 0.69–1.66; fresh biopsy HER2-positive subgroup HR 1.05, 95% CI 0.46–2.38).
Results assessed by blinded independent central review were consistent with investigator assessments for ORR, DOR and PFS. Gender-stratified analyses, which were not prespecified, showed ORRs of 36.4% versus 27.1% in male patients and 50.0% versus 25.0% in female patients for evorpacept plus TRP versus TRP.
CD47 and Retained HER2 as Candidate Biomarkers
Post hoc analyses examined whether retained HER2 (搜索) positivity and tumor CD47 (搜索) expression identify patients most likely to benefit. Of 127 enrolled patients, 95 (74.8%) had retained HER2-positive disease by either fresh biopsy (n = 47) or ERBB2 (搜索) amplification in circulating tumor DNA (n = 86). In the updated analysis, ORR with evorpacept plus TRP versus TRP alone was 59.1% versus 24.0% in the fresh biopsy subgroup, 48.8% versus 25.6% in the ctDNA subgroup, and 48.9% versus 25.0% in the combined fresh biopsy or ctDNA subgroup. In all three subgroups, the 95% confidence intervals for ORR in the evorpacept arm excluded the 30% historical control rate.
Receiver operating characteristic and Youden index analyses identified a candidate cutoff of at least 5% of tumor cells with membrane CD47 (搜索) IHC3+ staining to define CD47-high. Among patients with retained HER2 (搜索)-positive disease and CD47-high tumors (n = 48), ORR was 63.6% with evorpacept plus TRP versus 23.1% with TRP alone, median DOR was 25.5 versus 8.4 months (HR 0.27, 95% CI 0.07–1.06), and median PFS was 19.5 versus 7.0 months (HR 0.38, 95% CI 0.17–0.84). The OS hazard ratio was 0.66 (95% CI 0.32–1.37).
In patients with retained HER2 (搜索)-positive disease and CD47 (搜索)-low tumors (n = 42), there was no evidence of benefit from adding evorpacept: ORR was 36.4% versus 30.0%, with a PFS hazard ratio of 1.48 (95% CI 0.73–3.01) and an OS hazard ratio of 1.74 (95% CI 0.81–3.72) favoring TRP. Among the 32 patients without evidence of retained HER2-positive disease, ORR was 18.8% with evorpacept plus TRP versus 31.3% with TRP alone, regardless of CD47 expression. The authors note this classification should not be interpreted as confirmed HER2 tissue loss, as post-HER2-directed treatment tissue confirmation was unavailable in these patients.
Interaction tests using the 5% CD47 (搜索) threshold produced unadjusted P values of 0.161 for ORR, 0.006 for PFS and 0.039 for OS. The study was not powered to detect treatment-by-subgroup interactions. In the TRP-alone arm, CD47-high tumors showed a trend toward shorter PFS (HR 1.42, 95% CI 0.70–2.85) and shorter OS (HR 1.54, 95% CI 0.73–3.22) than CD47-low tumors.
Safety Profile
Treatment-emergent adverse events of any grade occurred in 100% of patients in both arms. The most common were decreased neutrophil count/neutropenia (69.8% with evorpacept plus TRP versus 55.6% with TRP), anemia (58.7% versus 38.1%) and diarrhea (41.3% versus 36.5%). Grade 3 or higher events occurred in 90.5% versus 79.4%, most commonly neutropenia (55.6% versus 39.7%), anemia (23.8% versus 17.5%) and leukopenia (17.5% versus 9.5%).
Febrile neutropenia was reported in 3.2% of patients receiving evorpacept plus TRP and 7.9% of those receiving TRP. Grade 5 treatment-emergent events occurred in five patients in the evorpacept arm and seven in the control arm. Three grade 5 events were considered treatment-related: two in the evorpacept arm (esophageal perforation; renal insufficiency, acute respiratory insufficiency and anasarca, both possibly related to ramucirumab and trastuzumab with potential contribution from underlying gastric cancer (搜索) but not considered related to evorpacept) and one in the TRP arm (pneumonia, considered related to TRP). Discontinuation rates were similar between arms.
Mechanism and Development Path
Evorpacept is a high-affinity engineered fusion protein containing the N-terminal D1 domain of SIRPα linked to a modified, inactive Fc domain of human IgG1. The inactive Fc was designed to mitigate off-tumor CD47 (搜索)-targeted antibody-dependent cellular phagocytosis (ADCP) toxicities seen with other anti-CD47 agents, including magrolimab. Because prophagocytic Fcγ receptor binding depends on the combination partner antibody, evorpacept was paired with trastuzumab to supply a tumor antigen-bound active Fc domain. In the phase 1 ASPEN-01 study, evorpacept plus TRP produced an ORR of 72.2% in previously treated gastric cancer (搜索).
The authors state that this is the first randomized study to demonstrate both clinical activity of CD47 (搜索)–SIRPα inhibition and a manageable safety profile in solid tumors. They compare the results with second-line ramucirumab plus paclitaxel data: 28% ORR in the phase 3 RAINBOW trial, which enrolled patients regardless of HER2 (搜索) status, and 29% in the DESTINY-Gastric04 trial in HER2-positive metastatic gastric/GEJ cancer. The internal control arm in ASPEN-06 produced a similar ORR of 26.6%.
Limitations cited include the open-label design, limited sample size particularly in subgroups, the low proportion of patients with fresh biopsy confirmation of HER2 (搜索) status, exploratory use of ctDNA for defining HER2 status, the post hoc nature of the CD47 (搜索) analyses, and the risk of overfitting when a biomarker threshold is derived and evaluated in the same dataset. CD47 IHC scoring was performed centrally and the authors state it may require additional validation before routine clinical use.
The study did not proceed to phase 3 for strategic reasons. ALX Oncology, which sponsored the trial, said it elected not to pursue a US registrational path with a phase 3 trial in gastric cancer (搜索) and will consider development partnerships for the program. The company said findings support its ongoing phase 2 ASPEN-09-Breast trial (NCT07007559) of evorpacept plus trastuzumab and chemotherapy in HER2-positive metastatic breast cancer (搜索), with topline data from 80 patients expected in mid-2027. The authors also suggest future development may be more relevant in earlier-line settings or in combination with next-generation Fc-competent HER2 (搜索)-directed antibodies such as zanidatamab, given the emergence of trastuzumab deruxtecan as second-line therapy.