The ALX Oncology ASPEN-9 phase 2 trial investigates a flexible, data-driven IHC cutoff for CD47-high tumors to optimize patient stratification and improve response assessment, with adjustments informed by interim biomarker analyses.
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What is the prespecified IHC cutoff and decision rule for CD47-high in ASPEN-9 and can it be adjusted based on interim analyses?
1. Prespecified IHC Cutoff for CD47-high in ASPEN-9
ALX Oncology anticipates that approximately half the patient population in the ASPEN-9 trial will be CD47-high. This expectation is based on prior clinical data and literature consistency. For instance, in HER2-positive gastric and breast cancer studies, the prevalence of CD47-high tumors ranges roughly from 40% to 57% of patients, thereby supporting a cutoff that identifies about 50% CD47 overexpressors in ASPEN-9 123.
Regarding the exact IHC cutoff threshold, it was mentioned that the cutoff definition for CD47-high involved IHC 3+ expression on more than 10% of tumor cells. However, management clarified that the precise cut point is still under evaluation as it may vary by tumor type, with gastric cancer typically showing higher baseline CD47 expression than breast cancer. The current ASPEN-9 study’s goal is to empirically define and "lock in" this cutoff based on accumulating data, making the cut point a critical outcome of the ongoing trial rather than being fully predetermined 456.
The use of IHC 3+ as a threshold (percentage positive >10%) is consistent with prior studies (including gastric cancer) where various cutoffs like IHC 3 and IHC 2/3 were tested without significant difference in response signals. Nonetheless, ASPEN-9 aims to clarify this further 4.
2. Decision Rule and Endpoint
The trial’s primary endpoint has been updated to focus on the response rate specifically in the CD47-high subgroup. This change was driven by the strong predictive power of CD47 expression for clinical benefit observed in prior studies across different tumor types including breast and gastric cancers 67.
The trial remains an open-label, single-arm phase 2 study enrolling HER2-positive metastatic breast cancer patients who progressed on prior HER2-directed therapy (in-HER2). Biomarker-driven patient stratification using CD47 expression will be fundamental in interpreting the efficacy data 7.
Secondary endpoints include response rates by HER2 status (using ctDNA confirmation) and other biomarker subgroup analyses. This allows tracking responses in CD47-high only, HER2-positive only, and CD47-high plus HER2-positive “double-positive” groups 7.
3. Adjustability Based on Interim Analyses
The IHC cutoff for determining CD47-high is not irrevocably locked at trial start. Management explicitly stated that part of the purpose of the ASPEN-9 trial is to generate robust data to inform the optimal cutoff value. The cutoff will be data-driven and established using the study’s biomarker data 456.
Expansion of patient enrollment from 80 to 120 patients was undertaken to ensure adequate numbers of CD47-positive patients and sufficient statistical power to refine and confirm the cutoff and related decision rules. This enrollment flexibility supports adjustment of biomarker cut points based on interim results 86.
Interim data from the 80-patient cohort is expected in mid-2027, and these results will provide the comprehensive biomarker and efficacy data needed to finalize cutoffs and support future regulatory discussions. Early data while possible to disclose, are not the primary basis for the cutoff adjustment, but full robust analysis is anticipated at the interim readout 86.
The open-label design and ongoing biomarker assessments allow adaptive interpretation but not necessarily formal statistical adaptation of the cutoff mid-trial. However, the trial design explicitly contemplates learning and potentially refining the biomarker selection boundaries with emerging data 46.
Summary:
| Aspect | Detail | Citation(s) |
|---|---|---|
| Prespecified IHC Cutoff | Initially anticipated ~50% prevalence; cutoff roughly IHC 3+ expression on >10% tumor cells | 4125 |
| Nature of Cutoff | Not absolutely fixed upfront; planned as data-driven determination within trial | 456 |
| Primary Endpoint Change | Updated to response rate in CD47-high subgroup | 67 |
| Sample Size Upsizing | Increased from 80 to 120 patients to ensure sufficient CD47-high patients for robust biomarker analysis | 86 |
| Interim Analysis Impact | Interim data will guide finalization of cutoffs; cutoff may be adjusted based on interim findings | 4586 |
| Handling Borderline or Insufficient Tissue | Minimal concern due to use of diagnostic tissue and standard IHC assay; <10% expected missing data | 5 |
The ASPEN-9 trial utilizes a prespecified but flexible IHC cutoff for defining CD47-high status, initially guided by existing clinical and literature data (approximately IHC 3+ at >10%), with the goal of confirming and potentially adjusting this cutoff based on robust interim biomarker data. The primary endpoint focuses on response rate in the CD47-high population to leverage the biomarker's predictive power. Expansion in trial size ensures sufficient CD47-high patient numbers to enable meaningful statistical analysis. The study design allows adjustment of the cutoff decision rule after initial data assessment but emphasizes generating a data-driven, clinically relevant cutoff to support regulatory and clinical decision-making.
This adaptive but evidence-based approach balances precision targeting of patient subsets with the need for statistical rigor and regulatory clarity, positioning ALX Oncology to maximize the potential of the CD47 biomarker in guiding therapy with avorpicept in the post-HER2 setting.
References: Inline citations correspond to the company filing excerpt numbers as listed in the analysis above.
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