Evaluation of adnexal features and histological response to intralesional SP-002 in nodular basal cell carcinoma.

2596 Background: No FDA approved nonsurgical therapies exist for primary nBCC at high-risk sites, e.g., H-zone, representing a significant unmet medical need. Recombinant IFN-alfa-2b previously achieved ∼85% complete histologic clearance in superficial and nBCC, but required multiple (9-12) injections and was associated with systemic toxicity. SP-002 encodes human IFN-γ and enables sustained, localized cytokine expression with anti tumor activity, achieved with a once weekly, three dose regimen that demonstrates a superior therapeutic index. Methods: Two early phase clinical studies of SP-002 in nBCC were completed: a single lesion study (ASN-002-001, NCT02550678, n=16), and a combination multilesion study with 4 weeks of vismodegib (ASN-002-003, NCT04416516, n=21, 46 lesions). Pretreatment biopsies from ASN-002-001 served as discovery specimens, while pretreatment biopsies from ASN-002-003 were prospectively assessed by central review for adnexal features (AdnF; follicular or eccrine differentiation) using standardized criteria. Post-treatement excision specimens were evaluated by local histopathology laboratories for CHC per protocol-defined criteria. CHC rates were calculated by AdnF. Results: ASN-002-001: sporadic low frequency/risk BCC, AdnF(+) rate was 20%. CHC rates were 33% (5e10vp), 83% (1.5 and 3.0e11vp). ASN-002-003: high-frequency multilesion BCC, AdnF(+) rate was ∼50%. CHC rates were 75% (1 nBCC)/52.9% (3 nBCC) (1.0e11vp) and 52.4% (3 nBCC) (1.5e11vp)-ITT. When analyzed by AdnF status, CHC rates were 97% in AdnF(-) lesions and 11.5% in AdnF(+) lesions. Baseline biopsies in non-responders demonstrated follicular/eccrine structures especially papillary mesenchymal bodies, harboring CKT15(+) stem cells (SC) and nuclear β-catenin, indicating active WNT signaling. Dual repression of programmed cell death effectors, CASP8/RIPK3, was also observed at baseline in lesions with residual disease with focal loss or widespread loss across tumor islands in β-catenin active regions. Either or both CASP8/RIPK3 were present in all complete responders at baseline and their absence may indicate risk for incomplete response to SP-002. Conclusions: SP-002 achieved high CHC rates at doses of 1.5e11vp/3.0e11vp and AdnF(-) lesions (most nBCC) had clearance rates comparable to surgical excision (>90%).Adnexal differentiation identifies a biologically distinct, treatment-resistant subset with WNT pathway activation, adnexal niches harboring CKT15(+) SC, and impaired IFN-γ cell death. These findings support AdnF as a predictive biomarker and position SP-002 as a promising non-surgical option for selected patients with nBCC. Clinical trial information: NCT02550678 , NCT04416516 . CHC rate AdnF(-)n/N lesions (%) CHC rate AdnF(+)n/N lesions (%) ASN-002-001 (n=15, 15 lesions) 11/12 (91.6%) 0/3 (0%) ASN-002-003 (n=21, 46 lesions) 23/23 (100%) 3/23 (13%) 34/35 (97.1%) 3/26 (11.5%)