Desmocolin-3–directed immunotherapy in recurrent/metastatic head and neck squamous cell carcinoma.

2503 Background: Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are aggressive tumors. In pre-treated R/M HNSCC observed response rates were 13.0% (nivolumab; CheckMate 141) and 14.6% (pembrolizumab; KEYNOTE- 040), with median PFS 2.0 months and 2.1 months, respectively. Desmocollin3 (DSC3) is a surface protein expressed by HNSCC. DSC3 directed immunotherapy (CADI-05) is useful in DSC3 expressing cancer like Squamous NSCLC, bladder cancer, and melanoma. This study evaluated its efficacy (ORR, PFS, OS) in DSC3 expressing R/MHNSCC. Methods: In this investigator initiated single-arm, study patients with RMHNSCC expressing DSC3 were recruited. Tumor infiltrating lymphocytes (TIL), PD-L1, and P16 were also evaluated. All patients received 0.1ml CADI-05 intradermally + intralesional (for fungating/discharging solid lesions were present) every 4 weeks. Additional treatment was administered as per PI discretion. All patients were followed up until disease progression, or death. Results: Between May 2024 and July 2025, 20 patients were enrolled (males 17, females 3). The mean age was 55 yrs (range 34-87 yrs). Primary sites included tongue 9, buccal mucosa 9. All had undergone two lines of therapy with a mean of 2.55. Of 20 patients, 15 had progressed on prior therapy (6 stage IVC). Baseline mean parameters were mean DSC3 TPS - 41%, (95% CI, 32.67 - 49.33), mean PD-L1 CPS 27 (95% CI,10.61 - 33.39), mean TIL 17% (95% CI ,10.43 - 23.57). All were HPV negative. Additional therapy received included EGFR TKI (15), EGFR mAb (2), oral metronomic therapy (1) and none (2). Disease control rate was 45% (9/20) with overall response rate (ORR) 35% [7/20; 2 CR and 5 PR]. At a median follow-up of 155 days, mean (median) PFS and overall survival were 165 (115) and 197 (155) days, respectively. Mean (median) duration of response was 280 (332) days with 8 patients alive at the last follow up. This is significantly better than achieved with current therapies. Responders had higher DSC3 expression compared to non-responders (mean DSC3 50% vs 29%; p= 0 .002537). ORR was higher in patients with Stage IVA (57% ) compared to IVC (20% ) DSC3 TPS was higher than PD-L1 CPS in all patients with disease control. TIL and PD-L1 levels were not correlated with response. Injection site ulcer was the only side effect seen in 8 (40%), which include 6 (75%) of the responders. No systemic adverse events were observed. Conclusions: DSC3 targeted immunotherapy was safe and improved outcomes in pre-treated R/M HNSCC expressing DSC3, with disease control rate 45%, response rate 35%. Median duration of response was 332 days with median PFS and OS of 115 and 155 days, respectively.