1191 Neoadjuvant phase 1b results: dose escalation of intratumoral PH-762 for cutaneous SCC, melanoma, or Merkel cell ( NCT06014086)
Year: 2026
Type: conference-paper
Study design: Clinical Trial
Abstract: Background Systemic PD-1 blockade is effective but may cause immune-related toxicity. 1–3 PH-762 is a self-delivering INTASYL-linked small interfering RNA (siRNA) designed to silence the PD-1 immune checkpoint by reducing PD-1 expression after intratumoral administration (figure 1). To our knowledge, this is the first reported clinical demonstration of intratumoral siRNA directed at the PD-1 immune-checkpoint pathway in invasive skin cancers.4 We report final locked analyses of single-agent PH-762Methods PHIO-762-2301 ( NCT06014086) was a phase 1b, multicenter, open-label, noncomparative dose-escalation study in adults with an injectable 1.0–3.0-cm cutaneous squamous cell carcinoma (cSCC), melanoma, or Merkel cell carcinoma (MCC). PH-762 was the sole therapeutic agent. Participants received four weekly intratumoral injections into one lesion at 1.14, 2.39, 5.01, 10.50, or 22.00 mg/mL. Excision on day 36 enabled histologic assessment of residual viable tumor. Pathologic responses were pathologic complete response (pCR; no viable tumor), near-pCR (< 10% viable tumor), or partial (< 50% viable tumor). Clinical response used modified immune Response Evaluation Criteria in Solid Tumors (iRECIST). The primary endpoint was safety/tolerability; pathologic and clinical responses were secondary endpoints.Results Twenty-two participants completed treatment (cSCC, n = 20; melanoma, n = 1; MCC, n = 1) across five cohorts. Treatment-emergent adverse events occurred in 19/22 (86.4%) and treatment-related events in 11/22 (50.0%); no dose-limiting or immune-related toxicities, adverse events of special interest, serious adverse events, or deaths occurred. Across all participants, pathologic responses were pCR in 9/22 (40.9%), near-pCR in 2/22 (9.1%), partial response in 3/22 (13.6%), and nonresponse in 8/22 (36.4%). Among cSCC participants, 13/20 (65.0%) had any pathologic response, including pCR in 9/20 (45.0%); 12/20 (60.0%) had clinical response, including complete clinical response in 3/20 (15.0%). At 22.00 mg/mL (all cSCC), 6/7 (85.7%) had a pathologic response, including pCR/near-pCR in 5/7 (71.4%) ( figure 2). The MCC lesion had a partial pathologic response with stable disease by iRECIST; the melanoma lesion had pathologic nonresponse with stable disease by iRECISTConclusions Four weekly intratumoral doses of single-agent PH-762 were well tolerated through 22.00 mg/mL, without dose-limiting or immune-related toxicities. The final analysis documents complete and near-complete pathologic responses, including in the highest-dose cohort. The single melanoma and MCC cases are descriptive and do not support tumor-specific conclusionsTrial Registration TRIAL REGISTRATION ClinicalTrials.gov: NCT06014086References Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379:341–351.Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016;374:2542–2552.Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–2532.Cuiffo B, Maxwell M, Yan D, et al. Self-delivering RNAi immunotherapeutic PH-762 silences PD-1 to generate local and abscopal antitumor efficacy. Front Immunol. 2024;15:1501679.Ethics Approval The study was approved by Advarra Institutional Review Board (#PRO 00073270 ). All participants provided written informed consent.Abstract 1191 Figure 1INTASYL mechanism to deliver siRNA to silence PD-1 expressionAbstract 1191 Figure 2Pathologic and clinical responses following intratumoral PH-762 for invasive skin cancers
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225378299