A phase 1 dose-escalation and expansion study of CUE-101, given as monotherapy and in combination with pembrolizumab, in patients with recurrent/metastatic HPV16+ head and neck squamous cell cancer (R/M HNSCC).
Authors: Alexander Dimitrios Colevas, Christine H. Chung, Douglas Adkins, Cristina P. Rodriguez, Jong Chul Park, Michael K. Gibson, Ammar Sukari, Francis P. Worden, Faye M. Johnson, Nabil F. Saba, Barbara Burtness, Ricklie Ann Julian, Julie E. Bauman, Robert M. Jotte, Tanguy Y. Seiwert, Lara Dunn, Marya F. Chaney, Steven Margossian, Matteo Levisetti, Sara I. Pai
Journal: Journal of Clinical Oncology (2024)

6004 Background: Immuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein and 4 molecules of attenuated human interleukin-2 (IL-2), to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ HNSCC. Methods: CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ R/M HNSCC. Escalating doses of CUE-101 monotherapy (0.06 mg/kg to 8 mg/kg) were evaluated in R/M HNSCC refractory to ≥ 1 platinum or checkpoint inhibitor (CPI) based therapy, alone or combined with pembrolizumab (1 mg/kg to 4 mg/kg + 200 mg pembrolizumab) in the first line treatment of PD-L1+ R/M HNSCCs. Enrollment at the recommended phase 2 dose (RP2D) was expanded. Therapy was administered every 3 weeks (Q3W) until disease progression or intolerable toxicity. Safety, PK/PD, and antitumor activity were assessed. Results: Enrollment in both monotherapy and combination cohorts is now completed (N=80 patients, 49 in monotherapy and 31 CUE-101 plus pembrolizumab). Following dose escalation, 4 mg/kg Q3W of CUE-101 was selected for RP2D for both monotherapy and pembrolizumab combination cohorts. At data cut-off, adverse events (AEs) have been manageable and 92% grade ≤2. The most frequent grade 3 AEs reported include lymphocyte count decreased (7.6%), anemia (6.3%), decreased appetite (5.1%) and infusion-related reactions (5.1%). In combination with pembrolizumab no unanticipated significant safety concerns have emerged. Exposure-dependent PD effects of CUE-101 are consistent with IL-2 pharmacology and indicate preferential expansion of CUE-101 on E7-specific T cells. Among the 19 evaluable patients treated with the RP2D of CUE-101 plus pembrolizumab, an ORR of 47% (1 CR, 8 PRs), a Disease Control Rate (ORR + durable SDs) of 74%, and mPFS of 5.8 months [95% CI 2.56; NA] were observed. A median OS has not been reached. Of the 9 patients with confirmed objective responses, all achieved &gt;99% reduction in HPV16 cfDNA in plasma during their treatment course. Among the 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) and mOS of 20.8 months [95% CI 11.0; NA] were observed. Conclusions: An ORR of 47% and a mPFS of 5.8 months were observed in R/M HNSCC patients treated with CUE-101 4 mg/kg + pembrolizumab as 1L therapy. A median OS of 20.8 was observed in patients treated with CUE-101 monotherapy as post-platinum/CPI therapy. CUE-101 continues to demonstrate safety, tolerability and meaningful clinical benefit in patients with HPV16+ R/M HNSCC. Clinical trial information: NCT03978689 .