Preliminary Safety of PDS0101 (Versamune +HPVmix) and Pembrolizumab Combination Therapy in Subjects with Recurrent/Metastatic Human Papillomavirus-16 Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)

Abstract

Purpose/Objective(s) Persistent HPV16 DNA infection is associated with up to 70% of OPSCC and recurrent/metastatic disease is often incurable and poorly palliated by standard therapies. Despite significant advances documented with checkpoint inhibitor (CPI) immunotherapy, clinical benefit and efficacy remains limited in most patients due to a lack of meaningful tumor-directed T cell responses. Major barriers to effective cancer vaccine delivery include a relative absence of shared neo-antigens between tumors and weak T-cell activation. PDS0101 is a T-cell activating immunotherapy directed against preserved HPV neoantigens E6/7 that is based on a cationic lipid nanoparticle platform that promotes antigen processing and cross presentation. It has been shown to specifically upregulate type I interferons, allowing generation of high levels of polyfunctional HPV16-specific CD8 and CD4 T cells in vivo as well as immune memory. VERSATILE-002 (NCT04260126) is a phase 2 study of the combination of PDS0101 and pembrolizumab in first line treatment (CPI naïve) and CPI refractory patients with recurrent or metastatic HPV16-related OPSCC. Herein, we report preliminary safety data for CPI naïve patients. Materials/Methods Subjects are treated with pembrolizumab 200mg IV every three weeks plus SC PDS0101 following pembrolizumab on days one of C1-4 and C12. An initial safety cohort was assessed during Cycle 1 and 21 days following, for dose limiting toxicity (DLT) and thereafter for safety and tolerability of the combination. Results Fifteen CPI naïve subjects, median age 60 yrs (range 46-68), all male, 14 (93%) of whom were White and not Hispanic or Latino, received at least one cycle of combination therapy. All were confirmed HPV16 postive and to have a CPS score >=1 (8 with CPS >=20); 8 (53%) were ECOG 0 and 93% had received prior curative intent HNSCC therapy. At the time of safety review, subjects had received a median of 4 doses (range 1-4) of PDS0101 and pembrolizumab. Treatment-emergent adverse events (TEAEs) were documented in 9 (60%) subjects: self-limited, Grade 1 local inject site reactions predominated (7 subjects, 47%), with occasional ≤ Gr2 fatigue, nausea or diarrhea (13% of subjects or fewer). Five subjects had serious adverse events (SAEs), all unrelated to PDS0101 and pembrolizumab. No DLTs, drug discontinuation related to toxicity or immune-related AEs have been documented to date. Conclusion The combination of PDS0101 and pembrolizumab is safe and well tolerated without evidence of enhanced or significant toxicity. Persistent HPV16 DNA infection is associated with up to 70% of OPSCC and recurrent/metastatic disease is often incurable and poorly palliated by standard therapies. Despite significant advances documented with checkpoint inhibitor (CPI) immunotherapy, clinical benefit and efficacy remains limited in most patients due to a lack of meaningful tumor-directed T cell responses. Major barriers to effective cancer vaccine delivery include a relative absence of shared neo-antigens between tumors and weak T-cell activation. PDS0101 is a T-cell activating immunotherapy directed against preserved HPV neoantigens E6/7 that is based on a cationic lipid nanoparticle platform that promotes antigen processing and cross presentation. It has been shown to specifically upregulate type I interferons, allowing generation of high levels of polyfunctional HPV16-specific CD8 and CD4 T cells in vivo as well as immune memory. VERSATILE-002 (NCT04260126) is a phase 2 study of the combination of PDS0101 and pembrolizumab in first line treatment (CPI naïve) and CPI refractory patients with recurrent or metastatic HPV16-related OPSCC. Herein, we report preliminary safety data for CPI naïve patients. Subjects are treated with pembrolizumab 200mg IV every three weeks plus SC PDS0101 following pembrolizumab on days one of C1-4 and C12. An initial safety cohort was assessed during Cycle 1 and 21 days following, for dose limiting toxicity (DLT) and thereafter for safety and tolerability of the combination. Fifteen CPI naïve subjects, median age 60 yrs (range 46-68), all male, 14 (93%) of whom were White and not Hispanic or Latino, received at least one cycle of combination therapy. All were confirmed HPV16 postive and to have a CPS score >=1 (8 with CPS >=20); 8 (53%) were ECOG 0 and 93% had received prior curative intent HNSCC therapy. At the time of safety review, subjects had received a median of 4 doses (range 1-4) of PDS0101 and pembrolizumab. Treatment-emergent adverse events (TEAEs) were documented in 9 (60%) subjects: self-limited, Grade 1 local inject site reactions predominated (7 subjects, 47%), with occasional ≤ Gr2 fatigue, nausea or diarrhea (13% of subjects or fewer). Five subjects had serious adverse events (SAEs), all unrelated to PDS0101 and pembrolizumab. No DLTs, drug discontinuation related to toxicity or immune-related AEs have been documented to date. The combination of PDS0101 and pembrolizumab is safe and well tolerated without evidence of enhanced or significant toxicity.