Johnson, Jennifer M.

ABSTRACT Background ASP‐1929 photoimmunotherapy—cetuximab conjugated to IRDye 700DX and red light (690 nm) for localized drug activation—results in rapid, selective cell killing. Methods This phase Ib/II open‐label study evaluated ASP‐1929 photoimmunotherapy plus pembrolizumab in patients with recurrent/metastatic HNSCC (≥ 1 accessible lesion, PD‐L1 combined positive score ≥ 1, ineligible for standard locoregional therapy). Primary objectives were safety/tolerability and objective response rate (ORR). Secondary objectives included overall survival (OS) and progression‐free survival (PFS). Results Eighteen patients (median age 63 years, 74% male) comprised the photoimmunotherapy‐evaluable population. The confirmed ORR was 27.8% (95% CI 9.7–53.5); four of five responders had complete responses (95% CI, 6.4–47.6). Median OS was 25.6 months (95% CI, 14.6–not evaluable); median PFS was 2.9 months (95% CI, 1.4–14.6). The most common serious adverse reactions were dysphagia and tongue edema (each n = 2; 10.5%). Conclusions ASP‐1929 photoimmunotherapy plus pembrolizumab was generally tolerable, with promising efficacy in patients with recurrent/metastatic HNSCC.

6026 Background: We examined a large patient dataset based on E1305, a completed phase III randomized trial of platinum-based chemotherapy with or without bevacizumab (Argiris et al. JCO 2019), to evaluate prognostic factors in the first-line treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (RM SCCHN) and expand on our previous observations in cooperative group trials (Argiris et al. Cancer 2004). Methods: All 403 patients enrolled in E1305 were analyzed. Overall survival (OS) was the outcome of interest. Clinical and tumor characteristics were examined using Cox proportional hazards models. Variables which were significant in the univariate setting at a level of ≤ 0.10 were included in a multivariable model, and backwards selection was performed (threshold of p ≤ 0.05). The final multivariable model was then applied to the two treatment arms, separately. Variables for which the hazards ratio (HR) within an arm was more than 10% different than that for the whole cohort, were removed from the final cohort model. Results: The median OS in the whole study cohort was 11.8 months. A prognostic score model for OS was built, using the 4 independent prognostic factors identified in the multivariable model: ECOG performance status (1 vs 0), prior radiation, primary region (non-oropharynx vs oropharynx), and metastatic disease bone or liver (vs other sites/no metastases). Prognostic score was dichotomized (0-2 and > 2). Patients with 0-2 risk factors (n = 249) had a median OS of 15.2 months (90% CI: 13.8, 18.1), while patients with > 2 risk factors (n = 154) had a median OS of 7.6 months (90% CI: 6.5, 9.3); HR of 2.14 (95% CI: 1.73, 2.66), p < 0.0001. Compared to our previous 5-factor model from analysis of older trials in a similar setting, the variable “bone/liver metastasis” is new, but “tumor cell differentiation” and “weight loss” were not significant and not included in the new model for OS. Conclusions: The new proposed model includes 4 prognostic factors for OS (performance status, primary site, prior radiation, presence of bone/liver metastasis) in the first-line treatment of RM SCCHN.

Background Human telomerase reverse transcriptase (hTERT) is frequently classified as a ‘universal’ tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types. Methods A phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device 4 times across 12 weeks. Safety assessments and immune monitoring against native (germline, non-mutated, non-plasmid matched) hTERT antigen were performed. The largest cohort of patients enrolled had pancreatic cancer, allowing for additional targeted assessments for this tumor type. Results Of the 93 enrolled patients who received at least one dose, 88 had at least one adverse event; the majority were grade 1 or 2, related to injection site. At 18 months, 54.8% (51/93) patients were disease-free, with median disease-free survival (DFS) not reached by end of study. For patients with pancreatic cancer, the median DFS was 9 months, with 41.4% of these patients remaining disease-free at 18 months. hTERT immunotherapy induced a de novo cellular immune response or enhanced pre-existing cellular responses to native hTERT in 96% (88/92) of patients with various cancer types. Treatment with INO-1400/INO-1401±INO-9012 drove hTERT-specific IFN-γ production, generated hTERT-specific CD4+ and CD8+ T cells expressing the activation marker CD38, and induced hTERT-specific activated CD8 +CTLs as defined by cells expressing perforin and granzymes. The addition of plasmid IL-12 adjuvant elicited higher magnitudes of cellular responses including IFN-γ production, activated CD4+ and CD8+ T cells, and activated CD8+CTLs. In a subset analysis of pancreatic cancer patients, the presence of immunotherapy-induced activated CD8+ T cells expressing PD-1, granzymes and perforin correlated with survival. Conclusions Plasmid DNA-encoded hTERT/IL-12 DNA immunotherapy was well-tolerated, immune responses were noted across all tumor types, and a specific CD8+ phenotype increased by the immunotherapy was significantly correlated with survival in patients with pancreatic cancer.