PRGN-2009 and bintrafusp alfa for patients with advanced or metastatic human papillomavirus-associated cancer

Abstract

Background: This first-in-human phase 1 study (NCT04432597) evaluated the safety and recommended phase 2 dose (RP2D) of PRGN-2009, a gorilla adenoviral-vector targeting oncoproteins E6, E7 (human papillomavirus (HPV)16/18) and E5 (HPV16), as monotherapy (Arm 1A) and combined with the bifunctional TGF-β "trap"/anti-PD-L1 fusion protein bintrafusp alfa (BA; Arm 1B), in patients with recurrent/metastatic HPV-associated cancer.

Methods: Patients with ≥ 1 prior treatment (immunotherapy allowed) received PRGN-2009 (1 × 10¹¹ particle units or 5 × 10¹¹ particle units, subcutaneously) every 2 weeks for 3 doses, then every 4 weeks (Arm 1A), or PRGN-2009 (RP2D, schedule per Arm 1A) and BA (1200 mg, intravenously) every 2 weeks (Arm 1B). Primary endpoints were safety and RP2D of PRGN-2009; secondary objectives included overall response rate (ORR) and overall survival (OS).

Results: Seventeen patients were treated. In Arm 1A (n = 6) there were no dose limiting toxicities or grade 3/4 treatment-related adverse events (TRAEs), 5 × 10¹¹ PU was selected as RP2D, no responses were observed, and median OS (mOS) was 7.4 months (95% CI 2.9-26.8). In Arm 1B (n = 11), grade 3/4 TRAEs occurred in 27% of patients, ORR was 20% for all patients (22% in checkpoint-resistant patients), and mOS was 24.6 months (95% CI 9.6-not reached). Multifunctional HPV-specific T cells were increased or induced de novo in 80% of patients and not impacted by anti-vector antibodies. Higher serum IL-8 at baseline associated with shorter OS.

Conclusions: PRGN-2009 was well tolerated, and immune responses were observed to PRGN-2009. Encouraging anti-tumor activity and OS were noted in the combination with BA arm, consisting mainly of checkpoint-resistant patients. Trial Registration ClinicalTrials.gov Identifier: NCT04432597.

Keywords: Cervical cancer; Gene therapy; HPV; Immune checkpoint blockade; Oropharyngeal cancer; TGF-beta inhibition.

Fig. 1

Tumor response and patient survival. A Waterfall plot demonstrating best percentage of change in target lesions from baseline among individual patients, across arms. The horizontal dotted lines represent 20% tumor growth and 30% tumor shrinkage. B Swimmer plots demonstrating the duration of treatment, for individual patients, across arms (one PR confirmed in Arm 1B). C Progression free survival (PFS) in Arm 1B. D Overall survival (OS) in Arm 1B; marks on the curve indicate patients who were censored. CR, complete response; PR, partial response, SD, stable disease; PD, progressive disease

Fig. 2

Augmentation and induction of HPV16 and HPV18-specific T cells in patients with or without detectable pre-existing responses. A Augmentation of HPV-specific T cell responses in two representative patients where pre-existing responses were detected. Development of HPV-specific T cell responses in patients where no such pre-existing responses were detected for B HPV16 and C HPV18. The timepoint (in days) evaluated for each patient is indicated along the x-axis, and the CD4 + or CD8 + phenotype readout is indicated in the legend. D Development of low levels of neutralizing antibodies does not abrogate development of HPV16 or HPV18 T cell responses. Absolute number of T cells producing cytokines and/or positive for CD107a in response to HPV16 or HPV18 peptide stimulation versus vector-neutralizing antibody titer in a patient from Arm 1A and Arm 1B. CD4 + or CD8 + phenotype readout is indicated in the legend

Fig. 3

Increase in activated memory T cells and mature NK cells as early as 2 weeks after first PRGN-2009 dose and BA in patient achieving CR. A Percent change in total CD8 + T cell frequencies at 2 weeks (D15) compared to baseline. Dotted lines indicate + 25% and − 25% change. B Heat map of percent changes at D15 compared to baseline of refined CD8 + T cell subsets based on maturation and activation markers. C Percent change in total NK cell frequencies at 2 weeks (D15) compared to baseline. D Heat map of percent changes at D15 compared to baseline of refined NK cell subsets based on maturation and activation markers. Binned percent change is indicated in legend. Patients are color-coded by best overall response (BOR) (CR, red; PR, orange; SD, purple; progressive disease (PD), black; including the unconfirmed PR with PR)

Fig. 4

Lower serum concentrations of IL-8 prior to start of treatment correlate with prolonged survival. A Heat map of percent changes in serum analytes at day 15 compared to baseline in patients from Arms 1A and 1B. Patients within each arm are ordered from lowest to highest pre-therapy IL-8 serum concentration. Binned percent change is indicated in legend. Patients are color-coded by BOR: CR, red; PR, orange; SD, purple; PD, black; including the unconfirmed PR with PR. Kaplan–Meier survival curves by Mantel-Cox log-rank tests for B PFS and C OS for all patients treated on study, including Arms 1A and 1B together, stratified by baseline levels of serum IL-8. The cutoff was set at 23.0 pg/ml