VGX-3100 Elicits Regression and Clearance in HPV-16/18–Associated Cervical HSILs

The investigational DNA immunotherapy VGX-3100 significantly improved rates of histologic regression with concurrent human papillomavirus (HPV)–16/18 clearance compared with placebo in patients with HPV-16/18–associated cervical high-grade squamous intraepithelial lesions (HSILs), according to findings from the phase 3 HPV-303CHN trial (ChiCTR2300071848) presented at the 2026 SITC Annual Meeting.¹

Data demonstrated that at week 36, 52.5% of patients in the VGX-3100 arm (n = 139) achieved the composite primary end point of histologic regression with HPV-16/18 clearance vs 35.3% of those in the placebo arm (n = 68), translating to a between-group difference of 17.2% (95% CI, 2.7%-30.6%; P = .025). The secondary virologic end point of HPV-16/18 DNA negativity was met by 55.4% vs 38.2% of patients, respectively (difference, 17.2%; 95% CI, 2.6%-30.8%).

Safety findings also showed agent was well tolerated, with no serious adverse effects (AEs) attributed to treatment.

"We believe that these findings support the opportunity for VGX-3100 as an extremely promising nonsurgical immunotherapy option, which avoids the requirement to remove tissue and/or to delay or prevent surgical excision entirely in eligible women with HPV-16/18–associated cervical HSILs," presenting author Jeffrey Skolnik, MD, senior vice president of clinical development at Inovio Pharmaceuticals, said in the presentation.

How was HPV-303CHN designed?

Cervical HSILs arise from persistent HPV-16/18 infection, and surgical excision, the current standard approach, removes the lesion without addressing the underlying virus and has been associated with adverse obstetric outcomes.

VGX-3100 is a DNA immunotherapy targeting the E6 and E7 oncoproteins of HPV-16 and HPV-18. It is intended to elicit T-cell responses specific to these antigens, with the aim of clearing the virus and resolving the lesion.

The randomized, double-blind, placebo-controlled trial enrolled patients at 22 sites in China between November 30, 2021, and June 5, 2025. The trial included patients 18 years of age or older with cervical HSIL graded on histology as cervical intraepithelial neoplasia grade 2 (CIN2) or grade 3 (CIN3). Patients also needed to HPV-16 and/or HPV-18. An adequate colposcopic examination needed to show that a lesion could be biopsied.

Patients were randomly assigned 2:1 to receive VGX-3100 at 6 mg or placebo on day 1, week 4, and week 12 via intramuscular injection followed by electroporation with the CELLECTRA 5PSP device. Randomization was stratified by CIN grade (CIN2 vs CIN3), body-mass index (≤25 vs >25 kg/m²), and age (<25 vs ≥25 years).

The modified intention-to-treat (mITT) population comprised randomly assigned patients who completed all 3 doses and underwent at least 1 efficacy assessment after treatment. Patients who had an unscheduled biopsy or another therapeutic intervention before week 36, or whose data were missing at that point, were counted as nonresponders. Follow-up is continuing through week 88.

The mean age was 31.7 years (± 6.0) in the VGX-3100 arm vs 33.1 years (± 6.2) in the placebo arm, and 55.4% vs 57.4% of patients, respectively, had CIN3 at baseline. Most patients were HPV-16 positive (94.2% vs 95.6%); 7.2% vs 4.4% were HPV-18 positive, and 14.4% vs 19.1% were also positive for another high-risk HPV type. Prior HPV vaccination was reported in 28.1% vs 27.9% of patients.

What did additional efficacy analyses show?

At week 36, an independent pathology committee classified histology as normal in 70 patients in the VGX-3100 arm vs 26 patients in the placebo arm. CIN1 was observed in 17 vs 9 patients, CIN2 in 20 vs 11 patients, and CIN3 in 20 vs 16 patients, respectively; histology data were missing for 11 and 6 patients, respectively.

The direction of benefit favored VGX-3100 across all prespecified subgroups. Among patients with baseline CIN2, the primary end point was met by 61.3% of the VGX-3100 arm (n = 62) vs 41.4% of the placebo arm (n = 29; difference, 19.9%; 95% CI, –2.1% to 40.1%); in those with baseline CIN3, the rates were 45.5% of the VGX-3100 arm (n = 77) vs 30.8% of the placebo arm (n = 39; difference, 14.7%; 95% CI, –4.4% to 31.7%). In patients younger than 25 years, the rates were 57.1% in the VGX-3100 arm (n = 14) vs 16.7% in the placebo arm (n = 6); in those 25 years or older, the rates were 52.0% (n = 125) vs 37.1% (n = 62), respectively. In patients with a body-mass index of 25 kg/m² or less, the rates were 53.0% of the VGX-3100 arm (n = 117) vs 39.7% of the placebo arm (n = 58); in those with a body-mass index above 25 kg/m², the rates were 50.0% (n = 22) vs 10.0% (n = 10; difference, 40.0%; 95% CI, 3.6% to 63.3%), respectively.

Which immune responses were linked with clinical response?

Compared with placebo, VGX-3100 generated stronger antibody and T-cell responses against HPV at weeks 15 and 36, including higher HPV-16 and HPV-18 E7 antibody titers and greater HPV-16/18 E6/E7–specific interferon-γ ELISpot activity.

Among VGX-3100–treated patients with baseline CIN3 (n = 72), 60.0% of responders (n = 35) showed an increase in HPV-16 E7–specific ELISpot responses from baseline to week 15 vs 32.4% of nonresponders (n = 37). Responders in this group also had greater increases in CD8-positive CD69-positive, CD8-positive CD137-positive, and CD8-positive PD-1–positive T-cell subsets; no such pattern emerged among patients with CIN2 or those given placebo.

In an exploratory analysis, week 15 HPV-16 E7 spot-forming units discriminated responders from nonresponders with an area under the curve (AUC) of 0.715 (95% CI, 0.598-0.831). The AUCs for the combined model and the CD69-positive, CD137-positive, and PD-1–positive subsets were 0.680, 0.667, 0.666, and 0.664, respectively. No correction for multiple comparisons was applied to these analyses.

What did the safety analysis show?

In the safety population, any-grade AEs occurred in 94.2% of patients in the VGX-3100 arm (n = 139) vs 94.1% of those in the placebo arm (n = 68). Treatment-related AEs (TRAEs) occurred in 84.2% vs 85.3% of patients, respectively; drug-related AEs occurred in 30.9% vs 48.5%, and device-related AEs occurred in 84.2% vs 85.3%. Most AEs reflected local reactions at the injection site and were generally grade 1 or 2 and transient, Skolnik noted.

Serious AEs occurred in 3.6% vs 2.9% of patients, and none were treatment related. Grade 3 or higher AEs occurred in 6.5% vs 8.8% of patients; no grade 3 or higher TRAEs were reported in the VGX-3100 arm vs 1 (1.5%) in the placebo arm. No AEs of special interest or grade 5 AEs occurred in either arm.

Invasive squamous cell carcinoma identified at week 36 led 1 patient (0.7%) in the VGX-3100 arm to withdraw from the study; investigators judged it unrelated to study treatment.

What is next for VGX-3100?

Patients in HPV-303CHN are continuing follow-up through week 88 to further characterize safety and tolerability.

The data follow the October 30, 2026, FDA accelerated approval of doruxapapogene ralaplasmid and lalikinogene sifuplasmid-gxfd (Voceryq; formerly INO-3107), a DNA immunotherapy from Inovio delivered using the same platform technology, to lessen how often adults with recurrent respiratory papillomatosis require surgical removal of papillomas.²

References

1. Lyu N, Wang W, Zhao J, et al. VGX-3100 DNA immunotherapy for HPV-16/18–associated cervical high-grade squamous intraepithelial lesions: a randomized, double-blind, placebo-controlled phase III trial (HPV-303CHN). Paper presented at: 2026 Society for Immunotherapy of Cancer Annual Meeting; November 4-8, 2026; Phoenix, AZ. Abstract 1184
2. INOVIO announces FDA accelerated approval of VOCERYQ, an immunotherapy to reduce the frequency of surgery in adults with recurrent respiratory papillomatosis (RRP). News release. Inovio Pharmaceuticals. October 30, 2026. Accessed November 6, 2026. https://ir.inovio.com/news/news-details/2026/INOVIO-Announces-FDA-Accelerated-Approval-of-VOCERYQ-an-Immunotherapy-to-Reduce-the-Frequency-of-Surgery-in-Adults-with-Recurrent-Respiratory-Papillomatosis-RRP/default.aspx