PFS, OS Numerically Improve Via IMNN-001 Combo in Epithelial Ovarian Cancer

IMNN-001 is a novel, interleukin 12 (IL-2) gene therapy; it features a lipopolymer nanoparticle delivery system that encases an IL-12 DNA-based plasmid.

Results from the phase 1/2 OVATION-2 trial (NCT03393884) demonstrated numerical overall survival (OS) and progression-free survival (PFS) improvements among patients with newly diagnosed epithelial ovarian cancer who received perioperative IMNN-001 plus chemotherapy, according to a presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Findings showed that at a median follow-up of 24 months, patients in the intention-to-treat (ITT) population given IMNN-001 plus chemotherapy (n = 59) achieved a median PFS of 14.9 months (95% CI, 12.55-21.19) compared with 11.9 months (95% CI, 10.09-14.92) in patients treated with chemotherapy alone (n = 54; HR, 0.79; 95% CI, 0.51-1.23).

At 24 months of follow-up, the median OS was 40.5 months (95% CI, 28.09-not evaluable [NE]) in the IMNN-001 arm vs 29.4 months (95% CI, 24.94-45.60) in the chemotherapy arm (HR, 0.74; 95% CI, 0.42-1.30; P = .2963). With follow-up extended to 31 months, the median OS was 46.0 months (95% CI, 39.20-NE) and 33.0 months (95% CI, 27.14-NE), respectively (HR, 0.69; 95% CI, 0.40-1.19; P = .1865).

“There are limitations to [these] data in the sense that this was not a powered study for looking at statistical significance of survival. Hence, we [are conducting the] confirmatory phase 3 [OVATION-3] study [NCT06915025],” lead study author Premal Thaker, MD, MS, said in a presentation of the data.

Thaker is the David G. and Lynn Mutch Distinguished Professor of Obstetrics and Gynecology, director of Gynecological Oncology Clinical Research, and interim chief of the Division of Gynecologic Oncology at Washington University School of Medicine in St Louis, Missouri.

IMNN-001 and OVATION-2 Deep Dive

The use of immune checkpoint inhibitors in the first- or later-line treatment of patients with epithelial ovarian cancer has generated modest improvements in response rates, but OS improvements have been lacking, Thaker explained. Despite these outcomes, immunotherapy is still viewed as an intriguing approach for this patient population, she said.

IMNN-001 is a novel, IL-2 gene therapy; it features a lipopolymer nanoparticle delivery system that encases an IL-12 DNA-based plasmid.

OVATION-2 was a randomized, open-label, multicenter trial that enrolled patients 18 years or older with a suspected histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma that was FIGO stage III or IV.² Prior to recruitment for the randomized phase 2 portion, 15 patients received IMNN-001 in combination with chemotherapy as a safety lead-in.¹

In phase 2, patients were randomly assigned 1:1. In the experimental arm, patients received IMNN-001 at 100 mg/m² on days 8 and 15 of the first 21-day neoadjuvant cycle, then days 1, 8, and 15 of the next 2 neoadjuvant cycles, and on days 1, 8, and 15 of 3 adjuvant cycles; carboplatin at area under the curve 6 on day 1 of each neoadjuvant and adjuvant cycle; and paclitaxel at 175 mg/m² on day 1 of each neoadjuvant and adjuvant cycle. In the control arm, patients received the same perioperative chemotherapy regimen without IMNN-001.

Safety and PFS served as the trial’s primary end points. Secondary end points included OS, overall response rate (ORR), surgical response, chemotherapy response score, and serologic response rates.

The mean age in the ITT population was 64.2 years (SD, 10.6) in the IMNN-001 arm compared with 64.4 years (SD, 8.3) in the control arm. The mean body weights were 74.8 kg (SD, 20.3) and 76.8 kg (SD, 18.2), respectively. The respective body surface areas were 1.81 m² (SD, 0.27) and 1.84 m² (SD, 0.23).

The majority of patients had an ECOG performance status of 0 (IMNN-001, 51.7%; chemotherapy alone, 64.8%). The most common stage between the 2 cohorts was stage IIIC (56.9%; 55.6%). Notably, Thaker explained that the cohorts were generally well balanced, but a high proportion of patients in the IMNN-001 group had an ECOG performance status of 1 (43.1% vs 31.5% for chemotherapy), an ECOG performance status of 2 (5.2% vs 3.7%), and stage IV disease (31.0% vs 22.2%).

The majority of patients in both arms did not have BRCA mutations (IMNN-001, 70.7%; chemotherapy alone, 75.9%). Homologous recombination deficient mutations other than BRCA were not present in most patients in both groups (69.0%; 70.4%).

Further Efficacy and Safety Data

Additional findings showed that patients treated in the IMNN-001 arm experienced an ORR of 53.4%, which comprised a complete response (CR) rate of 1.7% and a partial response (PR) rate of 51.7%. The stable disease (SD) and progressive disease (PD) rates were 20.7% and 0%, respectively; 3.4% of patients were NE for response. Those treated with chemotherapy alone had an ORR of 57.4%. The respective CR, PR, SD, PD, and NE rates were 1.9%, 55.6%, 22.2%, 7.4%, and 1.9%.

The serologic response rates were 75.9% in the IMNN-001 arm and 79.6% in the chemotherapy-alone arm. Notably, 6.9% and 9.3% of patients, respectively, were NE for serologic response.

R0 resection was achieved by 64.6% of patients in the IMNN-001 cohort compared with 52.1% of those in the chemotherapy-alone arm. The respective rates of R1 resection were 10.4% and 29.2%. R2 resection occurred in 25.0% and 18.8% of patients, respectively.

CT response scores in the IMNN-001 arm included CRS3 (26.1%), CRS2 (39.1%), and CRS1 (34.8%). These respective rates were 13.0%, 52.2%, and 34.8% in the chemotherapy-alone arm.

In patients who received a PARP inhibitor as first-line maintenance prior to PD, patients in the IMNN-001 cohort (n = 13) experienced a median PFS of 33.8 months (95% CI, 14.95-NE) compared with 22.1 months (95% CI, 11.47-NE) in those given chemotherapy alone (n = 18; HR, 0.80; 95% CI, 0.31-2.12; P = .6604). In those not given a PARP inhibitor as maintenance, the median PFS was 13.3 months vs 10.2 months, respectively (HR, 0.63; not statistically significant).

In the PARP inhibitor–treated population, the median OS at 24 months of follow-up was NE (95% CI, 29.22-NE) for the IMNN-001 arm vs 37.1 months (95% CI, 26.61-NE) in the chemotherapy-alone arm (HR, 0.41; 95% CI, 0.13-1.26; P = .1230). At 31 months of follow-up, the median OS was NE (95% CI, 45.96-NE) and 37.1 months (95% CI, 27.14-NE), respectively (HR, 0.38; 95% CI, 0.13-1.06; P = .0647).

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients in the IMNN-001 arm vs 96.6% of patients in the chemotherapy-alone arm. The rates of serious TEAEs were 72.9% and 36.2%, respectively. TEAEs of special interest were reported at respective rates of 66.1% and 27.6%, which included abdominal pain (66.1% vs 27.6%). Cytokine release syndrome (CRS) was another TEAE of special interest; however, no instances of CRS occurred in either arm.

TEAEs led to dose reduction of IMNN-001 in 15.2% of patients, including abdominal pain (11.9%). TEAEs led to the discontinuation of the study drug in 23.7% of patients. TEAEs led to death in 1 patient in the IMNN-001 cohort (pancytopenia and respiratory failure) and 1 patient in the chemotherapy arm (upper gastrointestinal hemorrhage).

Serious TEAEs related to IMNN-001 or chemotherapy that occurred in more than 10% of patients included thrombocytopenia (any-grade, 15.3%; grade 3, 6.8%), nausea (11.9%; 8.5%, respectively), abdominal pain (13.6%; 13.6%), febrile neutropenia (11.9%; 11.9%), anemia (11.9%; 11.9%), vomiting (10.2%; 8.5%), and pyrexia (10.2%; 1.7%). Grade 4 thrombocytopenia that was classified as a serious TEAE related to IMNN-001 or chemotherapy was reported in 6.8% of patients.

References

1. Thaker P, Richardson D, Hagemann A, et al. A phase I/II study of the safety and efficacy of intraperitoneal IMNN-001 in combination with neoadjuvant chemotherapy (NACT) of paclitaxel and carboplatin in patients newly diagnosed with advanced epithelial ovarian cancer (EOC): updated survival analysis from OVATION-2 trial. J Clin Oncol. 2025;43(suppl 16):5516. doi:10.1200/JCO.2025.43.16_suppl.5516
2. Study of IMNN-001 (also known as GEN-1) with NACT for treatment of ovarian cancer (OVATION 2). ClinicalTrials.gov. Updated May 4, 2025. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT03393884