Ofranergene Obadenovec Plus Paclitaxel Misses the Mark in Platinum-Resistant Ovarian Cancer

The addition of ofranergene obadenovec (ofra-vec; VB-111) to paclitaxel failed to significantly improve survival outcomes compared with paclitaxel alone in patients with platinum-resistant ovarian cancer, according to data from the phase 3 OVAL trial (GOG 3018; NCT03398655) presented at the 2023 ASCO Annual Meeting.¹

The median progression-free survival (PFS) with ofra-vec plus paclitaxel (n = 204) was 5.29 months vs 5.36 months with paclitaxel alone (n = 205; HR, 1.0320; 95% CI, 0.8252-1.2908; P = .7823). Additionally, the median overall survival (OS) was 13.37 months in the investigative arm and 13.14 months in the control arm (HR, 0.9738; 95% CI, 0.7475-1.2687; P = .8440).

“The addition of ofra-vec to paclitaxel did not improve PFS or OS, which was unexpected in view of the phase 1/2 experience, and the interim analysis of CA-125 response,” lead study author Rebecca C. Arend, MD, MSPH, of the University of Alabama at Birmingham School of Medicine, said in a presentation of the data. “Future studies in the platinum-resistant setting should include agents that exploit the potential synergy of targeting angiogenesis and vascular integrity in cancer.”

Ofra-vec is a nonreplicating adenoviral vector with a murine PPE-1-3X promoter and pro-apoptotic TNFR1 chimeric transgene that is hypothesized to have a dual mechanism of action of vascular disruption and immune activation.

Study participants were randomly assigned 1:1 to receive placebo every 8 weeks plus paclitaxel at 80 mg/m² once weekly (n = 200) or ofra-vec at 1 x 10¹³ viral particles every 8 weeks plus paclitaxel at the same dose once weekly (n = 200). Treatment continued until disease progression.

The co-primary end points of OVAL were PFS and OS by blinded independent central review. PFS was first tested at 0.015 significance level and OS was tested at a significance level of 0.05 if the PFS reached significance, and at a level of 0.035 if otherwise. The overall significance level for the trial was 0.05, and a 90% power was leveraged to detect hazard ratio for PFS and OS.

Secondary end points comprised objective response rate (ORR) by CA-125 and RECIST v1.1 criteria combined and individually, as well as OS₁₀₀. Translational scientific objectives comprised histopathology, expression, and biomarkers.

A total of 537 patients underwent screening and 409 patients were randomized; 204 were assigned to the investigative arm and 205 were assigned to the control arm. Ultimately, 203 patients were treated with ofra-vec plus paclitaxel and 202 were treated with placebo plus paclitaxel.

In the investigative arm, 185 patients discontinued treatment; the most common reason for this was progressive disease (PD) by RECIST criteria (n = 136), followed by PD not by RECIST criteria (n = 20), safety (n = 8), patient request (n = 8), investigator decision (n = 7), WOC (n = 3), and death (n = 3). Eighteen patients were still receiving treatment at the time of data cutoff.

Across the arms, the median age was 61.6 years; 78.8% of patients were White and 92% were not Hispanic or Latino. In the investigative arm, 77.5% of patients had epithelial ovarian cancer, 12.3% had primary peritoneal disease, and 10.3% had fallopian tube disease; in the control arm, these rates were 72.7%, 13.7%, and 13.7%, respectively. Of those who received ofra-vec plus paclitaxel, 61.8%, 38.2%, and 0% had an ECOG performance status of 0, 1, or 2, respectively; these rates were 62%, 36.6%, and 1.5%, respectively, for those who received paclitaxel alone.

More than half the patients across the ofra-vec/paclitaxel (58.8%) and placebo/paclitaxel (67.8%) arms had stage III disease. Most patients had grade 3 disease (92.2%; 90.2%) and serous adenocarcinoma (89.2%; 94.6%). Additionally, 20.1% of those in the investigative arm and 17.6% of those in the control arm had BRCA-positive disease.

The mean number of prior therapies received in both arms was 3. In the investigative arm, 7.4% of patients had 1 prior line, 30.9% had 2 lines, 32.4% had 3 lines, 17.6% had 4 lines, 10.8% had 5 lines, and 1.0% had 6 or more lines; in the control arm, these rates were 8.8%, 29.3%, 20.5%, 11.7%, and 0.5%, respectively. More than half of patients in the investigative and control arms were previously exposed to PARP inhibitors (62.7%; 66.3%) and antiangiogenics (70.1%; 69.3%). Additionally, 79.9% of patients in the ofra-vec arm were evaluable for CA-125 response, as were 75.1% of those in the placebo arm.

Regarding safety, adverse effects (AEs) were experienced by 98.5% of those in the investigative arm and 99.5% of those in the placebo arm; 90.1% and 75.9% of patients, respectively, had AEs related to ofra-vec or placebo, and 93.1% of patients in both arms had AEs related to paclitaxel. Grade 3 or higher toxicities were observed in 60.6% and 53.7% of patients, respectively; these effects were related to ofra-vec or placebo in 25.6% and 14.8% of patients, respectively.

Additionally, 31% of those in the ofra-vec arm experienced serious AEs vs 26.6% of those in the placebo arm; these effects were related to ofra-vec or placebo in 5.9% and 3.0% of patients, respectively, and related to paclitaxel in 7.9% and 5.9% of patients, respectively.

In the investigative arm, AEs resulted in dose interruption or discontinuation of ofra-vec for 16.7% and 3.9% of patients, respectively. In this arm, dosing of paclitaxel was interrupted for 62.6% of patients, reduced for 27.1% of patients, and discontinued for 6.9% of patients—all due to AEs. Three patients experienced serious AEs that resulted in ofra-cel discontinuation. Three patients had fatal AEs but none were determined to be related to the study drug.

In the placebo arm, 6.9% and 14.8% of patients, respectively, needed dose interruptions or discontinuation due to toxicity. In this group, dosing of paclitaxel was interrupted, reduced, or discontinued in 47.3%, 25.1%, and 9.9% of patients, respectively. Serious toxicities resulting in discontinuation of placebo or paclitaxel occurred in 3.4% and 3.0% of patients, respectively. Four patients experienced a fatal AE, but none were determined to be related to placebo.

“The AE pattern was as expected for an adenovirus-based viral therapy and reflected the product’s established safety profile,” Arend concluded.

Reference

Arend RC, Monk BJ, Shapira-Frommer R, et al. Randomized controlled phase III trial of weekly paclitaxel ± ofranergene obadenovec (VB-111) for platinum-resistant ovarian cancer (OVAL study/GOG 3018). J Clin Oncol. 2023;41(suppl 16):5505. doi:10.1200/JCO.2023.41.16_suppl.5505