Enadenotucirev/Paclitaxel Combo Shows Promising Preliminary Survival in Platinum-Resistant Ovarian Cancer

Victor Moreno, MD, PhD

Enadenotucirev, a tumor selective adenovirus, in combination with paclitaxel has demonstrated encouraging progression-free survival (PFS) and manageable safety rates in patients with platinum-resistant ovarian cancer, according to results from a phase 1 study (OCTAVE; NCT02028117) published in the Journal for ImmunoTherapy of Cancer.¹

“The results of this study indicate that enadenotucirev can be administered intravenously [IV], but not IP [intraperitoneal], in combination with paclitaxel with manageable tolerability and no DLTs [doselimiting toxicities] in patients with heavily pretreated ovarian cancer,” the study authors, led by Victor Moreno, MD, PhD, wrote in the report. “The safety information gathered in this study, taken together with the increased immune-cell infiltration, encouraging PFS, and signs of durable responses, suggests that further exploration of tumor-selective viruses in ovarian cancer is warranted.”

Enadenotucirev is a group B Ad11p/Ad3 chimeric adenoviral vector immunotherapy with the ability to selectively replicate in epithelial tumor cells for specific killing of malignant cells.

In a prior mechanism of action phase 1 trial (NCT02053220), enadenotucirev demonstrated feasibility for IV and intratumoral dosing of the adenovirus in patients with colorectal cancer, non–small cell lung cancer, urothelial cell cancer, and renal cell carcinoma undergoing primary resection.2 Both methods of delivery were found to be well tolerated, and no severe treatment-associated adverse events were reported.

“The significant unmet need in platinum-resistant ovarian cancer and the potential to assess pharmacodynamic activity in peritoneal biopsies made ovarian cancer an attractive target for assessing a novel tumor-selective virus,” Moreno et al wrote.

The multicenter, open-label phase 1 OCTAVE study consisted of a phase 1a portion for dose escalation with a standard 3 + 3 design, in which patients received two 4-week cycles of enadenotucirev administered intraperitoneally. The virus was administered on days 1, 8, and 15 of each cycle at a starting dose of 1 × 10¹² viral particles up to the highest planned dose of 1×10¹³ viral particles. However, due to DLTs observed in a separate study at this dose, 1 × 10¹³ was not tested in this study. The phase 1b portion then sought to find the dose in combination with IV paclitaxel with cohorts for both IP and IV dosing of enadenotucirev. In the IV cohort, the virus was administered on days 1, 3, and 5 of each cycle and paclitaxel was given at a fixed dose of 80 mg/m² on days 9, 16, and 23 of each cycle.¹

The primary end point of phase 1a was the maximum tolerated dose of enadenotucirev and the combination for phase 1b. In phase 1b, the primary end point was PFS. Secondary end points included safety and tolerability, overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and immune response to enadenotucirev.

Patients were eligible to enroll if they had nonresectable epithelial ovarian, fallopian tube, or primary peritoneal cancer and platinum-resistant disease. Those with no other treatment options were allowed into phase 1a regardless of platinum sensitivity.

An ECOG performance status of 0 or 1 and adequate renal, hepatic, bone marrow, and coagulation function were also required. A history of significant immunodeficiency or renal or autoimmune disease was cause for exclusion from the trial.

Cohorts and Results Among 63 patients screened in the United Kingdom and Spain, a total of 38 patients were treated. Overall, the median age was 63 (range, 36-77) and serous adenocarcinoma was the most common histology (71%). Patients had a median of 41.8 months (range, 7.2-278.7) since receiving a diagnosis during which time they had received a median of 5 prior regimens (range, 1-12). Ninety-two percent had undergone prior surgery for their cancer, all patients had received prior paclitaxel, and 55% had received prior monoclonal antibodies, including most commonly bevacizumab (Avastin).

Seven patients were treated in cohort A1 of the dose-escalation portion of the study with the 1×1012 dose of IP enadenotucirev. Three patients were treated at a dose level of 6 × 1012 IP enadenotucirev (cohort A2). No DLTs were observed in either of these cohorts.

In the planned B1 cohort of IP enadenotucirev plus paclitaxel, a higher level of catheter complications was reported and this arm (n = 8) was discontinued. Investigation then shifted to the combination given via IV for further cohorts (n = 20).

In the IV cohorts, the median PFS was 6.2 months (95% CI, 2.8-11.1) by independent assessment per RECIST criteria (TABLE1 ). The PFS rate was 63.8% at 4 months and 54.7% at 6 months. For the 10 patients treated in cohorts A1 and A2 with enadenotucirev monotherapy, the median PFS was 1.7 months (95% CI, 1.2-3.5), and the PFS rates were 11.1% and 0% at 4 and 6 months, respectively. For the 8 patients in the discontinued B1 cohort, the median PFS was 6.4 months (95% CI, 1.3-6.4), and the PFS rates were 66.7% at both 4 and 6 months.

As of an extended data cutoff of January 11, 2021, the median OS for the IV combination cohorts was 14.1 months (95% CI, 6.8-not available). For the monotherapy cohorts, the median OS was 8.0 months and was 6.4 months for the enadenotucirev IP plus paclitaxel cohort.

Per independent assessment, the ORR was 10% (95% CI, 1%-32%) in the IV cohorts, and no responses were observed in any of the other cohorts. Stable disease was observed in 35% of patients in the IV cohorts along with 25% of the enadenotucirev IP plus paclitaxel cohort, resulting in a CBR of 45% (95% CI, 23%-69%) in the IV combination cohorts and 25% (95% CI, 3%-65%) in the IP combination cohort.

These survival rates were considered in line with prior reports for weekly paclitaxel alone in similar populations, but the response rates were considered lower.

The DOR was unable to be assessed but stable reductions in target lesion burden were maintained for up to 60 weeks for 1 patient.

Treatment-emergent adverse events (TEAEs) were observed in all patients, 63% had an event of grade 3 or higher in severity, and 29% of patients had events that were considered to be related to treatment with the virus, including most commonly neutropenia and anemia. Serious TEAEs were reported in 32%, with abdominal pain being most common. All 5 serious TEAEs related to treatment, most often in IP cohorts, resolved.

Of any grade, gastrointestinal, general disorders and administration site concerns, blood/lymphatic system disorders, and infections or infestations were the most common types of TEAEs. General disorders were not commonly grade 3 or higher.

Two patients died after experiencing TEAEs, including 1 with general health deterioration that may have been related to treatment. No evidence of virus-related hepatic or renal injury was reported.

Immune response was assessed in 6 patients with matching pre- and posttreatment biopsies who were treated with IV enadenotucirev and paclitaxel. After treatment, increased intratumoral infiltration of CD8-positive T cells was observed and an increased proportion of granzyme B positive cells; however, no association was found between these observations and survival or response due to the limited number of samples. Yet, a reduction in tumor burden was reported in the patient with the greatest increase in T-cell infiltration.

“The use of next-generation viral vectors encoding and delivering immune-activating therapies within the tumor microenvironment may improve the efficacy of adenovirusbased therapy and also help to further ameliorate highly immunosuppressive tumor microenvironments to improve the activity of immune-checkpoint inhibitors in a number of cancers, including ovarian cancer,” the authors concluded.

_REFERENCES

_{1. Moreno V, Barretina-Ginesta MP, García-Donas J, et al. Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial. J Immunother Cancer. 2021;9(12):e003645. doi:10.1136/ jitc-2021-003645}

_{2. Garcia-Carbonero R, Salazar R, Duran I, et al. Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection. J Immunother Cancer. 2017;5(1):71. doi:10.1186/s40425-017-0277-7}