Table 1 Clinical trials of antiangiogenic agents in maintenance therapy in EOC (frontline settings)

GOG-0218 [40, 41]

Double-blind, placebo-controlled (n = 1873)

Newly diagnosed stage III or IV EOC with gross residual disease after maximal debulking effort

Arm 1: Carboplatin AUC 6, paclitaxel 175 mg/m² q3 weeks for six cycles + placebo q3 weeks cycles 2–22

Arm 2: Carboplatin AUC 6, paclitaxel 175 mg/m² q3 weeks for six cycles + Bevacizumab 15 mg/kg q3 weeks cycles 2–6 and placebo q3 weeks cycles 7–22

Arm 3: Carboplatin AUC 6, paclitaxel 175 mg/m² q3 weeks for six cycles + Bevacizumab 15 mg/kg q3 weeks cycles 2–22

mPFS:

Arm 1: 10.3

Arm 2: 11.2 (HR: 0.91, 0.80–1.04, p = 0.16)

Arm 3: 14.1 (HR: 0.72, 0.63–0.82, p < 0.001)

mOS:

Arm 1: 41.1

Arm 2: 40.8 (HR: 1.06, 0.94–1.20, p = 0.34)

Arm 3: 43.4 (HR: 0.96, 0.85–1.09, p = 0.53)

Exploratory subset analyses:

Stage III disease:

Arm1: 44.2

Arm 2: 42.9 (HR: 1.08, 0.93–1.25)

Arm 3: 44.3 (HR: 1.05, 0.92–1.20, p = 0.49)

Stage IV disease:

Arm1: 32.6

Arm2: 34.5 (HR: 0.99, 0.78–1.26)

Arm 3: 42.8 (HR: 0.75, 0.59–0.95)

The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the PFS by about 4 months.

In ITT population, no survival differences were found between patients receiving bevacizumab compared to chemotherapy alone. Patients with FIGO stage IV disease may derive a survival advantage from bevacizumab when administered with and following frontline chemotherapy.

ICON7 [21, 42]

Open-label study (n = 1528)

Newly diagnosed stage I–IIA grade 3 EOC, any stage with clear cell histology and stage III or IV EOC all after maximal debulking effort

Arm 1: Carboplatin AUC 5 or 6, paclitaxel 175 mg/m² q3 weeks for six cycles + placebo q3 weeks cycles 1 or 2 through cycle 18

Arm 2: Carboplatin AUC 5 or 6, paclitaxel 175 mg/m² q3 weeks for six cycles + Bevacizumab 7.5 mg/kg q3 weeks cycles 1 or 2 through cycle 18

mPFS:

Total cohort

Arm 1: 17.5

Arm 2: 19.9 (HR: 0.93, 0. 83–1.05, p < 0.001)

High-risk progression^a

Arm 1: 10.5

Arm 2: 16.0 (HR: 0.73, 0.60–0.93, p < 0.001)

mOS:

Total cohort

Arm 1: 58.6

Arm 2: 58.0 (HR: 0.99, 0.85–1.14, p = 0.02)

High-risk progression^a

Arm 1: 30.2

Arm 2: 39.7 (HR: 0.78, 0.63–0.97, p = 0.01)

Bevacizumab improved PFS in women with OC. The benefits with respect to both PFS and OS were greater among those at high-risk for disease progression.

ROSiA [43]

Single-arm study (n = 1021)

Stage IIB to IV or grade 3 stage I to IIA OC without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within the preceding 6 months

Bevacizumab (15/7.5 mg/kg) q3w, 4–8 cycles of paclitaxel (investigator’s choice of 175 mg/m² q3w or 80 mg/m² weekly) plus carboplatin AUC 5– 6 q3w

mPFS:

25.5 (23.7–27.6)

In high-risk disease:

18.3 (16.8–20.6)

In non-high-risk disease:

32 (30.9–40.2)

mOS:

The 2-year OS rate was 85% (83–87%)

The median PFS of 25.5 months is the longest reported to date. OS results are immature with events in only 23% of patients.

Extended bevacizumab-containing therapy is both tolerable and feasible.

Herzog et al. study [45]

Randomised, double-blind, placebo-controlled, phase IIB study

Women with advanced stage EOC or primary peritoneal cancer who achieved clinical complete response after tumour debulking and one regimen of standardized platinum/taxane-containing therapy

Arm 1: Sorafenib 400 mg or BID)

Arm 2: Placebo

mPFS:

Arm 1:12.7 (HR: 1.09, 0.72 –1.63)

Arm 2: 15.7

No significant difference between sorafenib and placebo arms for PFS.

AGO-OVAR16 [46, 47]

Randomised, double-blind, placebo-controlled, phase III trial (n = 940)

Histologically confirmed OC stages II-IV who have not progressed after first-line chemotherapy

Arm 1: Pazopanib (800 mg once daily)

Arm 2: Placebo

mPFS:

Arm 1:17.9 (HR: 0.77, 0.64 –0.91, p = 0.0021)

Arm 2: 12.3

mOS:

Arm 1: 59.1 (HR: 0.96, 0.805 –1.145, p = 0.6431)

Arm 2: 64.0

Pazopanib maintenance therapy prolonged PFS; however, no difference in OS was observed between pazopanib and placebo. At the time of the final OS analyses, 494 (89.7% of the planned 551) events had occurred.

AGO-OVAR12 [48]

Double-blind placebo-controlled randomised phase III trial (n = 1366)

Histologically confirmed OC (stage IIB–IV) who had undergone initial debulking surgery

Arm 1: Carboplatin (AUC 5 or 6) plus paclitaxel (175 mg/m²) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg

Arm 2: Placebo BID on days 2–21 every 3 weeks for up to 120 weeks

mPFS:

Arm 1:17.6

Arm 2: 16.6 (HR: 0.86, 0.75–0.98, p = 0.029)

mOS:

Arm 1: 62

Arm 2: 62.8 (HR: 0.99, 0.83–1.17, p = 0.86)

PFS improvement seen with nintedanib combination therapy did not affect OS compared with placebo.

TRINOVA-3 [49]

Double-blind study phase III, (n = 1015)

Biopsy confirmed OC (stages III-IV)

Arm 1: six cycles of paclitaxel (175 mg/m²) and carboplatin (AUC 5 or 6) q3 weeks, plus weekly intravenous trebananib 15 mg/kg

Arm 2: 6 cycles of paclitaxel (175 mg/m²) and carboplatin (AUC 5 or 6) q3 weeks, plus weekly placebo

mPFS:

Arm 1: 15·9

Arm 2: 15·0 (HR: 0·93, 0·79–1·09, p = 0·36)

Trebananib plus carboplatin and paclitaxel as first-line treatment did not improve PFS in advanced OC.