abstract
Standard first-line chemotherapy with or
without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a
randomised, double-blind, placebo-controlled phase 3 trial
Background
Angiogenesis is a target in
the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase
inhibitor of VEGF receptor, platelet-derived growth factor receptor, and
fibroblast growth factor receptor, has shown activity in phase 2 trials
in this setting. We investigated the combination of
nintedanib with
standard carboplatin and paclitaxel chemotherapy in patients with newly
diagnosed advanced ovarian cancer.
Methods
In
this double-blind
phase 3 trial, chemotherapy-naive patients (aged 18
years or older) with International Federation of Gynecology and
Obstetrics (FIGO) IIB–IV ovarian cancer and upfront debulking surgery
were stratified by postoperative resection status, FIGO stage, and
planned carboplatin dose. Patients were randomly assigned (2:1) via an
interactive voice or web-based response system to receive six cycles of
carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175
mg/m
2) in addition to either 200 mg of nintedanib
(nintedanib group) or placebo (placebo group) twice daily on days 2–21
of every 3-week cycle for
up to 120 weeks. Patients, investigators, and
independent radiological reviewers were masked to treatment allocation.
The primary endpoint was investigator-assessed progression-free survival
analysed in the intention-to-treat population. This trial is registered
with
ClinicalTrials.gov, number
NCT01015118.
Findings
Between
Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366
randomly assigned by nine study groups in 22 countries: 911 to the
nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients
in the nintedanib group experienced disease progression or death
compared with 266 (58%) of 455 in the placebo group. Median
progression-free survival was significantly longer in the nintedanib
group than in the placebo group (
17·2 months [95% CI 16·6–19·9]
vs
16·6 months [13·9–19·1]; hazard ratio 0·84 [95% CI 0·72–0·98];
p=0·024). The most common adverse events were gastrointestinal
(diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%]
grade 4 vs placebo group nine [2%] of 450 grade 3 only) and
haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200
(22%)
grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%]
grade 4; thrombocytopenia: 105 [12%] and 55 [6%]
vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%]
vs
26 [6%] and five [1%]).
Serious adverse events were reported in 376
(42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in
the placebo group. 29 (3%) of 902 patients in the nintedanib group
experienced serious adverse events associated with death compared with
16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib
group and six (1%) in the placebo group with a
malignant neoplasm
progression classified as an adverse event by the investigator.
Drug-related adverse events leading to death occurred in three patients
in the nintedanib group (one without diagnosis of cause; one due to
non-drug-related sepsis associated with drug-related diarrhoea and renal
failure; and one due to peritonitis) and in one patient in the placebo
group (cause unknown).
Interpretation
Nintedanib
in combination with carboplatin and paclitaxel is an active first-line
treatment that significantly increases progression-free survival for
women with advanced ovarian cancer, but is associated with more
gastrointestinal adverse events. Future studies should focus on
improving patient selection and optimisation of tolerability.
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