In a phase III trial reported in the Journal of Clinical Oncology, Andreas du Bois, MD, PhD, Professor of Gynecologic Oncology at Kliniken Essen-Mitte in Essen, Germany, and colleagues found that maintenance therapy with the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor pazopanib (Votrient) significantly prolonged progression-free survival vs placebo in women without disease progression after first-line chemotherapy.1
A second interim analysis of overall survival showed no benefit of pazopanib maintenance. Exploratory analyses suggested that the progression-free survival benefit was limited to non–East Asian patients and that treatment had a detrimental impact on survival in East Asian patients.
Study Details
In this double-blind trial, 940 women from 17 countries in Europe, Asia, North America, and Australia with International Federation Gynecology Obstetrics (FIGO) stage II to IV disease, no evidence of progression after surgery, and a minimum of five cycles of platinum-taxane chemotherapy were randomly assigned between June 2009 and August 2010 to receive pazopanib at 800 mg/d (n = 472) or placebo (n = 468) for up to 24 months. The primary endpoint was investigator-assessed progression-free survival using RECIST version 1.0 criteria in the intent-to-treat population.
The pazopanib and placebo groups were generally balanced for age (median, 56 and 57 years), ethnicity (77% and 78% white, 22.5% and 22.0% Asian), primary tumor (ovarian in 90% and 88%, peritoneal in 7% and 6%, fallopian in 3% and 4.5%), FIGO stage (II in 8.5% and 9%, III in 75% and 74%, IV in 16% and 17%), histology (eg, serous in 72% and 74%, undifferentiated in 8% and 9%), Eastern Cooperative Oncology Group performance status (0 in 76.5% and 77%, 1 in 23% and 22%), and geographic region (Europe for 68% and 68%, Asia for 22% and 22%, and United States/Australia for 10% and 11%).
The groups were also well balanced for first-line treatment outcome (complete macroscopic resection in 56% and 60%, upfront surgery in 75% and 69%, interval surgery in 25% and 31%, no evidence of disease or complete response after initial therapy in 84% and 86%), treatment duration (mean, 8.9 and 11.7 months), time from diagnosis to study entry (median, 7.0 and 7.1 months), and time from last dose of chemotherapy to study entry (median, 7.4 and 8.0 weeks).
Improved Progression-Free Survival
Median follow-up was 24.3 months. Median progression-free survival was 17.9 months in the pazopanib group vs 12.3 months in the placebo group (hazard ratio [HR] = 0.77, P = .0021). On blinded central assessment, the hazard ratio was significant in favor of pazopanib treatment (0.80, 95% confidence interval [CI] = 0.68–0.95).
The study was designed with 80% power to detect a 27% increase in median overall survival. A second interim overall survival analysis based on events in 35.6% of the population did not show any significant difference between groups (HR = 1.08, 95% CI = 0.87–1.33, P =.499).
Subsequent anticancer therapy was administered to 61% of placebo patients and 50% of pazopanib patients, with time to subsequent therapy being significantly longer in the pazopanib group.
Exposure and Outcome in East Asian Patients
Exploratory post hoc analysis suggested that the progression-free survival benefit of pazopanib was driven by outcomes in the non–East Asian population (78% of total study population). In the non–East Asian population, pazopanib treatment was associated with a hazard ratio of 0.69 (95% CI = 0.57–0.84) and a 5.9-month increase in median progression-free survival; the hazard ratio in the East Asian subgroup (22% of population) was 1.16 (95% CI = 0.78–1.73).
The second interim overall survival analysis showed no significant difference for pazopanib vs placebo in the non–East Asian population (HR = 0.98, 95% CI = 0.77–1.24, P = .859) and a significant detrimental effect in the East Asian population (HR = 1.71, 95% CI = 1.01–2.89, P = .047).
Dose reductions occurred in 58% of the pazopanib group (14% in placebo group). Reductions occurred in 75% of the East Asian subgroup vs 36% of other patients, and the mean daily doses of pazopanib were 473 mg vs 617 mg.
Almost all pazopanib dose reductions were due to adverse events. Most of these occurred during the first 6 weeks of treatment, with the mean dose level remaining nearly constant thereafter.
Adverse Events
The most common adverse events of any grade in the pazopanib group were hypertension (58% vs 20% in the placebo group), diarrhea (53% vs 17%), fatigue (41% vs 26%), abdominal pain (35% vs 31%), neutropenia (32% vs 8%), and liver-related toxicity (30% vs 9%). Grade 3 or 4 hypertension (30.8% vs 5.6%), neutropenia (9.9% vs 1.5%), liver-related toxicity (9.4% vs 0.7%), diarrhea (8.2% vs 1.1%), fatigue (2.7% vs 0.2%), thrombocytopenia (2.5% vs 0.7%), and palmar-plantar erythrodysesthesia (1.9% vs 0.2%) were significantly more common in pazopanib recipients (all P < .05).
Treatment was discontinued due to adverse events in 33.3% vs 5.6% of patients, with pazopanib discontinuations occurring almost exclusively during the first 12 weeks of treatment. The most common reasons for discontinuation in the pazopanib group were hypertension (14% vs 2%), diarrhea (5% vs <1%), and AST (3.6% vs 0%) or ALT elevation (4.0% vs 0%).
The investigators concluded:
Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity. ■
Disclosure: The study was supported by GlaxoSmithKline Pharmaceuticals. For full disclosures of the study authors, visit jco.ascopubs.org.
Reference
1. du Bois A, Floquet A, Kim J-W, et al: Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 32:3374-3382, 2014.
