Pazopanib Maintenance Improves Progression-Free Survival in Ovarian Cancer, but Benefit Limited to Non–East Asian Patients
In a phase III trial reported in the Journal of Clinical Oncology, du Bois et al found that maintenance therapy with the VEGFR and PDGFR inhibitor pazopanib (Votrient) significantly prolonged progression-free survival vs placebo in women with ovarian cancer without progression after first-line chemotherapy. A second interim analysis of overall survival showed no overall benefit of pazopanib maintenance. Exploratory analyses suggested that 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 ovarian cancer and no evidence of progression after surgery and at least five cycles of platinum-taxane chemotherapy were randomly assigned between June 2009 and August 2010 to receive pazopanib 800 mg/day (n = 472) or placebo (n = 468) for up to 24 months. The primary endpoint was progression-free survival. Overall, 77% and 78% of patients were white and 22.5% and 22% were Asian.
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). 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, 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 which treatment was associated with a hazard ratio of 0.69 (95% confidence interval [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, P = .859) and a significant detrimental effect in the East Asian population (HR = 1.71, 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 mean dose level remaining nearly constant thereafter.
Adverse Events
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 patients (all P < .05). Treatment was discontinued due to adverse events in 33.3% vs 5.6% of patients.
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.”
Andreas du Bois, MD, PhD, of Kliniken Essen-Mitte, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by GlaxoSmithKline Pharmaceuticals. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
