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Nintedanib prolongs PFS, worsens GI toxicity in advanced ovarian cancer
The addition of nintedanib to first-line chemotherapy with carboplatin and paclitaxel conferred a slight improvement in PFS among women with advanced ovarian cancer, according to the results of a phase 3 randomized controlled trial.
However, this regimen appeared associated with greater gastrointestinal adverse events.
“Despite high proportions of patients achieving a response with standard first-line chemotherapy, most women relapse,” Andreas du Bois, MD, professor of gynecologic oncology at Kliniken Essen Mitte in Germany, and colleagues wrote. “So far, addition of a third drug has only led to additional toxic effects without improved outcome.”
Andreas du Bois
The oral triple angiokinase inhibitor nintedanib (Ofev, Boehringer Ingelheim) has shown efficacy in phase 2 trials of women with advanced ovarian cancer.
Du Bois and colleagues conducted a double blind trial to evaluate the addition of nintedanib to standard carboplatin and paclitaxel in women with newly diagnosed advanced ovarian cancer.
Following surgical debulking, all patients received six cycles of carboplatin (area under the curve, 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m2). Researchers randomly assigned patients to also receive 200 mg nintedanib or placebo twice-daily on days 2 through 21 of every 3-week cycle for up to 120 weeks.
PFS served as the primary endpoint.
Median follow-up was 22.4 months (interquartile range, 21.8-27.7).
The analysis included data from 1,366 women (median age, 58 years; range, 21-84; nintedanib, n = 911; placebo = 455).
Fifty-three percent (n = 486) of patients assigned nintedanib experienced disease progression or death, compared with 58% (n = 266) of patients assigned placebo.
However, patients in the nintedanib group achieved longer median PFS (17.2 months vs. 16.6 months; HR = 0.84; 95% CI, 0.72-0.98), a difference that met statistical significance.
The most frequent adverse events included diarrhea (grade 3, 21% vs. 2%; grade 4, < 1% vs. 0), neutropenia (grade 3, 20% for both groups; grade 4, 22% vs. 16%), thrombocytopenia (grade 3, 12% vs. 5%; grade 4, 6% vs. 2%) and anemia (grade 3, 12% vs. 6%; grade 4, 1% for both groups).
Gastrointestinal adverse events — such as diarrhea, nausea, vomiting and decreased appetite — occurred more frequently in patients assigned nintedanib.
Serious adverse events occurred more frequently in the nintedanib arm (42% vs. 34%).
Twenty-nine patients assigned nintedanib and 16 patients assigned placebo experienced serious adverse events. Twelve patients assigned nintedanib and six patients assigned placebo developed a malignant neoplasm progression classified as an adverse event.
Drug-related adverse events leading to death occurred in three patients assigned nintedanib (one due to non–drug-related sepsis associated with diarrhea and renal failure; one due to peritonitis; and one without diagnosis of cause) and one patient assigned placebo (cause unknown).
The researchers acknowledged the relatively short follow-up, as well as the potential unmasking due to the occurrence of adverse events, as study limitations.
“Pending the OS results, further studies are needed to prospectively assess the clinical value of nintedanib in patients with advanced ovarian cancer and especially in cohorts with lower tumor burden,” du Bois and colleagues wrote.
Advances in gynecologic surgery will necessitate new regulatory standards for ovarian cancer trials, Sean Kehoe, MD, Lawson Tait professor of gynecological cancer at University of Birmingham, wrote in an accompanying editorial.
“Evidence is accumulating that shows changing practice regarding use of primary surgery,” Kehoe wrote. “Hence, has the time come to standardize both surgery and patient selection for surgery? This debate seems necessary. Recruiting centers will probably need to reveal not only their normal complete resection rates in operated patients, but also those patients they deemed unsuitable for primary surgery. Otherwise, the population recruited becomes more skewed than at present.” – by Cameron Kelsall
Disclosure: Boehringer Ingelheim funded this study. Du Bois reports personal fees and honoraria from Amgen, AstraZeneca, Merck, PharmaMar and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures. Kehoe reports no relevant financial disclosures.