AstraZeneca.

Background-Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer.

Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.

Background On August 14, 2014, the United States Food and Drug Administration approved the anti-angiogenesis drug, bevacizumab, for women with advanced cervical cancer based on a 2012 interim analysis of 271 deaths on GOG protocol 240. We now report the planned protocol-specified final analysis of the primary objective, overall survival (OS). Methods A phase III randomized trial using a 2×2 factorial design was conducted to determine whether intravenous chemotherapy [(cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2) or (topotecan 0.75 mg/m2 days 1–3 plus paclitaxel 175 mg/m2)] with or without bevacizumab (15 mg/kg) improves OS in recurrent/persistent/metastatic cervical cancer. Patients were prospectively stratified by performance status, prior radiosensitizing platinum, and disease status. We estimated enrolling 450 patients with 346 deaths at final analysis to provide 90% power to detect a 30% reduction in risk of death. Findings On March 7, 2014, 348 deaths occurred among 452 patients. Regimens administering bevacizumab continued to demonstrate significant improvement in OS: 16.8 vs 13.3 mos (HR 0.77;95% CI 0.62–0.95;p=0.0068). Updated progression-free survival also favored bevacizumab (HR 0.68;95% CI 0.56–0.84;p=0.0002). Final OS among 20% (n=91) not treated with prior pelvic radiotherapy was 24.5 (bevacizumab) vs 16.8 mos (without bevacizumab). Fistula (any grade) occurred in 14.5% (n=32) receiving bevacizumab (all previously irradiated). Grade 3+ fistula developed in 5.9% (n=13) and did not result in surgical emergency, sepsis and/or death. Post-progression OS was not significantly different among those who did and did not receive bevacizumab (median 8.4 vs 7.1 mos: HR 0.32;95% CI 0.66–1.05;p=0.06). Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the survival curves remaining separated. Following progression on bevacizumab, a negative rebound effect was not observed. This represents proof-of-concept of the efficacy and tolerability of anti-angiogenesis therapy in advanced cervical cancer. Funding National Cancer Institute (USA).

IMPORTANCE Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. OBJECTIVE To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. DESIGN, SETTING, AND PARTICIPANTS The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to Ն23.0 months). Data were collected from

BACKGROUND A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P = 0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P = 0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P = 0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P = 0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%). CONCLUSIONS Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.)

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