OA: Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer: ROSiA Single-Arm Phase 3B Study

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 Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer: ROSiA Single-Arm Phase 3B Study
Jan 2017

 Eligible patients had histologically confirmed epithelial ovarian carcinoma, fallopian tube carcinoma, or primary peritoneal carcinoma of International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV (any grade) or stage I to IIA (grade 3), or clear cell carcinoma, or carcinosarcoma.

 Unlike ICON7, patients could be enrolled after neoadjuvant chemotherapy and interval debulking surgery, with bevacizumab initiated after surgery.

 To gain an impression of the impact on safety of prolonging bevacizumab therapy, we considered the safety results in the context of previous data from randomized phase 3 trials. As the ROSiA study was designed to enroll a patient population similar to that treated in ICON7, interpretation of the results in the context of ICON7 results seems reasonable, although the bevacizumab dose more closely resembles that in GOG-0218.

Objective: The aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer.

Patients and Methods: In this multinational prospective single-arm study (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IV or grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator’s choice of 175 mg/m² q3w or 80 mg/m² weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety.

Results: Between December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1–50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7–27.6 months).

Conclusion: Extended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for frontline bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.

 Bevacizumab was discontinued because of disease progression in 332 patients (33%), unacceptable toxicity in 176 patients (17% [proteinuria in 55 patients; hypertension in 30 patients]), and consent withdrawal in 111 patients (11%). In 145 patients, study therapy was discontinued before the maintenance bevacizumab phase; the remaining 876 patients received at least 1 cycle of maintenance bevacizumab. Among the 176 patients who discontinued bevacizumab because of unacceptable toxicity, the median time to discontinuation was 9.9 months (range, 0–35 months); the median time to bevacizumab discontinuation because of consent withdrawal was 10.1 months (range, 0–28 months).

 

....Overall survival results are immature with events in only 23% of patients. Unfortunately, further long-term follow-up is not planned within the framework of the study, as the ROSiA safety study was designed with PFS as the primary efficacy outcome rather than OS.

In summary, results from this large multinational frontline study in ovarian cancer indicate that extended bevacizumab-containing therapy is both tolerable and feasible. The single-arm study design does not allow us to draw definitive conclusions on the impact of treatment duration on efficacy; however, the median PFS of 25.5 months is the longest reported to date.