Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial

Summary

Background

Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer.

Methods

In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB–IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m²) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2–21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118.

Findings

Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6–19·9] vs 16·6 months [13·9–19·1]; hazard ratio 0·84 [95% CI 0·72–0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown).

Interpretation

Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability.

Funding

Boehringer Ingelheim.

Introduction

Ovarian cancer is the fifth most common cause of cancer-related death among women in Europe¹ and has one of the lowest cancer survival rates,2, 3 with one study estimating a 5-year survival of just 36·1%.⁴ Standard treatment for advanced ovarian cancer involves surgical resection and chemotherapy with carboplatin and paclitaxel.⁵ Despite high proportions of patients achieving a response with standard first-line chemotherapy,6, 7, 8 most women relapse. So far, addition of a third drug has only led to additional toxic effects, without improved outcome.9, 10, 11, 12, 13, 14, 15, 16

Research in context

Evidence before this study

Before the start of the study in 2009 and after data cutoff (April 29, 2013), we searched PubMed and abstracts submitted to international clinical oncology meetings using the keywords “ovarian cancer” and anti-angiogenic drugs that have been clinically assessed in this indication: “bevacizumab”, “trebananib”, “aflibercept”, “pazopanib”, and “cediranib” to identify publications that focused on anti-angiogenic treatment options for patients with ovarian cancer. Identified trials were reviewed and confirmed that targeting angiogenesis is effective at prolonging progression-free survival in patients with ovarian cancer, showing the key part that angiogenesis plays in ovarian tumour progression. Although anti-angiogenic drugs are being investigated in a first-line setting, selection of patients most likely to benefit from these treatments remains controversial, and there remains an unmet need in patients with ovarian cancer. Encouraging early-phase clinical activity of nintedanib in patients with ovarian cancer, including a favourable tolerability profile in combination with carboplatin and paclitaxel, provided further support for this trial.

Added value of this study

This is, to our knowledge, the first phase 3 trial of nintedanib in ovarian cancer. In this trial, the addition of nintedanib to the standard first-line chemotherapy regimen of carboplatin and paclitaxel significantly increased progression-free survival compared with placebo in women with advanced ovarian cancer. The effect of nintedanib treatment seemed greatest in patients without characteristics known to be associated with a high risk for early disease progression, mostly shown by a lower postoperative tumour burden. We judged efficacy noted in this post-hoc subgroup analysis to be clinically meaningful. Treatment with nintedanib was accompanied by an increase in gastrointestinal adverse events.

Implications of all the available evidence

This is the fourth phase 3 trial of anti-angiogenic first-line therapy of advanced ovarian cancer to show a significant improvement in progression-free survival compared with placebo, further confirming the importance of angiogenesis in disease progression in patients with advanced ovarian cancer. Further studies of nintedanib are needed to help define its role in the management of ovarian cancer.

Angiogenesis has a key role in ovarian tumour progression¹⁷ and anti-angiogenic drugs are being actively investigated in the first-line setting. Bevacizumab, an anti-VEGF monoclonal antibody, in combination with standard chemotherapy followed by bevacizumab maintenance has shown superior progression-free survival compared with standard chemotherapy alone.18, 19, 20 Furthermore, an overall survival benefit was noted in a subgroup analysis of the phase 3 ICON7 trial19, 20 in patients considered to have high-risk tumours (International Federation of Gynecology and Obstetrics [FIGO] stage IV, or FIGO stage III if residual tumour after debulking surgery was >1·0 cm). By contrast, the ICON collaborators19, 20, 21 did not report any significant benefit in the complementary subgroup of non-high-risk patients with FIGO stage up to III and no or minimum macroscopic residual tumour of less than or equal to 1 cm maximum diameter. The AGO-OVAR 16 phase 3 trial²² of the tyrosine kinase inhibitor pazopanib as maintenance therapy, which preferentially included patients with absent or limited macroscopic tumour and excluded patients with progressive disease during initial chemotherapy or persisting bulky tumours after chemotherapy, showed that pazopanib was effective in these patients.

Nintedanib is a potent, oral inhibitor of the VEGF receptors (VEGFRs) 1–3, fibroblast growth factor receptors (FGFRs) 1–3, and platelet-derived growth factor receptors (PDGFRs) α and β, with anti-angiogenic activity.²³ Tolerability of nintedanib in combination with carboplatin and paclitaxel at a dose of 200 mg twice daily has been established in two phase 1 studies.24, 25 In a randomised, placebo-controlled phase 2 trial of post-chemotherapy maintenance therapy with nintedanib in patients with relapsed ovarian cancer, nintedanib was well tolerated and improved progression-free survival.²⁶

Here, we report the findings of a phase 3 trial (AGO-OVAR 12), in which we investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer.