Background/Aims: Epithelial ovarian cancer (EOC) is the sixth most commonly diagnosed cancer among women. Results with available therapies are far from being satisfactory and, therefore, current research is focusing on new anticancer drugs to improve the clinical response of these patients. Nintedanib is an oral multiple tyrosine kinases inhibitor, which targets angiogenesis. Considering the current scenario, the aim of this systematic review is to highlight the prevailing knowledge about pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of Nintedanib for the treatment of advanced EOC. Methods: We performed a systematic review of the literature, screening all available articles about the treatment of advanced EOC with Nintedanib, including phase I, II, and III trials. Results: Although in early phase clinical trials, Nintedanib has demonstrated anticancer activity and tolerability as monotherapy or in combination with carboplatin and paclitaxel. In the phase III trial AGO-OVAR 12, it obtained a modest improvement in progression-free survival (PFS) as first-line combination therapy for patients with advanced EOC. Interestingly, a PFS increase was observed in patients with non-high progression risk or low tumor burden. Conclusion: Despite the promising results, further studies are needed to evaluate Nintedanib efficacy in women affected by EOC.

Epithelial ovarian cancer (EOC) is the sixth most commonly diagnosed cancer among women, with an incidence of 6.1 cases per 100,000 women, a rate of mortality of 4.3 deaths per 100,000 women and a cumulative lifetime risk of 0.5% [1]. Women affected by EOC have late and nonspecific symptoms, such as dyspepsia, abdominal distension, anorexia, pelvic pain, and low back pain [2]. For this reason, most of them present with International Federation of Gynecology and Obstetrics (FIGO) stages III–IV EOC at the time of diagnosis [3]. First-line treatment for advanced EOC is based on surgical cytoreduction and chemotherapy (CT) with carboplatin and paclitaxel [4]. Although several patients show an initial response to first-line treatment, disease recurrence occurs in more than 50% of them. Overall, patients with EOC at stages III–IV have a 5-year survival rate of about 20–30% [5]. As current results with available therapies are far from being satisfactory, there is an ongoing need to develop novel agents and maintenance strategies to prolong overall survival (OS) and improve life quality of women with advanced EOC. The need of new treatment options is mandatory either in the first-line setting of metastatic disease, or even more in the second- or third- management of recurrent EOC [6].

The goal of surgical treatment is to achieve a residual disease of less than 1 cm or the resection of all macroscopic disease, as they are associated with a significantly increase in OS and progression-free survival (PFS). The association of paclitaxel and carboplatin for 6–8 cycles after the surgical procedure decreases the recurrence risk. The use of primary CT with interval surgery is usually offered to patients with poor performance status at presentation or with very extensive cancer dissemination [7]. Despite optimal upfront surgery and first-line medical management, around 70% of women relapse in the first 3 years. In the setting of disease recurrence, there are patients whose disease recurs 6 months or more after primary treatment (platinum-sensitive) and patients whose disease recurs within 6 months (platinum-resistant). The most common choice of treatment in the first group of patients is to repeat a platinum-based CT, while in the other group, the choice of treatment is to administer a different chemotherapeutic drug [8]. However, the patients with recurrent EOC have a poor prognosis [9].

Currently, targeted agents, which inhibit specifically critical pathways for cellular survival and proliferation, are undergoing clinical investigation [6, 10‒13]. Angiogenesis has a critical role in the pathogenesis of EOC, promoting tumor growth and progression [14]. Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR) play a critical role in angiogenesis, but platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) also contribute to this process. Levels of VEGF are markedly elevated in the ascitic fluid of women with EOC, suggesting a key role in increasing endothelial cell permeability in ascites genesis [15]. In addition, high VEGFR expression in EOC has been associated with increased tumor growth, metastases and higher mortality rates [16].

Bevacizumab, a monoclonal humanized antibody directed against circulating VEGF, was the first antiangiogenic drug studied in advanced EOC. Two randomized phase III clinical trials (the International Collaboration on Ovarian Neoplasms trial [ICON7] [17] and the Gynecologic Oncology Group study 218 [18]) demonstrated a benefit in PFS in patients with primary EOC treated with standard CT in combination with Bevacizumab [19]. For this reason, the European Medicines Agency approved the addition of Bevacizumab to standard primary treatment of EOC. The role of this drug has been also investigated for the treatment of recurrent EOC. In this setting, Bevacizumab showed a clinical advantage as monotherapy or as combination therapy in randomized phase III trials (OCEANS trial [20] for recurrent platinum-sensitive EOC and AURELIA trial for platinum-resistant EOC). Recently, the Food and Drug Administration has approved Bevacizumab in combinatory regimens for the treatment of patients with platinum-resistant recurrent EOC.

Current therapeutic strategies have focused on developing multi antiangiogenic tyrosine-kinase inhibitors (TKIs) that can block multiple intracellular signaling pathways simultaneously [21]. As both PDGF and FGF pathways have been implicated in resistance to VEGF inhibition, the combined inhibition of VEGF and PDGF and/or FGF would be more effective in blocking angiogenesis than isolated VEGF inhibition [22]. Among these drugs, Nintedanib has been tested in clinical phase II–III trials for the treatment of advanced EOC.

Previously known as BIBF 1120, Nintedanib is an oral second-generation TKI that inhibits intracellular signal cascade of growth factors involved in angiogenesis and tumor stroma development.

Considering the current scenario, the aim of this systematic review is to highlight the current knowledge about pharmacokinetics (PKs), pharmacodynamics, clinical efficacy, and safety of Nintedanib for the treatment of advanced EOC.

Study Design and Registration

The review protocol was registered in PROSPERO international prospective register of systematic reviews (registration number: CRD42018092073) before data extraction. The review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement and the Cochrane Reviewers’ Handbook. Outcomes were defined, screened, selected, and reported following the recommendations of the Core Outcome Sets in Women’s and in Newborn Health initiative.

Search Strategy

A systematic literature search to find all published studies in English language evaluating PKs, pharmacodynamics, clinical efficacy, and safety of Nintedanib for the treatment of EOC was performed from inception to August 2017 in the following electronic bibliographic databases: MEDLINE, EMBASE, Global Health, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), Health Technology Assessment Database and Web of Science, research registers (such as www.cliniclatrials.gov). The following search terms were used: “Nintedanib,” “BIBF 1120” alone or in combination with “cancer,” “ovarian cancer,” “efficacy,” “safety,” “tolerability,” “toxicity.”

Study Selection and Data Extraction

Titles and/or abstracts of studies retrieved using the search strategy, and those from additional sources were screened independently by 2 review authors (F.B. and A.S.L.) to identify studies that potentially meet the aims of the systematic review. The full text of these potentially eligible studies was retrieved and independently assessed for eligibility by other 2 review team members (F.G. and S.F.). Any disagreement between them over the eligibility of particular studies was resolved through discussion with a third (external) collaborator. A standardized, pre-piloted form was used to extract data from the included studies for assessment of study quality and evidence synthesis. Two authors (F.B. and J.C.) independently extracted data from studies about study features and included populations, type of intervention (duration of therapy and drug posology) and outcomes about PKs, pharmacodynamics, clinical efficacy, and safety defined according to the Common Terminology Criteria for Adverse Events developed by the National Cancer Institute (NCI CTCAE). Any discrepancies were identified and resolved through discussion (with a third external collaborator where necessary).

Study Selection

As detailed in Figure 1, the search of the abovementioned electronic bibliographic databases retrieved 452 items. After duplicates were removed, the titles of these publications were screened and assessed for eligibility, excluding 246 items for title or abstract (n = 169) or language (n = 25). After evaluating the full publication text of 51 studies, 15 studies were excluded, as they had inappropriate population, intervention or outcomes (n = 22), were case reports or series without highly valuable information (n = 3), letter to the editor or abstract (n = 3). In the end, a total of 16 studies were included in the present systematic review. Considering the characteristics of the studies included and the heterogeneity of the available articles in terms of methodology, no meta-analysis was attempted.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 flow diagram.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 flow diagram.

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Risk of Bias Assessment

It was not possible to perform the risk of bias for pre-clinical studies and studies on pharmacodynamics and PKs. Regarding clinical studies (n = 5):

  • Selection bias: 3 studies [23‒25] were open-label and they do use allocation strategy. 2 studies [26, 27] used an adequate method of random sequence generation.

  • Performance bias: 3 studies [23‒25] were open-label and they have not to give information about blinding of participants and personnel. In the other 2 studies, this information was clearly reported and adequate [26, 27].

  • Detection bias: 3 studies [23‒25] were open-label (authors were not blind for outcomes assessment). In 2 studies, it was unclear (not adequately detailed) [26, 27].

  • Attribution bias: 4 studies [23‒25, 27] adequately reported outcome data, whereas 1 study [26] reported unclear information about this point.

  • Reporting bias: 1 study [26] did not report data about Nintedanib efficacy in subgroup analysis of patients with ovarian cancer, so it was judged at high risk of selective data reporting. All the other 4 studies [23‒25, 27] clearly reported all the data about primary and secondary outcomes.

  • Other sources of bias: considered other sources of bias such as trial registration (on national/international data registries), baseline imbalance, blocked randomization in open-label trials, we judged 3 studies [23‒25] at the high risk, whereas all the others were at low risk [26, 27].

The assessment of the risk of study bias is summarized in Figure 2.

Fig. 2.

Risk of bias assessment for clinical studies.

Fig. 2.

Risk of bias assessment for clinical studies.

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Pharmacodynamics

Nintedanib competitively binds to the ATP binding-pocket of specific tyrosine kinase receptors, resulting in interference with receptor dimerization. This leads to block the intracellular signal transduction.

Nintedanib inhibits the proangiogenic pathways mediated by VEGFR-1, -2 and -3 (IC50 13–34 nmol/L), FGF receptor (FGFR) -1, -2 and -3 (IC50 37–108 nmol/L), and PDGF receptor-α and -β (IC50 59–65 nmol/L) to a high degree of specificity. It has been also demonstrated that Nintedanib blocks non-receptor kinases such as Flt-3 (IC50 26 nmol/L), proto-oncogene ret (Ret, IC50 35 nmol/L), lck (IC50 16 nmol/L), lyn (Lyn IC50 195 nmol/L), and proto-oncogene src (Src, IC50 156 nmol/L) [28].

Pharmacokinetics

Nintedanib is available as soft gelatin capsules of 100 and 150 mg. As summarized in Table 1, in a PK profile study in healthy volunteers, Nintedanib demonstrated a relative oral bioavailability of 4.7% (90% CI 3.62–6.08) [29]. The small percentage of Nintedanib absorbed in the gut is partially due to transport proteins activity (such as P-glycoprotein) and the first-pass hepatic metabolism. Nintedanib is rapidly absorbed and it achieves the maximum plasma concentration (Cmax) within 1–3 h after oral administration [29]. After food intake, Nintedanib exposure increases by approximately 20% compared to administration under fasting conditions (90% CI 95.3–152.5%). Its absorption is delayed (median timemax fasted: 2.00 h; fed: 3.98 h), regardless of the food type. In vivo, the binding of Nintedanib to human plasma proteins is high, having a bound fraction of 991.1%. The serum albumin is considered its major binding protein [30].

Table 1.

Pharmacokinetic features of Nintedanib

 Pharmacokinetic features of Nintedanib
 Pharmacokinetic features of Nintedanib

Following intravenous (IV) administration in healthy volunteers, this drug showed a total clearance of geometric mean (gMean) 1,390 mL/min and a volume of distribution of 1,050 L. The decline during the distribution phase was slower after oral administration than after IV administration [29].

The terminal half-life (t1/2) of Nintedanib is estimated to be ~13–19 h after oral administration. The renal excretion plays a negligible role in Nintedanib elimination, as preclinical data showed that the major route of elimination of [C14] Nintedanib is via fecal and biliar excretion, amounting to 93.4% of dose [31].

Nintedanib is metabolized to free acid moiety BIBF 1202 and the glucuronidated form of the free acid. Its prevalent metabolic reaction is hydrolytic cleavage by esterases resulting in BIBF 1202. BIBF 1202 is subsequently glucuronidated by uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, namely, UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of Nintedanib consisted of cytochrome (CYP) pathways, with CYP 3A4 being the predominant enzyme involved. Dallinger et al. [29] demonstrated that Nintedanib metabolites after oral administration are higher than after IV administration probably because of hepatic first-pass metabolism. The glucuronidated form of the free acid has different PK characteristics compared with Nintedanib, presenting a late Cmax and a t1/2 of 10 h. The free acid moiety has comparable PK characteristics compared with Nintedanib.

The PK of Nintedanib is considered time independent. In fact, in patients with advanced cancer, gMean area under curve (AUC) and Cmax appear to increase in proportion to increasing oral doses after both single doses and steady state [32, 33]. The observed values for Nintedanib accumulation on multiple bis in die (BID) dosing are 1.38-fold based on individual AUCs and 1.04-fold based on Cmax individual values [34]. Therefore, they are within the expected ranges based on the effective t1/2 of approximately 13 h. This observation supports that ester cleavage and glucunidation are nonsaturable reactions, as there were no differences to the free acid or its glucuronidated form in the dose rage administrated.

It has been demonstrated that Nintedanib exposure is approximately twofold higher in Child-Pugh A subjects and about eightfold higher in Child-Pugh B subjects than in healthy subjects. Thus, a single dose of Nintedanib at 100 mg has an acceptable safety and tolerability profile in subjects with hepatic impairment [30].

Efficacy

Preclinical Studies

The first in vitro study showed that Nintedanib inhibits the proliferation of VEGF-stimulated human umbilical vein endothelial cells and human skin microvascular endothelial cells, and the proliferation of PDGF-stimulated smooth muscle cells and pericytes [28]. More recently, it has been demonstrated that Nintedanib inhibits not only the proliferation of the stromal cells, but also of tumor cells, such as hepatocarcinoma (PLC5, Hep3B, SK-Hep1, and HuH7) [34] or pancreatic ductal adenocarcinoma cellular lines (AsPC-1, BxPC-3, MIA PaCa-2, and Panc-1) [35]. No information is available in the literature on ovarian tumor lines inhibition by Nintedanib.

In the animal model, Nintedanib shows antitumor effects in all human tumor xenografts reported to date, including ovarian cancer (SKOV-3) [28]. The anticancer effect of Nintedanib causes a decrease in microvessel density, pericyte coverage, vessel permeability, tumor perfusion, and leads to hypoxia, as well as the inhibition of phosphatidylinositol 3-kinase-protein kinase B (AKT) and mitogen-activated protein kinase signaling pathways [36]. More importantly, it has been showed that Nintedanib increases antitumor efficacy when administered in combination with standard cytotoxic agents [37].

Phase I Clinical Studies

Mross et al. [23] in a phase I dose-escalation study investigated for the first time Nintedanib in vivo. Among 61 patients with advanced cancer (no patients with EOC were included), 25 received Nintedanib 50–450 mg once daily (OD) and 36 patients received Nintedanib 150–300 mg BID in 4-week cycles with a week off. There was one complete response (CR) and 2 partial responses (PR). The dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of the patients.

In another phase I dose-escalation study, Okamoto et al. [24] tested Nintedanib in 20 patients with advanced refractory solid tumors (no patients with EOC were included). Among them, 3 patients received ­Nintedanib at 150 mg BID, 12 patients at 200 mg BID and 6 patients at 250 mg BID. Although no CR or PR was observed, 16 (76.2%) patients had stable disease for at least 2 treatment courses (56 days) across all the tested doses. More specifically, stable disease was observed in 100% of the patients at 150 mg, in 75% at 200 mg, and in 67% at 250 mg. Median PFS was 113 days (95% CI 77–119).

Levels of angiogenesis-related circulating proteins, such as soluble VEGFRs (sVEGFRs) and angiopoietins (Ang -1, 2), have been described as potential biomarkers for diagnosis and treatment response of advanced cancers, including EOC. Okamoto et al. in their study [24] showed a mean plasma level of sVEGFR2 at baseline (obtained from 15 patients) of 7.7 ± 1.7 ng/mL (range 5.3–11.0 ng/mL). It decreased significantly over the first 4 weeks of treatment with Nintedanib to 5.8 ± 1.3 ng/mL (< 0.001, range 3.2–8.8 ng/mL) across all doses tested. Furthermore, the decrease in sVEGFR2 showed an inverse linear correlation with the trough plasma levels of Nintedanib (r = –0.46). Circulating CD117-positive bone marrow derivate endothelial progenitors have been reported to contribute to tumor angiogenesis [38]. In the same study, a subset of these cells (CD45dimCD34+CD117+) was measured in the whole blood of 15 patients after Nintedanib administration. CD117 was expressed in the CD45dimCD34+ subset with a basal level of 60–80%. CD45dimCD34+CD117+ significantly decreased over all Nintedanib dose cohorts during the 1st cycle of therapy (p = 0.009 on day 8 and p = 0.004 on day 29) [24]. These findings demonstrated that Nintedanib may have inhibitory effects of differentiation and mobilization of endothelial progenitors on peripheral blood.

In another open-label dose evaluation phase I trial, 22 patients with advanced gynecological malignancies (10 patients with EOC) received Nintedanib BID at 100, 150, 200 or 250 mg in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5 min/mg/mL per min) every 3 weeks. Among 7 patients assessable for tumor response, one patient with EOC (in the 200 mg BID cohort) had CR, 2 patients with EOC (in the 150-mg BID cohort) and 2 patients with other gynecological cancers (in the 200-mg BID cohort) had PR. The PFS in these patients ranged from 177 to 282 days. Despite the small sample size, 10 patients with EOC were assessable for CA-125 levels (one or more pretreatment value > 35 U/mL). All these had a reduction in this marker (value decreased by ≥50%) [25]. Recently, 2 phase I studies are investigating the combination of ­Nintedanib with carboplatin (AUC 5 mg/mL per min) and pegylated liposomal doxorubicin (30 mg/m2) in patients with platinum-sensitive relapsed EOC (NCT01329549; NCT01314105). The results are awaited.

All the data about phase I clinical studies are summarized in Table 2.

Table 2.

Main findings of phase I, II, III trials of Nintedanib

 Main findings of phase I, II, III trials of Nintedanib
 Main findings of phase I, II, III trials of Nintedanib

Phase II Clinical Studies

In a multicenter double-blind phase II study, a cohort of 83 patients with recurrent EOC received Nintedanib after conventional CT based on combination of carboplatin and paclitaxel. The patients were randomized to receive either Nintedanib [250 mg per os (PO) BID, n = 43] or placebo (n = 40) for 36 weeks. The PFS rates at 36 weeks were 16.3% in the Nintedanib and 5% in the placebo groups (hazard ratio [HR] 0.65, 95% CI 0.42–1.02, p = 0.06) [26].

Currently, Nintedanib is undergoing intense clinical investigation in other 3 phase II trials for the treatment of patients with EOC. An ongoing multicenter double-blind placebo-controlled phase II trial is evaluating the efficacy and the safety of an oral combination of metronomic cyclophosphamide (100 mg IV) with and without Nintedanib (200 mg PO) in patients with histologically proven recurrent advanced EOC who have received 2 or more lines of CT or are platinum resistant (NCT01610869). Another ongoing multicenter double-blind placebo-controlled phase II trial is testing Nintedanib (200 mg PO BID) in combination with first-line CT and interval debulking surgery in patients with stage IIIC-IV EOC (NCT01583322). A further ongoing phase II trial is evaluating Nintedanib (200 mg PO) in patients with recurrent or persistent EOC, who have a treatment-free interval following response to Bevacizumab of < 6 months, or who have progressed during treatment with Bevacizumab (NCT01669798).

All the data about phase II clinical studies are summarized in Table 2.

Phase III Clinical Studies

In a multicenter double-blind randomized placebo-controlled phase III study (LUME-Ovar 1 or AGO-OVAR 12), Nintedanib (200 mg PO BID on days 2–21 of every 3 week cycle, n = 890) or placebo (n = 445) were administered in combination with carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min IV on day 1 for 6 cycles) and paclitaxel (175 mg/m2 IV on day 1 for 6 cycles) followed or not by Nintedanib maintenance therapy (200 mg PO BID for up to 120 weeks) as first-line treatment in patients with advanced EOC. Eligible patients had histologically confirmed FIGO stages IIB–IV EOC, fallopian tube, or primary peritoneal carcinoma. The patients had either previous debulking surgery or, if not possible in stages IIIC–IV, diagnosis confirmed by histology. Most importantly, a subgroup analysis demonstrated a higher PFS increase with Nintedanib compared with controls in not-high-risk or low-tumor burden subgroup, consisting in FIGO stage III and < 1 cm postsurgical residual tumor deposits, or FIGO stage IV (27.1 vs. 20.8 months, HR 0.75, 95% CI 0.61–0.92, p = 0.005). No significant difference in PFS was noted between the Nintedanib and placebo arms for high-risk or high tumor burden subgroup, consisting in FIGO stage III and > 1 cm postsurgical residual tumor or FIGO IV (HR 0.99, 95% CI 0.80–1.24) [27].

All data about phase III clinical studies are summarized in Table 2.

Safety, Tolerability, and Toxicity

Various studies investigated the safety and assessed the maximum tolerated dose (MTD) of Nintedanib used as a single agent or in combination with CT.

In the phase I study by Mroos et al. [23], grade 3 or more adverse events (AEs) for Nintedanib as monotherapy, administered OD and BID occurred in 5% patients with advanced cancers. The most common AEs were reversible hepatic enzyme elevation (12% grade 3 and 4% grade 4 vs. 0% grade 3 and 2.8% grade 4), increase in aspartate aminotransferase (AST, grade 3, 8 vs. 2.8%), increase in alanine aminotransferase (ALT, grade 3, 0 vs. 5.6%), increase in γ-glutamyl trans peptidase (γ-GT, grade 3, 4 vs. 5.6%), decrease in CD-4 lymphocyte (grade 3, 16 vs. 5.6%), hypertension (grade 3, 4 vs. 0%), and diarrhea (grade 3, 0 vs. 2.8%). The MTD of Nintedanib was defined as 250 mg for both OD and BID dosing.

In the phase I study by Okamoto et al. [24], the most common dose-limiting toxicity was grade 3 or 4 hepatic liver elevation, which occurred in 25% of patients with advanced cancers at 200 mg BID and in 50% of patients at 250 mg BID dose. For this reason, the MTD of Nintedanib was determined to be 200 mg BID.

Du Bois et al. [25] described that 41% of patients with advanced gynecological malignancies reported dose-limiting toxicities, receiving Nintedanib as monotherapy or in combination with carboplatin and paclitaxel. There was high incidence of AST, ALT, and γ-GT elevation in the 250 mg BID dose cohort. Moreover, 2 patients (15%) had grades 3 or 4 elevations of AST and/or ALT values during triple treatment including Nintedanib at 250 mg BID. The MTD was defined as 200 mg BID in a 20-day continuous dosing regimen. In the phase II trial, AEs of grades 3–4 were similar between the Nintedanib group and placebo (34.9 vs. 27.5%, p = 0.49). The most common AE in experimental arm concerned the liver function tests (raised AST, ALT, and γ-GT) in 51.2% of patients, but only one patient stopped the experimental regimen because of this AE [26].

In AGO-OVAR 12 trial, grade 3 or worse AEs occurred in 81% of patients in the Nintedanib group compared with 67% in the placebo group [27]. Grades 3–4 AEs were reported in 42% of patients in the Nintedanib group versus 34% in the placebo group. Overall, 24% of women in the Nintedanib arm compared with 15% in the placebo arm permanently discontinued Nintedanib because of AEs. Gastrointestinal symptoms were the most common AEs that led to discontinuation. Drug-related AEs leading to death occurred in 3 patients in the experimental arm (one without diagnosis of cause; one due to nondrug-related sepsis associated with drug-related diarrhea and renal failure; and one due to peritonitis) and in one patient in the placebo arm (cause unknown). Diarrhea of any grade occurred in 79% of women in the Nintedanib arm compared with 26% in the placebo arm. Moreover, 74% of patients with diarrhea in the Nintedanib group were able to continue the treatment at a lower dose after AEs resolution. Among patients in the experimental arm, 28% with bowel anastomoses experienced high-grade diarrhea compared with 20% without bowel anastomoses. Other gastrointestinal AEs of grade 3 or worse occurred in less than 5% of patients with incidences comparable between the 2 groups. The most common hematologic AEs in Nintedanib arm were thrombocytopenia, anemia, and neutropenia. Thrombocytopenia of grade 3 or worse occurred in 18% and in the 7% of women in the Nintedanib and in the placebo group respectively.

The quality of life was not adversely affected during treatment with Nintedanib, despite the more frequent occurrence of gastrointestinal AEs. The adjusted mean global health status and quality-of-life score over the treatment period was 68.82 (SE 0.49; 95% CI 67.86–69.78) in the Nintedanib group compared with 70.68 (SE 0.65; 95% CI 69.40–71.97) in the placebo group. The difference in adjusted mean score was –1.86 (SE 0.76; 95% CI –3.35 to –0.36) on the scale normalized to 100, which is considered a clinically trivial change.

It is noticeable that Nintedanib has limited drug-drug interaction potential, due to the minor role of CYP450 in its metabolism and the lack of induction or inhibition of this group of enzymes (IC50 > 50 μmol/L) by the drug [29]. In the phase I study by du Bois et al. [25], authors investigated the effect of Nintedanib at 200 mg BID on the PK parameters of paclitaxel or carboplatin. When comparing gMean AUC and Cmax values of paclitaxel before and after treatment with Nintedanib, an increase of 20–25% of their values occurred. This increase was not considered clinically relevant because no systematic increase was seen in either of the parameters between treatment periods. With respect to carboplatin, after Nintedanib administration, gMean Cmax values were bioequivalent, although an increase of 25% in gMean AUC was observed. As the increase was not systematic between the treatment periods, it was deemed clinically irrelevant. The gMean ratios and 90% CI of AUC and Cmax between treatment period 1 (absence of Nintedanib) and treatment period 2 (presence of Nintedanib) for each drug do not fall entirely within or out of the 0.8–1.25 range for bioequivalence. It has been reported in this study also that the single-dose and steady-state PK parameters of Nintedanib were comparable to those seen with it as monotherapy. This indicates that there are no unfavorable drug–drug interactions of paclitaxel and carboplatin on the PK of Nintedanib [25].

Most of the data on the action of antiangiogenic agents in EOC come from studies with Bevacizumab. A major challenge in the success of antiangiogenic therapy is the development of resistance, probably due to the induction of tumor escape mechanisms by the upregulation of growth factors, such as FGFR and PDGF receptor. Delivery of multi-target TKIs, such as Nintedanib, offers the advantage of blocking all these pathways. It is noticeable that TKIs, simultaneously targeting all these pathways, may have a higher potential antitumor effect, also preventing the activation of pathways that could lead to resistance.

Nintedanib is an orally available, high-clearance drug with linear PK characteristics with respect to time and dose. It has a dose-linear PK not only after single dose in healthy voluntaries, but also at steady state during multiple administration in cancer patients.

In phase I trials, Nintedanib administered at 200 mg BID with paclitaxel and carboplatin in patients with advanced cancers demonstrated an acceptable safety profile, and no clinically relevant drug-drug interaction. In fact, the minor role of CYP450 in its metabolism and thus the lack of CYP induction or inhibition contribute to reduce the interactions with other drugs.

In the AGO-OVAR 12 trial [27], the median PFS ­benefit of the Nintedanib addition to standard CT as first-line medical treatment after surgical debulking was low (17.2 vs. 16.6 months). Interestingly, its efficacy was particularly notable in patients with low-risk progression postsurgical disease, obtaining an extension of PFS by 7 months. In AGO-OVAR 16 phase III trial [39], Pazopanib, another multi-TKI, showed a similar extension of PFS (5.6 months) compared with placebo. In that trial, most of the patients in the experimental arm had a low postsurgical tumor burden, in line with the AGO-OVAR 12. Differently, Pazopanib was administered as maintenance monotherapy after at least 5 cycles of conventional CT, so that it would be interesting to investigate also Nintedanib in this setting. Moreover, the ICON7 phase III trial [40] suggested that Bevacizumab obtained a higher increase of both PFS and OS in patients with high-progression risk tumor (stage IV or stage III with residual disease > 1 cm following debulking surgery), while women with low-risk EOC did not have benefit from this drug [19]. All these findings suggest that a residual tumor burden may influence the response to this class of drugs. Further explanations are needed to draw conclusion on this topic.

For decades, the aim of surgical treatment of EOC was to obtain optimum debulking, originally defined as no residual or any tumor left of less than 1.6 cm, ­although this was recently redefined as no residual ­disease. To achieve the latter, more extensive surgical excision, sometimes necessitating the removal of liver metastases, the spleen, or diaphragmatic peritoneal stripping, is necessary sometimes with the aid of new minimally invasive robotic approach [40]. This extensive excision is not universally practiced, and arguably may be partly responsible for the variability in reported trials [41]. Equally, the patient should be fit enough to tolerate such surgery and, correctly, patients are carefully selected. In the near future, the criteria of inclusion for phase III trials should be more defined and homogenous, allowing a better cross-trial evaluation of the investigated drugs.

Regarding the safety profile of Nintedanib, liver enzymes elevation occurs frequently. Anyway, this AE tends to be fully reversible, and to respond rapidly (within 2 weeks) to treatment discontinuation or dose reduction. Unlike some other TKIs, Nintedanib does not seem to cause high incidence of relevant skin abnormalities and hypertension [6]. In the AGO-OVAR 12, grade 3 or worse AEs occurred in 81% of patients in the Nintedanib group compared with 67% in the placebo group. The most common grade 3 or worse AE was diarrhea (23 vs. 2%). Its incidence was more than twice as high as reported in another phase III trial [42], in which Nintedanib was administered as second-line treatment for advanced lung cancer in combination with Docetaxel. This difference may be due to the longer treatment duration, the different CT regimen (Paclitaxel instead of Docetaxel), and the more extended surgical treatment that received the EOC patients. The lower incidence of diarrhea in the phase II study of Nintedanib by Ledermann et al. [26] suggests that the disease or the CT regimen cannot completely explain the difference in the frequency of gastrointestinal AEs. In the AGO-OVAR 12 starting Nintedanib soon after debulking surgery, particularly if including bowel resection, might have contributed to the higher proportion of patients who experienced gastrointestinal AE compared with the other previous trials. The early onset of diarrhea within 2 months after surgery and the high proportion of patients in the control group who experienced at least low-grade diarrhea (any grade 31%) in this phase III trial seem to support this hypothesis. In the AGO OVAR 12 trial, Nintedanib also caused a not negligible incidence of hematological AEs. The incidence of grade 3 or worse (18%) thrombocytopenia may be linked to the combination with carboplatin. In fact, thrombocytopenia has never been described significantly associated to Nintedanib in previous clinical trials. Thus, this hematological AE may be due to an additive effect to the toxicity of carboplatin present in the regimen.

The evaluation of Nintedanib for the treatment of advanced EOC needs to be completed by further studies, especially taking into account the recurrence rate of this cancer [43, 44]. Consensus regarding an ­acceptable level of obtaining no macroscopic disease after primary surgery for this cancer would seem warranted. Alternatively, stratification in clinical trials, based on macroscopic clearance, could be undertaken. Anyway, well-designed trials with larger population samples are necessary to confirm the benefits obtained with Nintedanib in patients with low-risk tumor burden. Promising results might be obtained by the ongoing studies.

The treatment paradigm for advanced EOC is constantly evolving. Having a poor prognosis using the conventional available treatments, the investigation of targeted drugs with novel mechanisms of action is a priority of clinical research. Although Nintedanib showed to be active and safe in early clinical trials, in AGO OVAR 12 phase III trial it obtained in combination with standard CT a low PFS benefit. Despite this, a subgroup analysis demonstrated that its efficacy was particularly notable in patients with low postsurgical progression risk, with an extension of PFS by 7 months. Further studies are needed to assess the real impact of this drug on selected patients’ subpopulations with EOC.

None.

Ethical approval is not required for this type of article, which does not include any study performed by the authors.

The authors have no proprietary, financial, professional, or other personal interest of any nature in any product, service, or company. The authors alone are responsible for the content and writing of the paper.

F.B. and S.F. designed the systematic review and led its development. A.S.L. and J.C. screened the literature and included relevant data. F.B., A.S.L., and J.C. wrote the manuscript. F.G. and S.F. edited the manuscript for intellectual content. All the authors fulfill the International Committee of Medical Journal Editors (ICMJE) criteria and gave approval for the submission of the current version of the manuscript.

This work was not supported by any grant or other form of funding.

1.
IARC Publications Website – GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 v1.0, 2016.
2.
Cannistra SA: Cancer of the ovary. N Engl J Med 1993; 329: 1550–1559.
3.
Colombo N, Peiretti M, Parma G, Lapresa M, Mancari R, Carinelli S, Sessa C, Castiglione M; ESMO Guidelines Working Group: Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(suppl 5): v23–v30.
4.
National Comprehensive Cancer N: NCCN Clinical Practice Guidelines in OncologyTM. Ovarian Cancer. Version 1.2016.
5.
Kim SJ, Rosen B, Fan I, Ivanova A, McLaughlin JR, Risch H, Narod SA, Kotsopoulos J: Epidemiologic factors that predict long-term survival following a diagnosis of epithelial ovarian cancer. Br J Cancer 2017; 116: 964–971.
6.
Morotti M, Becker CM, Menada MV, Ferrero S: Targeting tyrosine-kinases in ovarian cancer. Expert Opin Investig Drugs 2013; 22: 1265–1279.
7.
Tangjitgamol S, Manusirivithaya S, Laopaiboon M, Lumbiganon P: Interval debulking surgery for advanced epithelial ovarian cancer: a Cochrane systematic review. Gynecol Oncol 2009; 112: 257–264.
8.
Colombo N, Peiretti M, Castiglione M; ESMO Guidelines Working Group: Non-epithelial ovarian cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20(suppl 4): 24–26.
9.
Oberaigner W, Minicozzi P, Bielska-Lasota M, Allemani C, de Angelis R, Mangone L, Sant M; Eurocare Working Group: Survival for ovarian cancer in Europe: the across-country variation did not shrink in the past decade. Acta Oncol 2012; 51: 441–453.
10.
Bogliolo S, Cassani C, Dominoni M, Musacchi V, Venturini PL, Spinillo A, Ferrero S, Gardella B: Veliparib for the treatment of ovarian cancer. Expert Opin Investig Drugs 2016; 25: 367–374.
11.
Bergamini A, Ferrero S, Leone Roberti Maggiore U, Scala C, Pella F, Vellone VG, Petrone M, Rabaiotti E, Cioffi R, Candiani M, Mangili G: Folate receptor alpha antagonists in preclinical and early stage clinical development for the treatment of epithelial ovarian cancer. Expert Opin Investig Drugs 2016; 25: 1405–1412.
12.
Leone Roberti Maggiore U, Valenzano Menada M, Venturini PL, Ferrero S: The potential of sunitinib as a therapy in ovarian cancer. Expert Opin Investig Drugs 2013; 22: 1671–1686.
13.
Leone Roberti Maggiore U, Valenzano Menada M, Venturini PL, Ferrero S: Sorafenib for ovarian cancer. Expert Opin Investig Drugs 2013; 22: 1049–1062.
14.
Gavalas NG, Liontos M, Trachana SP, Bagratuni T, Arapinis C, Liacos C, Dimopoulos MA, Bamias A: Angiogenesis-related pathways in the pathogenesis of ovarian cancer. Int J Mol Sci 2013; 14: 15885–15909.
15.
Zebrowski BK, Liu W, Ramirez K, Akagi Y, Mills GB, Ellis LM: Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol 1999; 6: 373–378.
16.
Wimberger P, Chebouti I, Kasimir-Bauer S, Lachmann R, Kuhlisch E, Kimmig R, Suleyman E, Kuhlmann JD: Explorative investigation of vascular endothelial growth factor receptor expression in primary ovarian cancer and its clinical relevance. Gynecol Oncol 2014; 133: 467–472.
17.
Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stahle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM; ICON7 Investigators: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–2496.
18.
Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX; Gynecologic Oncology Group: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473–2483.
19.
Leone Roberti Maggiore U, Bellati F, Ruscito I, Gasparri ML, Alessandri F, Venturini PL, Ferrero S: Monoclonal antibodies therapies for ovarian cancer. Expert Opin Biol Ther 2013; 13: 739–764.
20.
Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR: OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30: 2039–2045.
21.
Zhang J, Yang PL, Gray NS: Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009; 9: 28–39.
22.
Burger RA: Overview of anti-angiogenic agents in development for ovarian cancer. Gynecol Oncol 2011; 121: 230–238.
23.
Mross K, Stefanic M, Gmehling D, Frost A, Baas F, Unger C, Strecker R, Henning J, Gaschler-Markefski B, Stopfer P, de Rossi L, Kaiser R: Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 2010; 16: 311–319.
24.
Okamoto I, Kaneda H, Satoh T, Okamoto W, Miyazaki M, Morinaga R, Ueda S, Terashima M, Tsuya A, Sarashina A, Konishi K, Arao T, Nishio K, Kaiser R, Nakagawa K: Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther 2010; 9: 2825–2833.
25.
du Bois A, Huober J, Stopfer P, Pfisterer J, Wimberger P, Loibl S, Reichardt VL, Harter P: A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies. Ann Oncol 2010; 21: 370–375.
26.
Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I, Earl H, Perren T, Gore M, Persic M, Adams M, James L, Temple G, Merger M, Rustin G: Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 2011; 29: 3798–3804.
27.
du Bois A, Kristensen G, Ray-Coquard I, Reuss A, Pignata S, Colombo N, Denison U, Vergote I, Del Campo JM, Ottevanger P, Heubner M, Minarik T, Sevin E, de Gregorio N, Bidzinski M, Pfisterer J, Malander S, Hilpert F, Mirza MR, Scambia G, Meier W, Nicoletto MO, Bjorge L, Lortholary A, Sailer MO, Merger M, Harter P; AGO Study Group led Gynecologic Cancer Intergroup/European Network of Gynaecologic Oncology Trials Groups Intergroup Consortium: Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2016; 17: 78–89.
28.
Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68: 4774–4782.
29.
Dallinger C, Trommeshauser D, Marzin K, Liesener A, Kaiser R, Stopfer P: Pharmacokinetic properties of nintedanib in healthy volunteers and patients with advanced cancer. J Clin Pharmacol 2016; 56: 1387–1394.
30.
Marzin K, Kretschmar G, Luedtke D, Kraemer S, Kuelzer R, Schlenker-Herceg R, Schmid U, Schnell D, Dallinger C: Pharmacokinetics of nintedanib in subjects with hepatic impairment. J Clin Pharmacol 2017, Epub ahead of print.
31.
Stopfer P, Rathgen K, Bischoff D, Ludtke S, Marzin K, Kaiser R, Wagner K, Ebner T: Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica 2011; 41: 297–311.
32.
Mross K, Maessen P, van der Vijgh WJ, Bogdanowicz JF, Kurth KH, Pinedo HM: Absorption of epi-doxorubicin after intravesical administration in patients with in situ transitional cell carcinoma of the bladder. Eur J Cancer Clin Oncol 1987; 23: 505–508.
33.
Kropff M, Kienast J, Bisping G, Berdel WE, Gaschler-Markefski B, Stopfer P, Stefanic M, Munzert G: An open-label dose-escalation study of BIBF 1120 in patients with relapsed or refractory multiple myeloma. Anticancer Res 2009; 29: 4233–4238.
34.
Tai WT, Shiau CW, Li YS, Chang CW, Huang JW, Hsueh TT, Yu HC, Chen KF: Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity. J Hepatol 2014; 61: 89–97.
35.
Awasthi N, Hinz S, Brekken RA, Schwarz MA, Schwarz RE: Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer. Cancer Lett 2015; 358: 59–66.
36.
Awasthi N, Schwarz RE: Profile of nintedanib in the treatment of solid tumors: the evidence to date. OncoTargets Ther 2015; 8: 3691–3701.
37.
Kutluk Cenik B, Ostapoff KT, Gerber DE, Brekken RA: BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol Cancer Ther 2013; 12: 992–1001.
38.
Ge YZ, Wu R, Lu TZ, Xin H, Yu P, Zhao Y, Liu H, Xu Z, Xu LW, Shen JW, Xu X, Zhou LH, Li WC, Zhu JG, Jia RP: Circulating endothelial progenitor cell: a promising biomarker in clinical oncology. Medical Oncol 2015; 32: 332.
39.
du Bois A, Floquet A, Kim JW, Rau J, del Campo JM, Friedlander M, Pignata S, Fujiwara K, Vergote I, Colombo N, Mirza MR, Monk BJ, Kimmig R, Ray-Coquard I, Zang R, Diaz-Padilla I, Baumann KH, Mouret-Reynier MA, Kim JH, Kurzeder C, Lesoin A, Vasey P, Marth C, Canzler U, Scambia G, Shimada M, Calvert P, Pujade-Lauraine E, Kim BG, Herzog TJ, Mitrica I, Schade-Brittinger C, Wang Q, Crescenzo R, Harter P: Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 2014; 32: 3374–3382.
40.
Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Park-Simon TW, Rustin G, Joly F, Mirza MR, Plante M, Quinn M, Poveda A, Jayson GC, Stark D, Swart AM, Farrelly L, Kaplan R, Parmar MK, Perren TJ, ICON7 trial investigators: Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 2015; 16: 928–936.
41.
Griffiths CT, Parker LM, Fuller AF Jr: Role of cytoreductive surgical treatment in the management of advanced ovarian cancer. Cancer Treat Rep 1979; 63: 235–240.
42.
Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski MJ, Von Pawel J, Gottfried M, Bondarenko I, Liao M, Barrueco J, Gaschler-Markefski B, Novello S: Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial. J Clin Oncol 2013; 31:LBA8011.
43.
Laganà AS, Colonese F, Colonese E, Sofo V, Salmeri FM, Granese R, Chiofalo B, Ciancimino L, Triolo O: Cytogenetic analysis of epithelial ovarian cancer'’s stem cells: an overview on new diagnostic and therapeutic perspectives. Eur J Gynaecol Oncol 2015; 36: 495–505.
44.
Laganà AS, Sofo V, Vitale SG, Triolo O: Epithelial ovarian cancer inherent resistance: may the pleiotropic interaction between reduced immunosurveillance and drug-resistant cells play a key role? Gynecol Oncol Rep 2016; 18: 57–58.