Perspective For reprint orders, please contact: [email protected]

Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer

Guy Jerusalem*,1, Andrée Rorive2 & Joëlle Collignon2

Abstract The identification of additional chemotherapy agents for anthracycline- and taxane-pretreated advanced breast cancer (ABC) is an urgent medical need. Single agent chemotherapy is most times administered because combined therapy is only associated with modest, if any, improvement in median progression-free survival. Randomized trials failed to show overall survival benefit compared with single agent chemotherapy. We hope to modify the natural history of ABC by the consecutive use of treatments with documented activity in heavily pretreated patients. Quality of life remains an important end point as cure is in general not possible. We first review the activity of the approved and the most frequently used agents in heavily pretreated ABC. Thereafter, the potential role and safety profile of etirinotecan pegol is discussed given the results recently released of a Phase III trial comparing this agent to Treatment of Physician’s Choice.

The primary goals in advanced breast cancer (ABC) are palliation of symptoms and quality of life Keywords (QOL) because the treatments have only a very limited effect on overall survival (OS) [1,2]. Treatment • capecitabine decisions take into account disease burden and subtype, prior therapeutic exposure, availability, • chemotherapy • eribulin and patient and physician preference [3]. Endocrine and biological therapies are widely used to treat • etirinotecan pegol patients with hormone receptor- and/or HER2-positive breast cancer subtypes but those treatment • gemcitabine • irinotecan options are beyond the scope of this review. • ixabepilone • metastatic Anthracyclines and taxanes (AT) have the highest single agent activity in ABC. Unfortunately, breast cancer • randomized treatment failure occurs in a substantial number of patients within less than 12 months after start- trial • vinorelbine ing single agent chemotherapy and median OS for ABC remains still limited to 2–3 years [4–6]. Combinations are not routinely used in most patients. They are mainly reserved to a small subgroup of patients with rapidly progressing and/or symptomatic visceral disease. If patients have not received prior chemotherapy, AT are the preferred agents as front-line therapy in hormone receptor-negative patients or those who develop endocrine therapy-resistant breast cancer. However, chemotherapy regimens that contain anthracyclines (A) and/or taxanes (T) are routinely used as standard adjuvant treatment of high-risk early breast cancer [7,8] thus limiting their use in patients who subsequently develop metastatic disease. It is an urgent medical need to identify additional chemotherapy agents which have antitumoral activity in patients with ABC previously treated by AT. The aim of our paper is to discuss the potential role of a novel chemotherapeutic agent, etirinote- can pegol (also known as NKTR-102), in HER2-negative and estrogen receptor-negative or endo- crine therapy-resistant ABC previously treated by AT. Some of these patients may be candidates for a rechallenge by A or T but we will focus only on alternative chemotherapy agents. We will first review the evidence-based treatment options currently available in this patient population.

1Medical Oncology CHU Sart Tilman Liege & Liege University, Domaine Universitaire du Sart Tilman, B35, 4000 Liege, Belgium 2Medical Oncology CHU Sart Tilman Liege, Domaine Universitaire du Sart Tilman, B35, 4000 Liege, Belgium *Author for correspondence: Tel: +32 4366 8414; Fax: +32 4366 7688; [email protected] part of

10.2217/FON.15.80 © CHU Sart Tilman Liege Future Oncol. (2015) 11(12), 1775–1789 ISSN 1479-6694 1775 Perspective Jerusalem, Rorive & Collignon

Thereafter, we discuss the rationale for evalu- bevacizumab (75%). The combination therapy ating etirinotecan pegol, the promising results significantly increased only the ORR (19.8 vs in early clinical development and the results 9.1%). The median PFS (4.86 vs 4.17 months) released of the Phase III BEACON trial. and the median OS (15.1 vs 14.5 months) were similar in both treatment arms. Concerning side Current treatment options in heavily effects, similar incidence of diarrhea, hand-foot pretreated patients after failure of syndrome, thromboembolic events or serious antracyclines & taxanes bleeding episodes were observed between both ●●Capecitabine treatment groups. However, hypertension requir- Capecitabine is a standard of care for ABC. ing treatment (17.9 vs 0.5%) was more frequent Capecitabine is an orally administered prodrug in patients receiving bevacizumab. QOL meas- which is enzymatically converted to 5-fluoro- ured by the Functional Assessment of Cancer uracil by the enzyme thymidine phosphory- Treatment-Breast (FACT-B) was similar in both lase, which is highly active in tumor tissue. treatment arms. Capecitabine is approved by the US FDA as a single agent for patients with ABC that is Capecitabine + sunitinib resistant to both paclitaxel and A, and for those Another randomized Phase III trial evaluat- with breast cancer resistant to paclitaxel and ing the addition of a targeted agent to capecit- when further therapy by A is contraindicated. abine also failed to meet its primary end point Capecitabine is also approved by the EMA for PFS based on independent blinded radiologic the treatment of patients with metastatic breast review [15] . Sunitinib, an inhibitor of key mol- cancer after failure of standard chemotherapy. ecules involved in neoangiogenesis, administered This approval was based on single agent activity orally at a starting dose of 37.5 mg once daily demonstrated in Phase II trials in heavily pre- plus capecitabine (2000 mg/m² on days 1–14 of treated patients [9,10]. Blum et al. reported an a 3-week cycle) was compared with single-agent overall response rate (ORR) of 26%, a median capecitabine (2500 mg/m² on days 1–14 of a duration of response (DoR) of 8.3 months, a 3-week cycle) in patients with heavily pretreated median OS of 12.2 months and a median ABC. A total of 442 patients who received prior time to progression (TTP) of 3.2 months [10] . therapy with AT, and one or two prior chemo- All 75 patients included in this trial had failed therapy regimens for ABC or who presented treatment or had disease that was refractory to early relapse after an adjuvant regimen con- two or three previous chemotherapy regimens. taining AT were included. PFS was comparable All patients received prior therapy including between the treatment arms, with medians of T, nearly all patients (96%) also had received 5.5 months for the sunitinib plus capecitabine prior chemotherapy by A. Additional single arm arm and 5.9 months for the capecitabine mono- Phase II studies confirmed antitumoral activity therapy arm. There were also no significant of capecitabine in heavily pretreated ABC [11–13] . differences in ORR (19 vs 18%) or median OS (16.4 vs 16.5 months). Adverse events, except ●●Can the addition of targeted therapy to for hand–foot syndrome, were more severe in capecitabine improve outcome? the combination arm. Capecitabine + bevacizumab Bevacizumab, a humanized monoclonal anti- ●●Can a targeted therapy as monotherapy body directed against all isoforms of VEGF A, be more effective than capecitabine? failed to improve progression-free survival (PFS), Capecitabine or sunitinib? the primary end point in a Phase III trial hav- A randomized Phase III trial tested the hypoth- ing enrolled 462 patients comparing capecit- esis that single-agent sunitinib at the dose of abine to capecitabine + bevacizumab [14] . The 37.5 mg/day improves PFS compared with patients, who had been previously treated with capecitabine 1250 mg/m² (1000 mg/m² in AT, received capecitabine (2500 mg/m²/day) patients >65 years) twice daily on days 1–14 every twice daily on day 1 through 14 every 3 weeks, 3 weeks as treatment for ABC in patients who alone or in combination with bevacizumab received prior therapy by AT [16] . The trial was (15 mg/kg) on day 1. The mean delivered dose closed early by the independent data-monitoring intensity for capecitabine (80%) was similar to committee at first interim analysis (when only the combination therapy of capecitabine plus 482 of the expected 700 patients were enrolled)

1776 Future Oncol. (2015) 11(12) future science group Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer Perspective due to futility in reaching the primary end point. or 4 nonhematological toxic effects were similar The data indicated that PFS was shorter with between both treatment groups. sunitinib compared with capecitabine (median: 2.8 vs 4.2 months). Also other end points, ●●Is vinorelbine-gemcitabine a better median OS (15.3 vs 24.6 months) and ORR (11 treatment option compared with vs 16%) were numerically inferior in the suni- capecitabine? tinib treatment group. In addition, a post hoc A small randomized Phase III trial compared subset analysis failed to reveal any subpopulation capecitabine (at the dose of 1250 mg/m² twice that benefited more from sunitinib than from daily, on days 1–14 every 3 weeks) and the com- capecitabine treatment. Consequently, suni- bined therapy vinorelbine-gemcitabine (vinorel- tinib as monotherapy should not be considered bine 25 mg/m² + gemcitabine 1000 mg/m² on a t­reatment option in this patient population. days 1 and 15 every 4 weeks intravenously) in patients with ABC pretreated by AT [20]. Only ●●Vinorelbine 74 women were treated on each arm. This trial Vinorelbine which belongs to the family of vinca failed to meet the primary end point of dem- alkaloids is one of the most widely used drugs onstrating a significant prolongation of PFS in in ABC particularly because of its good toler- favor of the combination arm. The median PFS ance profile. Unfortunately, vinorelbine was not in the combined therapy arm was 5.4 months largely evaluated in randomized Phase III tri- compared with 5.2 months for capecitabine. als. Single-agent vinorelbine has some activity in Also, median OS (20.4 vs 22.4 months) and patients suffering from ABC previously treated ORR (28.4 vs 24.3%) were not significantly by AT [17,18]. Toi et al. administered vinorelbine improved. Exploratory subgroup analyses failed at a dose level of 25 mg/m² intravenously on to demonstrate any benefit in favor of the com- days 1 and 8 of a 3-week cycle in 50 evaluable bination arm among all subgroups tested. Side patients previously treated by AT [17] . The ORR effects were generally manageable. Neutropenia was 20.0%. The Kaplan–Meier estimate of TTP and fatigue were more common with vinorel- was less than 4 months (115 days). Seo et al. bine-gemcitabine and hand–foot syndrome in administered vinorelbine at a dose of 25 mg/m² patients receiving capecitabine. The authors intravenously on days 1, 8, 15 and 22, every concluded that given the favorable toxicity pro- 4 weeks in 24 evaluable patients who suffered file and the convenience of oral administration, from AT pretreated ABC [18]. They reported a single-agent capecitabine is the recommended median TTP of 3.7 months and a median DoR treatment for compliant patients. of 2.8 months. ●●Ixabepilone ●●Is vinorelbine-gemcitabine a better Ixabepilone, a semisynthetic analog of epothilone treatment option compared with B, binds to tubulins in a manner distinct from vinorelbine monotherapy? that of other microtubule-binding agents, and Martin et al. compared, in a randomized Phase leads to tubulin stabilization, which causes III trial, single-agent vinorelbine (30 mg/m², apoptosis [21] . In a Phase II study, single-agent days 1 and 8) and gemcitabine plus vinorel- ixabepilone showed clinical activity in ABC, bine (gemcitabine 1200 mg/m² + vinorelbine with an ORR of 12% in 113 response-assessable 30 mg/m², days 1 and 8) in 252 women with heavily pretreated patients, with disease refrac- ABC who had been pretreated by AT [19] . Both tory to anthracyclines, taxanes and capecitabine study treatments were administered intrave- (ATC) [22]. Ixabepilone 40 mg/m² was admin- nously every 21 days. The primary end point istered intravenously on day 1 of a 21-day cycle. median PFS was increased in the combined Median PFS and median DoR were 3.1 and treatment arm (6 months vs 4 months; HR: 5.7 months, respectively. Grade 3/4 treatment- 0.66; p = 0.0028). However, OS was similar related adverse events included peripheral sen- (15.9 vs 16.4 months). The ORR was higher sory neuropathy (14%), asthenia (13%), myalgia for patients receiving gemcitabine plus vinorel- (8%) and mucositis (6%). Resolution of grade bine (36 vs 26%). Some adverse events were 3/4 peripheral sensory neuropathy was observed more frequent in the combined treatment arm after a median period of 5.4 weeks. Given this (grade 3 or 4 neutropenia: 61 vs 44%; febrile promising activity in ABC resistant to ATC, neutropenia: 11 vs 6%). Incidences of grade 3 and the acceptable and manageable safety

future science group www.futuremedicine.com 1777 Perspective Jerusalem, Rorive & Collignon

profile, ixabepilone was further evaluated in with capecitabine can definitively not be con- Randomized Phase III trials. sidered a major step forward in the treatment of these heavily pretreated patients. Ixabepilone is Ixabepilone + capecitabine versus approved in the USA but not in Europe as mono- capecitabine therapy for the treatment of patients with ABC Two randomized Phase III trials have been per- resistant to ATC. Ixabepilone is also approved in formed. Thomas et al. compared ixabepilone combination with capecitabine for the treatment + capecitabine to capecitabine monotherapy of patients with metastatic or locally advanced in 752 patients suffering from A-pretreated or breast cancer resistant to treatment with AT, or -resistant and T-resistant ABC [23]. Patients whose cancer is T resistant and for whom further received either ixabepilone 40 mg/m² intrave- therapy by A is contraindicated. nously on day 1 of a 21-day cycle plus capecit- abine 2000 mg/m² orally on days 1–14 of a ●●Eribulin 21-day cycle, or capecitabine alone 2500 mg/m² Eribulin should be considered as a valid treat- on the same schedule. The primary end point ment option because a significantly increased PFS (evaluated by blinded independent review) OS has been shown compared with standard of was increased in the combined treatment arm care in a heavily pretreated patient population (median: 5.8 vs 4.2 months), with a 25% reduc- in the EMBRACE trial. This drug has been tion in the estimated risk of disease progression approved by the EMA and FDA as a single (HR: 0.75; p = 0.0003). Investigator assessed agent for patients with heavily pretreated ABC median PFS provided consistent results (5.3 vs based on the results of this trial [25]. Eribulin is 3.8 months). The ORR was also improved (35 a nontaxane tubulin-binding agent, it inhibits vs 14%). Unfortunately, the adverse events were the growth phase of the microtubules with- also much more frequent in the combined treat- out impacting the shortening phase and caus- ment arm: grade 3/4 treatment-related sensory ing tubulin sequestration into nonproductive neuropathy (21 vs 0%), fatigue (9 vs 3%) and aggregates. In this study, 762 women were neutropenia (68 vs 11%) and also increased rate randomly allocated (2:1) to eribulin mesilate of death as a result of toxicity (3 vs 1%). (1.4 mg/m² administered intravenously during Sparano et al. randomized 1221 patients suf- 2–5 min on days 1 and 8 of a 21-day cycle) fering from ABC previously treated by AT to or treatment of physician’s choice (TPC; 96% receive either ixabepilone (40 mg/m² intrave- received chemotherapy, which was most often nously on day 1) plus capecitabine (2000 mg/m² vinorelbine, gemcitabine or capecitabine). orally on days 1 through 14) or capecitabine alone All patients had previously received between (2500 mg/m² on the same schedule) given every two and five chemotherapy regimens, includ- 21 days [24]. This trial failed to meet its primary ing AT, and two or more regimens for ABC. end point OS. The median OS was 16.4 months Progressive disease had to be observed within in the combined therapy arm compared with 6 months or less of latest chemotherapy regi- 15.6 months in the capecitabine monotherapy men in eligible patients. The primary objective arm (difference not statistically significant). of the EMBRACE trial was to compare OS Concerning secondary end points, in the 79% between the two treatment groups; secondary of patients with measurable disease, the combi- end points included PFS, ORR and DoR. Most nation significantly improved the median PFS patients (73%) had received capecitabine previ- (6.2 vs 4.2 months) and the ORR (43 vs 29%). ously. Overall, 16% of the patients had HER2- It is important to note that reversible grade 3–4 positive disease and 19% of the patients suffered neuropathy occurred in 24% treated with the from triple-negative breast cancer. The study combination. met its primary end point. The median OS These results provide some support for the use was 13.1 months in patients receiving eribulin of ixabepilone plus capecitabine in patients with compared with only 10.6 months in patients metastatic disease pretreated or resistant to A and in the control arm (HR: 0.81; p = 0.041). The resistant to T, a population with limited effective median PFS was 3.7 months with eribulin treatment options. However, given the increased compared with 2.2 months in the TPC arm toxicity, the very short absolute increase in PFS in the intention-to-treat (ITT) population by and the absence of OS improvement with the independent review but this difference was not combined therapy, the association of ixabepilone statistically significant. The median PFS was

1778 Future Oncol. (2015) 11(12) future science group Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer Perspective similar in the investigator assessment of the ITT was also similar (11 vs 11.5%). The most com- population (3.6 vs 2.2 months), but in contrast mon adverse events for eribulin and capecitabine to the independent review analysis this differ- were neutropenia (54.2 vs 15.9%), hand–foot ence between treatment groups was signifi- syndrome (0.2% vs 45.1%), alopecia (34.6 vs cant (HR: 0.76; p = 0.002). The reason why 4.0%), leukopenia (31.4 vs 10.4%), diarrhea the difference was not statistically significant (14.3 vs 28.8%) and nausea (22.2 vs 24.4%), according to central review is a higher number respectively. of censored patients in the independent review analysis resulting in less events of progression. Topoisomerase 1 inhibitors The ORR was low in both treatment arms, 12% In summary, several drugs have proven antitu- in patients treated with eribulin compared with mor activity but all the currently available treat- 5% in patients receiving TPC (p = 0.002) by ment options for ABC after previous exposure to independent review in patients with measurable AT allow only disease control for a short period disease. Median DoR was not statistically dif- of time with median PFS in general less than 6 ferent between both treatment arms (eribulin: months (Table 1). Given the limited activity of 4.2 months vs TPC: 6.7 months). The clinical these treatments, the toxicity profile of the drugs benefit rate was 23% for eribulin and 17% for is of major importance because quality of life is TPC. Asthenia/fatigue and neutropenia were an important end point (Table 2). Capecitabine the most frequent adverse events in both treat- is frequently the first choice because of con- ment arms. In general, the side effects associated venient oral administration and very low risk with eribulin were manageable. Severe adverse of alopecia and myelotoxicity. To date, eribulin events (grade 3 or 4) more frequently observed is the only agent that has been shown, when in patients receiving erubilin compared with the administered as monotherapy, to prolong OS in control arm included neutropenia, leucopenia heavily pretreated ABC. Myelosuppression and and peripheral neuropathy. The incidence of neurotoxicity are limiting factors for the use of grade 3 and grade 4 neutropenia was respec- ixabepilone. Polychemotherapies are not used in tively 21 and 8% but neutropenic fever was most patients because no OS benefit compared uncommon. Peripheral neuropathy occurred in with single agent therapy has been observed in 35% of patients receiving eribulin (including the Phase III trials in this patient population. 8% grade 3 or grade 4 neuropathy) and was the Biological agents are not added to chemotherapy most common adverse event leading to discon- in a HER2-negative patient population because tinuation from this treatment (5%). Alopecia is the currently available results are all disappoint- a common side effect (45% of patients receiv- ing. We hope that the consecutive use of single ing eribulin including 26% grade 2 alopecia). agent chemotherapy will increase OS com- Hypersensitivity related to eribulin occurred pared with the natural history of the disease. in 1% of patients. A premedication to pre- Consequently the development of novel chemo- vent hypersensitivity was not administered therapy agents presenting significant antitumor and is also currently not indicated for patients activity in this patient population is important. r­eceiving eribulin. Dose-dependent side effects should also be taken into account when developing new agents. A can Eribulin or capecitabine induce dose-dependent irreversible cardiomyo- Eribulin was compared with capecitabine in pathy and very importantly, many of the drugs women with previously treated ABC in another frequently used (including T, eribulin, ixabepi- important Phase III trial [26]. Unfortunately, this lone and vinorelbine) are associated with severe trial failed to meet its co-primary end points OS neuropathy having a major impact on QOL. and PFS. Eligible patients had received previ- This neuropathy may limit also the duration of ously AT and were receiving study drug as first-, treatment for ABC or prevent retreatment for second- or third-line therapy for ABC. Eribulin recurrence with the same or other potentially mesylate 1.4 mg/m² was given on days 1 and 8 neurotoxic agents. Etirinotecan pegol is a new of a 21-day cycle. Capecitabine was administered promising drug with a specific safety profile orally at the dose of 2.5 g/m²/day on days 1–14 without alopecia, cardio- and neurotoxicity. of a 21-day cycle. The median OS was, respec- Before summarizing the results already avail- tively, 15.9 and 14.5 months. The median PFS able with this drug, it is also useful to review the was, respectively, 4.1 and 4.2 months. The ORR available data c­oncerning irinotecan in ABC.

future science group www.futuremedicine.com 1779 Perspective Jerusalem, Rorive & Collignon

Table 1. Key results of clinical trials in heavily pretreated patients. Regimen Patients (n) Response rate TTP or PFS (months) OS (months) Ref. Capecitabine Blum et al., Phase II [10] Capecitabine 75 26† TTP: 3.2 12.2 Capecitabine ± targeted therapy Miller et al., Phase III [14] Capecitabine 230 9.1 PFS: 4.17† 14.5 Capecitabine + bevacizumab 232 19.8 4.86† 15.1 Crown et al., Phase III [15] Capecitabine 221 18 PFS: 5.9† 16.4 Capecitabine + sunitinib 221 19 5.5† 16.5 Capecitabine or targeted therapy Barrios et al., Phase III [16] Capecitabine 224 16 PFS: 4.2† 24.6 Sunitinib 238 11 2.8† 15.3 Vinorelbine Toi et al., Phase II [17] Vinorelbine 50 20† TTP: <3 NR Vinorelbine ± gemcitabine Martin et al., Phase III [19] Vinorelbine 126 26 PFS: 4† 16.4 Vinorelbine + gemcitabine 125 36 6† 15.9 Vinorelbine + gemcitabine or capecitabine Pallis et al., Phase III [20] Capecitabine 74 24.3 PFS: 5.2† 22.4 Vinorelbine + gemcitabine 74 28.4 5.4† 20.4 Ixabepilone Perez et al., Phase II [22] Ixabepilone 126 11.5† PFS: 3.1 8.6 Ixabepilone + capecitabine vs capecitabine Thomas et al., Phase III [23] Capecitabine 377 14 PFS: 4.2† NR Capecitabine + ixabepilone 375 35 5.8† NR Sparano et al., Phase III [24] Capecitabine 612 29 PFS: 6.2 16.4† Capecitabine + ixabepilone 609 43 4.2 15.6† Eribilin vs best physician’s choice Cortes et al., Phase III [25] Eribulin 508 12 PFS: 3.6 13.1† Best physician’s choice 254 5 2.2 10.6† Eribulin vs capecitabine Kaufman et al., Phase III [26] Eribulin 554 11 PFS: 4.1† 15.9† Capecitabine 548 11.5 4.2† 14.5† Irinotecan Perez et al., Phase II [27] Irinotecan weekly 52 23 PFS: 2.8† 9.7 †The primary end points of the trials are pointed out. NR: Not reported; OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression.

1780 Future Oncol. (2015) 11(12) future science group Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer Perspective

Table 1. Key results of clinical trials in heavily pretreated patients (cont.). Regimen Patients (n) Response rate TTP or PFS (months) OS (months) Ref. Irinotecan (cont.) Perez et al., Phase II (cont.) [27] Irinotecan every 3 weeks 51 14 1.9† 8.6 Etirinotecan pegol Awada et al., Phase II [28] Etirinotecan 70 29† PFS: 4.7 10.3 †The primary end points of the trials are pointed out. NR: Not reported; OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression.

●●Irinotecan registration trial has not been undertaken and The use of drugs with a different mechanism this drug is not approved for ABC. of action from that of tubulin-targeted agents or A is an interesting approach in order to ●●Etirinotecan pegol limit cumulative dose toxicities. Irinotecan Etirinotecan pegol (NKTR-102) is a long-acting is an inhibitor of topoisomerase I, an enzyme topoisomerase-I inhibitor derived from camp- required for DNA replication. SN-38 the active tothecin. Etirinotecan pegol was designed to metabolite binds to the topoisomerase I–DNA reduce maximal SN-38 systemic concentrations complex, preventing the enzyme from resealing while providing continuous exposure to tumors, the DNA during replication and transcription, even when administered in an every 14- or 21-day thus causing DNA breaks, leading to apopto- schedule. The polymer design of etirinotecan sis [29]. Irinotecan has shown some single agent pegol modifies its distribution in the body. It activity in a variety of solid tumors, including consists of the topoisomerase-I inhibitor irinote- ABC, in Phase I and II studies [30–32]. A larger can bound to a proprietary polyethylene glycol randomized Phase II trial was conducted based core by a biodegradable linker. The linker slowly on these promising results to assess further two hydrolyses in vivo to form SN38, the active moi- schedules of irinotecan monotherapy in women ety of etirinotecan pegol. The maximum plasma with ABC refractory to A, T or both [27]. Patients concentration (Cmax) of SN-38 is reduced by up were randomly assigned to irinotecan in 6-week to tenfold with etirinotecan pegol potentially 2 cycles comprising 100 mg/m weekly for 4 resulting in less side effects [33]. Since etirinote- weeks, then a 2-week rest or 240 mg/m2 every can pegol has relatively large molecular weight, 3 weeks. Patients were allowed to have received it may accumulate more in tumor tissue than in a maximum of one adjuvant regimen and two normal tissue [34]. Etirinotecan pegol does not regimens for ABC, whether or not all of these freely cross intact vasculature to enter healthy tis- were based on A or T. More than half of those sue but may traverse the leaky blood vasculature­ patients had visceral metastases or received the of the tumor environment more readily. study drug as third- or fourth-line therapy. In In preclinical studies, relatively higher con- the weekly arm, the ORR was 23%, the median centrations of etirinotecan pegol have been DoR was 4.9 months and the median OS was observed in tumor tissue as compared with 9.7 months. In the every 3 weeks arm, the ORR plasma. Pharmacokinetic studies in mice, rats was 14%, the median DoR was 4.2 months and and dogs showed lower Cmax and clearance val- median OS was 8.6 months. Importantly, the ues for SN-38 and correspondingly greater sys- treatment was generally well tolerated, especially temic exposure to SN-38, following etirinote- in the weekly arm. Grade 3–4 adverse events can pegol dosing, compared with irinotecan [35]. with at least 10% incidence included neutro- The initial Phase I clinical trial has shown that penia (29%) and diarrhea (17%) in the weekly etirinotecan pegol administration resulted in arm and neutropenia (36%), vomiting (20%), a sustained and controlled exposure to SN38, dyspnea (18%), nausea (16%) and diarrhea which had a mean half life of about 50 days [33]. (12%) in the every 3-weeks arm. This study has Generally, the pharmacokinetics of etirinotecan shown that irinotecan has a promising antitumor pegol are predictable and do not require complex activity in refractory ABC with an acceptable dosing adjustments. Seventy-six patients suf- side effect profile but unfortunately a Phase III fering from various solid tumors were entered

future science group www.futuremedicine.com 1781 Perspective Jerusalem, Rorive & Collignon

Table 2. Main toxicities in clinical trials in heavily pretreated patients. Regimen Patients Main toxicities All grade Grade 3/4 Ref. (n) (%) (%) Capecitabine Blum et al., Phase II [10] Capecitabine 75 HFS 62.2 21.6/NR Diarrhea 58.1 16.2/2.7 Nausea 55.4 9.5/0 Stomatitis 33.8 12.2/0 Capecitabine ± targeted therapy Miller et al., Phase III [14] Capecitabine 230 Diarrhea 26.5 10.7/0 Stomatitis 5.6 0/0.5 HFS 60 24.2/0 Hypertension 2.4 0.5/0 Bleeding 11.2 0.5/0 TE 5.6 2.3/2.8 Proteinuria 7.4 0/0 Capecitabine + bevacizumab 232 Diarrhea 28 11.8/0 Stomatitis 8.7 1.7/0 HFS 69.9 27.5/0 Hypertension 23.5 17.9/0 Bleeding 28.8 0.4/0

TE 7.3 3.9/3 Proteinuria 22.3 0.9/0 Crown et al., Phase III [15] Capecitabine 221 Diarrhea 45 9/1 Nausea 42 1/0 HFS 61 24/0 Hypertension 4 0 Fatigue 25 3/<1 Neutropenia 18 4/<1 Thrombocytopenia 7 0/<1 Capecitabine + sunitinib 221 Diarrhea 58 8/1 Nausea 56 4/<1 HFS 54 16/NR Hypertension 22 2/0 Fatigue 30 10/<1 Neutropenia 48 30/1 Thrombocytopenia 48 13/4 Capecitabine or targeted therapy Barrios et al., Phase III [16] Capecitabine 224 Diarrhea 34 4/1 HFS 61 16/0 Nausea 28 <1/0 Fatigue 20 1/0 Anorexia 16 <1/0 Vomiting 11 1/0 Neutropenia 11 3/<1 Thrombocytopenia 3 <1/1 Sunitinib 238 Diarrhea 40 5/1 HFS: Hand–foot syndrome; NA: Not applicable; NR: Not reported; TE: Thromboembolic event.

1782 Future Oncol. (2015) 11(12) future science group Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer Perspective

Table 2. Main toxicities in clinical trials in heavily pretreated patients (cont.). Regimen Patients Main toxicities All grade Grade 3/4 Ref. (n) (%) (%) Capecitabine or targeted therapy (cont.) Barrios et al., Phase III (cont.) [16] Sunitinib (cont.) HFS 32 8/0 Nausea 32 1/0 Fatigue 30 6/1 Anorexia 23 1/0 Vomiting 28 2/0 Neutropenia 17 10/1 Thrombocytopenia 16 6/2 Vinorelbine Toi et al., Phase II [17] Vinorelbine 50 Neutropenia 94 34/40 Anemia 76 6/4 Thrombopenia 14 0/2 Febrile neutropenia 12 12/0 Nausea 64 2/0 Anorexia 62 8/0 Vinorelbine ± gemcitabine Martin et al., Phase III [19] Vinorelbine 126 Neutropenia NR 23/21 Febrile neutropenia NR 6/0 Alopecia NR 17/0 Fatigue NR 15/2 Vinorelbine + gemcitabine 125 Neutropenia NR 34/27 Febrile neutropenia NR 9/2 Alopecia NR 17/0 Fatigue NR 22/2 Vinorelbine + gemcitabine or capecitabine Pallis et al., Phase III [20] Capecitabine 74 Neutropenia 25 2.7/1.4 Anemia 50 1.4/0 Fatigue 28.4 1.4/0 HFS 23 5.4/0 Nausea 10.8 0 Vinorelbine + gemcitabine 74 Neutropenia 52.7 7.6/5.4 Anemia 60.8 1.4/0 Fatigue 35.1 4.1/0 HFS 6.8 1.4.0 Nausea 25.7 0 Ixabepilone Perez et al., Phase II [22] Ixabepilone 126 Peripheral sensory neuropathy 60 13/1 Fatigue 50 13/1 Myalgia 49 8/0 Mucositis 29 6/1 Neutropenia 79 31/23 HFS: Hand–foot syndrome; NA: Not applicable; NR: Not reported; TE: Thromboembolic event.

future science group www.futuremedicine.com 1783 Perspective Jerusalem, Rorive & Collignon

Table 2. Main toxicities in clinical trials in heavily pretreated patients (cont.). Regimen Patients Main toxicities All grade Grade 3/4 Ref. (n) (%) (%) Ixabepilone + capecitabine vs capecitabine Thomas et al., Phase III [23] Capecitabine 368 Peripheral sensory neuropathy 16 0/0 Fatigue 20 3/0.3 Neutropenia 43 9/2 HFS 62 17/0 Diarrhea 39 8/0.5 Ixabepilone + capecitabine 369 Peripheral sensory neuropathy 64 20/0.8 Fatigue 40 9/0 Neutropenia 89 32/36 HFS 64 18/0 Diarrhea 44 6/0 Sparano et al., Phase III [24] Capecitabine 612 Peripheral sensory neuropathy 20 0.8/0 Fatigue 22 3/0.2 Neutropenia 47 6/3 Diarrhea 39 9/0.5 HFS 68 20/NR Capecitabine + ixabepilone 609 Peripheral sensory neuropathy 65 22/0.7 Fatigue 42 11/0.8 Neutropenia 92 34/39 Diarrhea 43 7/0.2 HFS 64 21/NR Erubilin vs best physician’s choice Cortes et al., Phase III [25] Eribulin 508 Fatigue 54 8/1 Peripheral sensory neuropathy 35 8/<1 Neutropenia 52 21/24 Alopecia 45 0/0 Best physician’s choice 254 Fatigue 24 10/0 Peripheral sensory neuropathy 16 2/0 Neutropenia 30 14/7 Alopecia 10 0/0 Eribulin vs capecitabine Kaufman et al., Phase III [26] Eribulin 554 Fatigue 16.7 2/0 Peripheral sensory neuropathy 27.4 6.4/0.6 Neutropenia 54.2 24.6/21.1 Alopecia 34.6 NA HFS 0.2 0 Diarrhea 14.3 1.1/0 Capecitabine 548 Fatigue 15.4 2.2/0.2 Peripheral sensory neuropathy 13.7 0,9 Neutropenia 15.9 4.2/0.7 Alopecia 4 NA HFS 45.1 14.5/0 Diarrhea 28.8 5.1/0.2 HFS: Hand–foot syndrome; NA: Not applicable; NR: Not reported; TE: Thromboembolic event.

1784 Future Oncol. (2015) 11(12) future science group Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer Perspective

Table 2. Main toxicities in clinical trials in heavily pretreated patients (cont.). Regimen Patients Main toxicities All grade Grade 3/4 Ref. (n) (%) (%) Irinotecan Perez et al., Phase II [27] Irinotecan weekly 52 Neutropenia NR 19/10 Diarrhea NR 13/4 Vomiting NR 4/0 Nausea NR 6/0 Dyspnea NR 4/0 Irinotecan every 3 weeks 51 Neutropenia NR 12/24 Diarrhea NR 12/9 Vomiting NR 18/2 Nausea NR 16/0 Dyspnea NR 12/6 Etirinotecan pegol Awada et al., Phase II [28] Etirinotecan 70 Diarrhea 73 20/1 Nausea 73 4/0 Fatigue 47 11/0 Vomiting 47 7/0 Neutropenia 19 7/4 Dehydration 19 10/0 HFS: Hand–foot syndrome; NA: Not applicable; NR: Not reported; TE: Thromboembolic event. onto three dosing schedules (58–245 mg/m2). with a complete response and 18 with a par- The maximum tolerated dose was 115 mg/m2 tial response); ten patients achieved an ORR in for the weekly × 3 every 4 weeks schedule and each dosing schedule. In addition, 13 patients 145 mg/m 2 for both the every 14 days and every on the 14-day schedule and 17 patients on 21days schedules. Most adverse events related the 21-day schedule had some form of clini- to etirinotecan pegol were gastrointestinal dis- cal benefit, defined as complete response, par- orders and were more frequent at higher doses. tial response or stable disease for ≥6 months. Late onset diarrhea was observed in some Concerning secondary end points, median patients, the frequency of which usually cor- PFS was 3.3 months for patients on the 14-day related with dose density. Cholinergic diarrhea schedule and 5.6 months for patients on the commonly seen with irinotecan treatment did 21-day schedule. Median OS was 8.8 months for not occur in patients treated with etirinote- patients in the 14-day group and 13.1 months can pegol. Confirmed partial responses were for patients in the 21-day group. Concerning observed in eight patients with breast, colon, safety, both grade 3 or worse and serious adverse lung (small and squamous cell), bladder, c­ervical events, occurred more frequently in patients and ­neuroendocrine cancer. on the 14-day schedule than in those on the Awada et al. reported a randomized, two- 21-day schedule. The most common grade 3 stage, open-label Phase II trial assessing the or worse adverse events were diarrhea, fatigue, efficacy and safety of two different schedules neutropenia, dehydration and vomiting. Two of etirinotecan pegol in patients with ABC [28]. possible drug-related deaths (acute renal failure Seventy patients (35 in each group) who had and septic shock) were observed in the 14-day received T and undergone two or fewer previ- group. Diarrhea is an important dose limiting ous chemotherapy regimens for ABC, were ran- toxicity in patients receiving etirinotecan pegol. domly assigned to etirinotecan pegol 145 mg/m² Fifteen patients developed grade 3 or worse diar- every 14 days or every 21 days. The primary rhea (including one event of grade 4 severity, end point was the proportion of patients with occurring in a patient on the 14-day schedule). a confirmed ORR. A confirmed ORR was Given the long half-life of the drug, severe diar- recorded in 20 of 70 patients in the ITT (two rhea is in general observed after 7 months of

future science group www.futuremedicine.com 1785 Perspective Jerusalem, Rorive & Collignon

therapy. Grade 3 or worse diarrhea occurred disease according to the RECIST criteria. The with a median onset of 88 days in the 14-day final data collection date for primary outcome group and 90 days in the 21-day group. The measure was December 2014, with topline median duration of grade 3 or worse diarrhea results recently announced in March 2015 [37]. was 8.5 days in patients on the 14-day schedule The study recruited a total of 852 patients. and 15.8 days in those on the 21-day schedule. Ninety percent of the patients enrolled in the Patient education and appropriate management BEACON study had HER2-negative disease. is an important issue. Review of the 51 patients NKTR-102 provided a 2.1-month improve- who developed diarrhea of any grade revealed ment in median overall survival (OS) over TPC that the protocol stipulated management of (12.4 vs 10.3 months) but this difference is not diarrhea and retreatment guidelines were not statistically significant. By contrast, in a pre- followed for 30 patients (59%). In particular, specified subgroup of patients with a history of it is very important to wait for complete resolu- brain metastases, NKTR-102 showed a statis- tion of diarrhea before considering retreatment. tically significant improvement of 5.2 months Interestingly, myelosuppression was not fre- in median OS (10.0 months compared with quently observed in this Phase II study. Grade 3 4.8 months). The proportion of patients with or worse neutropenia occurred in five patients brain metastases with 12-month survival was (four on the every 14-day schedule), grade 3 or higher in the patients treated by NKTR-102 worse anemia in one patient in each treatment (44.4 vs 19.4%). In a pre-specified subgroup of arm and grade 3 or worse thrombocytopenia in patients with baseline liver metastases at study only one patient on the 14-day schedule. Febrile entry, NKTR-102 showed also a statistically sig- neutropenia occurred only in one patient. Also nificant improvement of 2.6 months in median very importantly, alopecia was rare (ten patients OS (10.9 vs 8.3 months). In these patients with with grade 1; one patient with grade 2). No car- baseline liver metastases, the proportion of diotoxicity or neurotoxicity was reported in this patients with 12-month survival was 46.9% in study. Only one patient presented cholinergic the NKTR-102 arm as compared to 33.3% in toxicity. Symptoms such as rhinitis, increased the control arm. The incidence of grade 3 and salivation, miosis, lacrimation, diaphoresis, higher adverse events was lower in the NKTR- flushing and intestinal hyperperistalsis are 102 arm (48%) compared with the TPC arm f­requently a­ssociated with irinotecan infusion. (63%). The most common grade 3 and above The promising results of this randomized adverse events observed with NKTR-102 were Phase II study led to the selection of the 21-day diarrhea (9.6%), neutropenia (9.4%), anemia schedule for the subsequent Phase III registra- (4.7%) and fatigue (4.5%). Rates of grade 1/2 tion trial, the BEACON Study (Breast Cancer alopecia were also lower in the NKTR-102 Outcomes With NKTR-102): a Phase III open- arm (10 vs 23%). We are looking forward to label, randomized, multicenter study of NKTR- the presentation of these data at an upcoming 102 versus TPC in patients with ABC previously medical­ meeting. treated with ATC (NCT01492101) [36]. The primary end point of the BEACON study is to Conclusion compare OS of patients who receive NKTR-102 Several drugs have proven efficacy in AT pre- once every 21 days to patients who receive TPC treated ABC but there are still unmet needs, selected from a list of seven single-agent intra- especially the impact of these agents on OS venous therapies: eribulin, ixabepilone, vinorel- improvement is still very low. We have also to bine, gemcitabine, paclitaxel, docetaxel or nab- better understand the best way to combine these paclitaxel. All patients had received two to five treatments although for most patients sequen- prior cytotoxic chemotherapy regimens with the tial monotherapy is probably the best choice. last dose administered within 6 months before Furthermore, the best sequence is not yet well entering the BEACON study. A minimum of known. Co-morbidities or residual toxicities two chemotherapy regimens had to be given for from prior cytotoxic therapy influence the treat- ABC. All therapies received prior to a diagnosis ment decisions. It is important to point out of ABC (e.g., neoadjuvant, adjuvant or repeated that most patients do not have a major benefit adjuvant therapy following a second resection) of any chemotherapy option after failure of AT. are counted as only one regimen. Patients Long-term responders are unfortunately the can have either measurable or nonmeasurable exception.

1786 Future Oncol. (2015) 11(12) future science group Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer Perspective

Future perspective be more attractive for the patients although com- Predictive markers for higher benefits or unaccep- pliance may be an issue. The low risk of alopecia table toxicity in specific patient populations would with etirinotecan pegol in addition to the lack of be useful to better identify subpopulations with neurotoxicity is of value in the context of QOL. a higher benefit. Unfortunately, we have major The results seen in difficult to treat subgroups doubts that chemotherapy will become more indi- (patients with liver or brain metastases) in the vidualized therapy based on predictive markers BEACON study are highly encouraging. in the next 5–10 years and that the best sequence We do not expect major advances in the field question will be answered by clinical trials. Other of chemotherapy in the next 5–10 years, in par- approaches such as targeted therapy in specific ticular if we are discussing a curative approach. subtypes or immunotherapy are more promising In addition, economic limitations will probably in order to observe more long-term survivors. become an increasing problem. Prevention, early Patient’s preference influenced by the side diagnosis and curative approaches will probably effects and by the mode of administration is of be considered a priority. The addition of targeted major importance when we treat an incurable agents in specific subpopulations and immuno­ disease such as ABC. However, we should not therapy are much more promising than the only discuss the various chemotherapy options development of new chemotherapy agents. We but also best supportive care in these heavily pre- should optimize the adjuvant therapy in order to treated patients. Of course, most patients will cure more patients or with the aim of decreas- opt for an active therapy but at least this alterna- ing side effects, in particular the long-term side tive approach should also be discussed with the effects. Available resources will be mostly used patient. QOL is a major issue. Oral agents may in research to individualize the adjuvant therapy.

Executive summary Current approach of metastatic breast cancer after failure of anthracyclines & taxanes ●● Generally sequential single agent regimen are used except if rapidly progressive disease or high visceral tumor burden. ●● No clear recommendations exist for the sequence. Current treatment options ●● Capecitabine: ūū Convenient oral administration, very low risk of alopecia and myelotoxicity; chemotherapy of reference after failure of anthacyclines and taxanes (AT). ●● Vinorelbine: ūū Frequently prescribed after failure of AT and capecitabine although not validated by large Phase III trials; favorable safety profile. ●● Ixabepilone: ūū Approved in the USA after failure of AT and capecitabine as monotherapy or in combination with capecitabine after failure of AT; absence of overall survival and neurotoxicity limit its use. ●● Eribuline: ūū Only drug with proven overall survival benefit in heavily pretreated patients; not better than capecitabine after failure of AT. Etirinotecan pegol ●● A long-acting topoisomerase I inhibitor derived from camptothecin: ūū Designed to reduce maximal SN38 systemic concentrations while providing continuous exposure; ūū Promising results in Phase II in heavily pretreated patients with late onset diarrhea as the most challenging toxicity; ūū Topline results released from the Phase III BEACON trial indicate improvement of overall survival in the subgroups of patients presenting liver or brain metastases receiving NKTR-102.

future science group www.futuremedicine.com 1787 Perspective Jerusalem, Rorive & Collignon

ABC pretreated by AT will remain an incurable Novartis. The authors have no other relevant affiliations disease with very poor long-term outcome. or financial involvement with any organization or entity with a financial interest in or financial conflict with the Disclosure subject matter or materials discussed in the manuscript In addition to the peer-review process, with the author(s) apart from those disclosed. consent, the manufacturer of the product(s) discussed in this No writing assistance was utilized in the production of article was given the opportunity to review the manuscript this manuscript. for factual accuracy. Changes were made at the discretion of the author(s) and based on scientific or editorial merit only. Open access This work is licensed under the Creative Commons Financial & competing interests disclosure Attribution-NonCommercial 3.0 Unported License. To G Jerusalem received research grants from Novartis, Roche view a copy of this license, visit http://creativecommons.org/ and MSD. He served as consultant for Roche, Celgene and licenses/by-nc-nd/3.0/

References paclitaxel-refractory metastatic breast cancer. 17 Toi M, Saeki T, Aogi K et al. Late Phase II Papers of special note have been highlighted as: J. Clin. Oncol. 17(2), 485–493 (1999). clinical study of vinorelbine monotherapy in • of interest; •• of considerable interest 10 Blum JL, Dieras V, Lo Russo PM et al. advanced or recurrent breast cancer previously treated with anthracyclines and taxanes. Jpn. 1 El Saghir N, Tfayli A, Hatoum HA, Nachef Multicenter, Phase II study of capecitabine in Z, Dinh P, Awada A. Treatment of metastatic taxane-pretreated metastatic breast J. Clin. Oncol. 35(6), 310–315 (2005). breast cancer: state-of-the-art, subtypes and carcinoma patients. Cancer 92(7), 1759–1768 18 Seo HY, Lee HJ, Woo OH, Park KH, Woo perspectives. Crit. Rev. Oncol. Hematol. 80, (2001). SU, Yang DS et al. Phase II study of 433–449 (2011). 11 Reichardt P, Von Minckwitz G, Thuss- vinorelbine monotherapy in anthracycline and taxane pre-treated metastatic breast 2 Pagani O, Senkus E, Wood W et al. Patience PC et al. Multicenter Phase II study International guidelines for management of of oral capecitabine (Xeloda®) in patients with cancer. Invest New Drugs 29(2), 360–365 metastatic breast cancer: can metastatic breast metastatic breast cancer relapsing after (2011). cancer be cured? J. Natl Cancer Inst. 102(7), treatment with a taxane-containing therapy. 19 Martin M, Ruiz A, Munoz M et al. 456–463 (2010). Ann. Oncol. 14(8), 1227–1233 (2003). Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with 3 Moreno-Aspitia A, Perez EA. Treatment 12 Fumoleau P, Largillier R, Clippe C et al. options for breast cancer resistant to Multicentre, Phase II study evaluating metastatic breast cancer previously treated with anthracyclines and taxanes: final results Anthracycline and Taxane. Mayo Clin. capecitabine monotherapy in patients with of the Phase III Spanish Breast Cancer Proc. 84(6), 533–545 (2009). anthracycline- and taxane-pretreated metastatic breast cancer. Eur. J. Cancer 40(4), Research Group (GEICAM) trial. Lancet 4 Hortobagyi GN. Treatment of breast cancer. 536–542 (2004). Oncol. 8(3), 219–225 (2007). N. Engl. J. Med. 339(14), 974–984 (1998). 13 Largillier R, Fumoleau P, Clippe C et al. 20 Pallis AG, Boukovinas I, Ardavanis A et al. A 5 Valero V, Hortobagyi GN. Are Capecitabine (X) monotherapy after multicenter randomized Phase III trial of Anthracycline-Taxane regimens the new vinorelbine/gemcitabine doublet versus standard of care in the treatment of anthracycline and taxane failure in metastatic breast cancer (MBC): long-term survival data. capecitabine monotherapy in anthracycline- metastatic breast cancer? J. Clin. Ann. Oncol. 17(Suppl. 9), ix74 (2006). and taxane-pretreated women with metastatic Oncol. 21(6), 959–962 (2003). breast cancer. Ann. Oncol. 23(5), 1164–1169 14 Miller KD, Chap LI, Holmes FA et al. 6 Bernard-Marty C, Cardoso F, Piccart MJ. (2012). Facts and controversies in systemic treatment Randomized Phase III trial of capecitabine compared with bevacizumab plus capecitabine 21 Bollag DM, McQueney PA, Zhu J et al. of metastatic breast cancer. Oncologist 9, Epothilones, a new class of microtubule- 617–632 (2004). in patients with previously treated metastatic breast cancer. J. Clin. Oncol. 23(4), 792–799 stabilizing agents with a taxol-like mechanism 7 Early Breast Cancer Trialists’ Collaborative (2005). of action. Cancer Res. 55(11), 2325–2333 Group (EBCTCG). Effects of chemotherapy (1995). 15 Crown JP, Dieras V, Staroslawska E et al. and hormonal therapy for early breast cancer 22 Perez EA, Lerzo G, Pivot X et al. Efficacy and on recurrence and 15-year survival: an Phase III trial of sunitinib in combination with capecitabine versus capecitabine safety of ixabepilone (BMS-247550) in a overview of the randomised trials. Lancet 365, Phase II study of patients with advanced 1687–1717 (2005). monotherapy for the treatment of patients with pretreated metastatic breast cancer. breast cancer resistant to an anthracycline, a 8 De Laurentiis M, Cancello G, D’Agostino D J. Clin. Oncol. 31(23), 2870–2878 (2013). taxane, and capecitabine. J. Clin. Oncol. et al. Taxane-based combinations as adjuvant 25(23), 3407–3414 (2007). chemotherapy of early breast cancer: a 16 Barrios CH, Liu MC, Lee SC et al. Phase III randomized trial of sunitinib versus 23 Thomas ES, Gomez HL, Li RK et al. meta-analysis of randomized trials. J. Clin. capecitabine in patients with previously Ixabepilone plus capecitabine for metastatic Oncol. 26(1), 44–53 (2008). treated HER2-negative advanced breast breast cancer progressing after anthracycline 9 Blum JL, Jones SE, Buzdar AU et al. cancer. Breast Cancer Res. Treat. 121(1), and taxane treatment. J. Clin. Oncol. 25(33), Multicenter Phase II study of capecitabine in 121–131 (2010). 5210–5217 (2007).

1788 Future Oncol. (2015) 11(12) future science group Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer Perspective

•• Key Phase III trial evaluating the schedules for patients with metastatic breast 32 Rowinsky EK, Grochow LB, Ettinger DS et al. combination of ixabepilone and capecitabine cancer refractory to an anthracycline, a Phase I and pharmacological study of the novel in advanced breast cancer. taxane, or both. J. Clin. Oncol. 22(14), topoisomerase I inhibitor 7-ethyl-10-[4-(1- 2849–2855 (2004). piperidino)-1-piperidino] 24 Sparano JA, Vrdoljak E, Rixe O et al. carbonyloxycamptothecin (CPT-11) Randomized Phase III trial of ixabepilone • Phase II trial reporting single agent activity administered as a ninety-minute infusion every plus capecitabine versus capecitabine in of irinotecan in breast cancer pretreated by 3 weeks. Cancer Res. 54(2), 427–436 (1994). patients with metastatic breast cancer anthacyclines and taxanes. 33 Jameson GS, Hamm JT, Weiss GJ, Alemany previously treated with an anthracycline and a 28 Awada A, Garcia AA, Chan S, Jerusalem GH, C, Anthony S, Basche M et al. A multicenter, taxane. J. Clin. Oncol. 28(20), 3256–3263 Coleman RE, Huizing MT et al. Two Phase I, dose-escalation study to assess the (2010). schedules of etirinotecan pegol (NKTR-102) safety, tolerability, and pharmacokinetics of •• Key Phase III trial evaluating the in patients with previously treated metastatic etirinotecan pegol in patients with refractory combination of ixabepilone and capecitabine breast cancer: a randomised Phase 2 study. solid tumors. Clin. Cancer Res. 19, 268–278 in advanced breast cancer. Lancet Oncol. 14(12), 1216–1225 (2013). (2013). 25 Cortes J, O’Shaughnessy J, Loesch D et al. • Promising Phase II data of etirinotecan 34 Hoch U, Staschen CM, Johnson RK, Eldon Eribulin monotherapy versus treatment of pegol in heavily pretreated advanced breast MA. Nonclinical pharmacokinetics and physician’s choice in patients with metastatic cancer leading to the design of the Phase III activity of Etirinotecan Pegol (NKTR-102), a breast cancer (EMBRACE): a Phase 3 BEACON trial. long-acting topoisomerase 1 inhibitor, in open-label randomised study. Lancet 29 Pommier Y, Tanizawa A, Kohn KW. multiple cancer models, Cancer Chemother. 377(9769), 914–923 (2011). Mechanisms of topoisomerase I inhibition by Pharmacol. 74, 1125–1137 (2014). •• Key Phase III trial showing overall survival anticancer drugs. Adv. Pharmacol. 29B, 35 Eldon MA, Staschen CM, Viegas T, Bentley benefit of eribulin compared with treatment 73–92 (1994). M. NKTR-102, a novel PEGylated-irinotecan of physician’s choice in heavily pretreated 30 de Forni M, Bugat R, Chabot GG et al. conjugate, results in sustained tumor growth breast cancer. Phase I and pharmacokinetic study of the inhibition in mouse models of human 26 Kaufman PA, Awada A, Twelves C et al. camptothecin derivative irinotecan, colorectal and lung tumors that is associated Phase III open-label randomized study of administered on a weekly schedule in cancer with increased and sustained tumor SN-38 eribulin mesylate versus capecitabine in patients. Cancer Res. 54(16), 4347–4354 exposure. Proc. Am. Assoc. Cancer Res. 306, patients with locally advanced or metastatic (1994). Abstract C157 (2007). breast cancer previously treated with an 31 Rothenberg ML, Kuhn JG, Burris HA, III, 36 US National Institutes of Health. anthracycline and a taxane. J. Clin. Nelson J, Eckardt JR, Tristan-Morales M http://clinicaltrials.gov Oncol. 33(6), 594–601 (2015). et al. Phase I and pharmacokinetic trial of 37 Press release: Nektar Therapeutics, San 27 Perez EA, Hillman DW, Mailliard JA et al. weekly CPT-11. J. Clin. Oncol. 11(11), Francisco, CA, USA, 15 March 2015. Randomized Phase II study of two irinotecan 2194–2204 (1993). http://ir.nektar.com

future science group www.futuremedicine.com 1789