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CCR Drug Update

Ixabepilone in Metastatic : Complement or Alternative to ? Antoinette R.Tan and Deborah L.Toppmeyer

Targeting the is a successful strategy in the analogue), and sagopilone (ZK-EPO, synthetic third-generation treatment of solid tumors. There is an ongoing effort to ; refs. 6–12). develop newer agents that can stabilize with Several schedules of have been studied in phase I improved efficacy and tolerability. represent a trials, including daily administration for 3 or 5 days as a novel group of microtubule inhibitors that were isolated from 1-h infusion every 3 weeks, as a 3-h infusion every 3 weeks, and the myxobacterium in the 1990s (1). They weekly dosing (13–16). Neutropenia was dose-limiting on all are naturally occurring macrolides that are structurally different schedules, and sensory neuropathy less prominent with a daily from the taxanes. Crystallographic studies show that epothi- and weekly schedule. The FDA-approved dose of ixabepilone lones and taxanes compete for the same binding site on h- for metastatic breast cancer is 40 mg/m2 as a 3-h i.v. infusion , but the actual binding interaction is different (2). Both every 3 weeks as monotherapy and in combination with taxanes and epothilones promote microtubule assembly; . however, epothilones A and B are 2.5-fold more potent than Several phase II trials of ixabepilone as monotherapy have in promoting tubulin polymerization (3). In addi- been conducted in different subsets of patients with advanced tion, preclinical studies show that epothilones have low breast cancer. Ixabepilone on an every 3-week and daily susceptibility to mechanisms of drug resistance. Specifically, schedule has shown activity in a population with minimal epothilones are poor substrates for P-glycoprotein and multi- prior exposure to taxanes. Roche´ et al. (17) evaluated drug resistance–associated protein 1, and their cytotoxic ixabepilone as first-line therapy in 65 patients with metastatic potential is not affected by mutations in h-tubulin or breast cancer who had received prior adjuvant . alterations in tau, a microtubule-associated protein that Ixabepilone was administered at 40 mg/m2 as a 3-h infusion promotes tubulin stabilization (4, 5). every 3 weeks. Only 17% had received a as part of an Ixabepilone (Ixempra, Bristol-Myers Squibb) is the first adjuvant regimen (z1 year from the last dose). The overall epothilone to be approved by the Food and Drug Administra- response rate was 41.5% [95% confidence interval (95% CI), tion (FDA). Ixabepilone is indicated for the treatment of 29.4-54.4%]; partial responses occurred in 27 patients. Prom- metastatic breast cancer as monotherapy in patients whose inent adverse events included neutropenia (grade 3, 27%; grade tumors are resistant to , taxanes, and capecita- 4, 31%) and sensory neuropathy (grade 3, 20%; grade 4, 0%). bine, and in combination with capecitabine in patients whose In a single center phase II study by Denduluri et al. (18), disease progresses after an anthracycline and taxane. A ixabepilone was administered at 6 mg/m2 daily for 5 days as a semisynthetic second-generation epothilone B analogue, ixabe- 1-h infusion every 3 weeks to 23 patients with metastatic breast pilone (aza-epothilone B, BMS-247550), is formulated in cancer with no prior taxane exposure. The overall response rate Cremophor EL. It differs in structure from the natural was 57% (95% CI, 34.5-76.8%); 13 patients had partial epothilone in that an oxygen atom is replaced by a nitrogen responses and 6 patients had stable disease for at least 6 weeks, atom on the macrolide ring, a chemical modification that which is indicative of ixabepilone antitumor activity in taxane- improves the metabolic stability of the natural product. naBve patients. Major toxicities included grade 4 neutropenia Preclinical studies show that ixabepilone has significant (13%) and grade 3 fatigue (13%). There were no grade 3 or 4 antitumor activity compared with paclitaxel in paclitaxel- sensory neuropathy events. resistant tumor models (3). There are several other epothilones Several phase II trials were conducted in metastatic breast in clinical trials that are not yet FDA approved and are being cancer patients previously treated with taxanes. In a single evaluated for the treatment of breast cancer. These include institution trial, 37 patients received ixabepilone 6 mg/m2 daily patupilone (natural epothilone B; EPO906), KOS-1584 (epo- for 5 days as a 1-h infusion every 3 weeks (19). All patients had thilone D analogue), BMS-310705 (water-soluble epothilone B at least one previous treatment with paclitaxel or in the neoadjuvant, adjuvant or metastatic setting. The overall response rate was 22% (95% CI, 9.8-38.2%) including one complete response. At this same center, a 3-day schedule of 2 Authors’ Affiliation: The Cancer Institute of New Jersey, New Brunswick, New ixabepilone at 8 mg/m every 3 weeks was investigated in 12 Jersey patients with prior taxane exposure (20). No responses were Received 5/29/08; revised 8/29/08; accepted 9/5/08. observed, suggesting the inferiority of this alternate schedule. Requests for reprints: Antoinette R. Tan,The Cancer Institute of NewJersey,195 Neutropenia and sensory neuropathy were notable toxicities on Little Albany Street, New Brunswick, NJ 08901. Phone: 732-235-6759; Fax: 732- 235-8681;E-mail: [email protected]. both studies. Thomas et al. (21) conducted a study in 49 F 2008 American Association for Cancer Research. patients pretreated with taxanes who were given ixabepilone at doi:10.1158/1078-0432.CCR-07-4704 40 mg/m2 as a 3-h infusion every 3 weeks. This trial initially

www.aacrjournals.org 6725 Clin Cancer Res 2008;14(21)November 1, 2008 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2008 American Association for Cancer Research. CCR Drug Update treated patients at 50 mg/m2 as a 1-h infusion, but the dose was was defined as tumor progression while on treatment or decreased to 40 mg/m2 due to neurotoxicity and the duration within 3 months of the last dose in the metastatic setting, or was increased to 3 hours after increased myelosuppression and recurrence within 6 months of the last adjuvant or neoadjuvant mucositis were reported from other studies. The inclusion dose. Patients who were not resistant to anthracyclines but criteria were strictly defined as progression on docetaxel or had received a minimum dose of 240 mg/m2 or paclitaxel as the most recent therapy or within 4 months of the 360 mg/m2 were eligible. Prior capecitabine was last dose or within 6 months of adjuvant taxanes. The majority not permitted. After 377 patients were enrolled, the definition of patients (86%) had undergone two or more prior cytotoxic of taxane resistance was broadened to progression within regimens; 98% had received a taxane as the most recent 4 months of the last dose in the metastatic setting or within metastatic treatment and 73% had experienced disease pro- 12 months of the last adjuvant or neoadjuvant dose. Appro- gression within 1 month of the last dose of taxane. The ximately, 40% of patients had received two prior response rate was 12% (95% CI, 4.7-26.5%; all partial regimens before enrollment on both arms. The combination responses). Prominent adverse events included neutropenia achieved a higher response rate (35% versus 14%; P < 0.0001) (grade 3, 33%; grade 4, 20%), fatigue (grade 3, 27%), and and increased median progression-free survival (5.7 versus gastrointestinal disturbances (grade 3, 20%). Grade 3 sensory 4.1 months; hazard ratio, 0.69; 95% CI, 0.58-0.83; P < 0.0001). neuropathy occurred in 12% of patients. Such studies are Overall survival data were not reported at the time of suggestive of at least partial non–cross-resistance between this publication. Peripheral sensory neuropathy and myelosup- ixabepilone and other microtubule-targeting agents. pression were more common with the combination. Notably, The basis for FDA approval of ixabepilone as a single agent ixabepilone did not potentiate capecitabine-associated toxicities. was an international, multicenter phase II trial conducted in There were 12 treatment-related deaths on the combination 126 metastatic breast cancer patients whose disease was arm attributed to neutropenia in patients with abnormal liver resistant to anthracyclines, taxanes, and capecitabine (22). function tests (grade z2 in five patients and grade 0/1 in seven Resistance to each agent was defined as progressive disease patients). In patients with hepatic impairment, increases in within 8 weeks of last dose of drug in the metastatic setting or ixabepilone exposures have been observed (27). According to recurrence within 6 months of adjuvant or neoadjuvant the FDA, ixabepilone and capecitabine are contraindicated in anthracycline or taxane therapy. Approximately 88% of patients patients with liver dysfunction defined as aspartate amino- had received two or more prior chemotherapy regimens for transferase or alanine aminotransferase >2.5 upper limit of metastatic disease. Ixabepilone was administered at 40 mg/m2 normal or bilirubin >1 upper limit of normal secondary as a 3-h infusion every 3 weeks. The overall response rate based to increased risk of toxicity and neutropenia-related death. In on independent radiologic review was 11.5% (95% CI, 6.3- addition, ixabepilone monotherapy is not recommend in 18.9%); 13 of 113 patients had a partial response. In addition, patients with aspartate aminotransferase or alanine amino- 13% experienced stable disease for z6 months. Similar to the transferase >10 upper limit of normal or bilirubin >3 other trials, neutropenia (grade 3, 31%; grade 4, 23%), sensory upper limit of normal. neuropathy (grade 3, 13%; grade 4, 1%), and fatigue (grade 3, Ixabepilone expands the treatment choices for patients with 13%; grade 4, 1%) were prominent. Based on these results, metastatic breast cancer. Results from this phase III study show ixabepilone has efficacy in metastatic breast cancer that is the activity of epothilones in anthracycline- and taxane- ‘‘triple-refractory,’’ or disease that has progressed after an pretreated breast cancer (25). However, the trial does not anthracycline, taxane, and capecitabine. answer the question of whether combination therapy provides Anthracyclines and taxanes are the mainstay of adjuvant superior activity over sequential treatment, as this was not a therapy as well as the cornerstone for treatment of metastatic crossover design. Other phase III doublet trials combining a breast cancer. Capecitabine is the only drug approved as microtubule-targeting drug with an have also monotherapy for patients whose tumor is resistant to an shown superiority compared with a single agent, including anthracycline and paclitaxel, or paclitaxel resistant (defined as docetaxel/capecitabine versus docetaxel and paclitaxel/gemci- progressive disease while on treatment with or without an tabine versus paclitaxel (28, 29), but prospective, randomized initial response) and whom further anthracycline therapy is studies with planned crossover therapy have shown that contraindicated (23). The rationale for testing the combination upfront combination versus sequential single-agent treatment of ixabepilone and capecitabine is based on their distinct does not confer a survival advantage (30, 31). mechanisms of actions and nonoverlapping toxicities. Phase Compared with both paclitaxel and docetaxel, administra- I/II results revealed that the combination was tolerable and tion of ixabepilone does not necessitate corticosteroids (unless showed antitumor activity (24). a hypersensitivity reaction occurs), but premedication with The FDA approval for combination therapy was based on the histamine blockers is required. This is a distinct advantage results of a phase III trial conducted in anthracycline- and compared with paclitaxel and docetaxel. A major question is taxane-resistant metastatic breast cancer. Seven hundred fifty- whether ixabepilone is superior to either of the solvent-based two patients were randomized 1:1 to receive either 40 mg/m2 of taxanes or nanoparticle formulation of paclitaxel (i.e., nab- ixabepilone as a 3-h infusion every 3 weeks and 2,000 mg/m2/d paclitaxel). Head-to-head comparison studies of ixabepilone of oral capecitabine in divided doses days 1 to 14 every 3 weeks with taxanes are under way. A randomized phase II trial of two (375 patients) or oral capecitabine alone 2,500 mg/m2/d schedules of ixabepilone (weekly 3 every 4 weeks versus every in divided doses on days 1 to 14 every 3 weeks (377 patients; 3 weeks) plus bevacizumab compared with paclitaxel (weekly refs. 25, 26). The primary end point was progression-free 3 every 4 weeks) plus bevacizumab as first-line therapy for survival. There were predefined strict inclusion criteria for patients with locally recurrent or metastatic breast cancer is chemotherapy resistance. Anthracycline and taxane resistance completed (NCT00370552). The IXTEND trial is a randomized

Clin Cancer Res 2008;14(21) November 1, 2008 6726 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2008 American Association for Cancer Research. Ixabepilone in Metastatic Breast Cancer phase II study evaluating the combination of ixabepilone and capecitabine (NCT00634088). These trials will better define capecitabine compared with docetaxel and capecitabine in the optimal position of ixabepilone in the treatment algorithm patients who have had more than one prior treatment regimen for patients with metastatic breast cancer. (NCT00546364). There is a planned phase III trial that will A potential role of ixabepilone is in the triple-negative evaluate paclitaxel/bevacizumab versus nab-paclitaxel (Abrax- population defined as estrogen receptor negative, ane)/bevacizumab versus ixabepilone/bevacizumab as first-line receptor negative, and HER2 negative. Although there is no treatment in patients with metastatic breast cancer. apparent mechanistic basis for unique sensitivity of microtu- Ixabepilone has also been combined with human epidermal bule-stabilizing agents in this subgroup, a subset analysis done growth factor receptor type 2 (HER2) targeted therapy. The on the phase III trial of ixabepilone and capecitabine versus Eastern Cooperative Oncology Group (E2103) evaluated capecitabine (where f25% of patients in each arm had triple- ixabepilone at 15 mg/m2 and (area under the negative disease) showed that the addition of ixabepilone curve, 2) given weekly on days 1, 8, and 15 of a 28-day cycle improved both overall response rate (27% versus 9%) and with weekly trastuzumab in 59 patients with HER2-positive median progression-free survival (4.1 versus 2.1 months) in metastatic breast cancer as first-line therapy (32). The overall the cohort of triple-negative patients (33). A randomized response rate was 44% (3 complete responses and 23 partial phase II trial is being conducted in patients with triple- responses) with a median progression-free survival of 8.0 months. negative metastatic breast cancer as first-line therapy comparing This is comparable to other taxane/trastuzumab combinations ixabepilone versus ixabepilone and cetuximab (NCT00633464) in patients who have not received prior chemotherapy. A with the latter drug chosen to target epidermal growth factor randomized phase II study in HER2-positive patients as first- receptor, which is overexpressed in this subtype. line treatment for metastatic disease comparing ixabepilone With promising activity in the metastatic setting, ixabepilone and trastuzumab versus docetaxel and trastuzumab is ongoing as a single agent has been evaluated as neoadjuvant therapy. A (NCT00490646). Additionally, the feasibility of ixabepilone total of 161 patients with tumors measuring 3 cm or more were in combination with a HER1/HER2 inhibitor is being evaluated treated with ixabepilone 40 mg/m2 as a 3-h infusion every in a phase I trial of lapatinib and ixabepilone with or without 3 weeks for four cycles (34). The pathologic complete response

Table 1. Select clinical trials of ixabepilone in metastatic breast cancer

Trial Phase Disease Prior No. Dose and schedule Clinical outcomes Peripheral characteristics regimens of pts sensory neuropathy grade z2(%) Roche´ II Prior anthracycline 065 Ixabepilone 40mg/m 2 q3w ORR, 41.5%; SD, 35%; 20(all grade 3)* et al. (17) as adjuvant TTP, 4.8 mo Denduluri II No prior taxane No limit 23 Ixabepilone 6 mg/m2 ORR, 57%; SD, 26%; 13 (all grade 2) et al. (18) daily for 5 d q3w TTP, 5.0mo Low et al. II Prior taxane No limit 37 Ixabepilone 6 mg/m2 ORR, 22%; SD, 35%; 22 (grade 2) (19) (adjuvant, daily for 5 d q3w TTP, 2.6 mo 3 (grade 3) neoadjuvant, or metastatic) Denduluri II Prior taxane No limit 12 Ixabepilone 8 mg/m2 ORR, 0% 25 (all grade 2) et al. (20) (adjuvant, daily for 3 d neoadjuvant, q3w (cycle 1) ! 10mg/m 2 or metastatic) daily for 3 d Thomas II Prior taxane in the Up to 3 49 Ixabepilone 40mg/m 2 q3w ORR, 12%; SD, 41%; 33 (grade 2) et al. (21) metastatic setting TTP, 2.2 mo 12 (grade 3) Perez II Resistant to Up to 3 126 Ixabepilone 40mg/m 2 q3w ORR, 11.5%; SD, 13%; 30(grade 2) et al. (22) anthracycline, PFS, 3.1 mo 13 (grade 3) taxane, and 1 (grade 4) capecitabine Thomas III Prior anthracycline, Up to 3 752 Ixabepilone 40mg/m 2 ORR, 35% vs 14% 27 vs 4 (grade 2) et al. resistant to q3w and capecitabine for capecitabine arm 20vs 0(grade 3) (25, 26) anthracycline, and 2,000 mg/m2/d (fP < 0.0001) 0.8 vs 0 (grade 4) resistant to taxane D1-14 vs PFS, 5.7 mo vs 4.1 mo capecitabine for capecitabine arm 2,500 mg/m2/d D1-14 (fP < 0.0001) Moulder II HER2 positive; 059 Ixabepilone 15 mg/m 2 ORR, 44%; 7 (all grade 3)* et al. (32) no prior treatment and carboplatin PFS, 8.0mo (AUC, 2) D1, 8, and 15 q4w, and trastuzumab weekly during CT then q3w for 6 cycles

Abbreviations: Pts, patients; ORR, overall response rate; SD, stable disease; TTP, time to progression; PFS, progression-free survival; AUC, area under the curve; CT, chemotherapy. *Grade 2 neuropathy not reported.

www.aacrjournals.org 6727 Clin Cancer Res 2008;14(21)November 1, 2008 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2008 American Association for Cancer Research. CCR Drug Update rate in the breast was 15%. Previous studies of single agent grade 2 neuropathy occurred in 22% to 33% of patients taxane given in the neoadjuvant setting yield a pathologic pretreated with taxanes compared with 13% in taxane-naBve complete response rate in the range of 9% to 12.5% (35). patients. In the adjuvant setting, ixabepilone would be given for Interestingly, in the triple-negative subset the pathologic a finite number of cycles and possibly on a weekly schedule, complete response rate in the breast was 26%. Pretreatment thereby reducing the occurrence of neuropathy. In addition, a core biopsies were obtained for gene expression profiling, and cremophor-free formulation of ixabepilone has undergone low expression of estrogen receptor was the most significant phase I testing as a 24-hour infusion every 3 weeks and might predictor for pathologic complete response to ixabepilone (36). be a potential alternative (38). The efficacy and tolerability of Pharmacogenomic analysis has identified a group of molecular ixabepilone as adjuvant treatment will be tested in a large trial, markers that could potentially differentiate sensitivity to PACS-08, which will randomize 2500 patients with stage II or paclitaxel versus ixabepilone (37). In this advancing era of III triple-negative breast cancer to 5-, epirubicin, personalized cancer therapy, identification of subgroups most and (FEC100) for three cycles followed by likely to benefit from ixabepilone is the ideal strategy. A phase either docetaxel for three cycles or ixabepilone for three cycles II trial is under way to validate these biomarkers prospectively. (NCT00630032). In this study, 300 patients with triple-negative breast tumors In summary, we have expanded the treatment choices in z2 cm will be treated with neoadjuvant doxorubicin and metastatic breast cancer to include the novel combination of cyclophosphamide for four cycles and then randomized to four ixabepilone and capecitabine in anthracycline- and taxane- cycles of ixabepilone every 3 weeks or weekly paclitaxel for pretreated patients. Furthermore, single agent ixabepilone given 12 weeks. The primary aim is to identify a gene expression as sequential treatment after progression from an anthracycline, profile that predicts pathologic complete response to paclitaxel taxane, and capecitabine is an alternative therapeutic option for compared with ixabepilone (NCT00455533). patients with triple-refractory disease. Until comparison trials Ixabepilone is also undergoing evaluation in the adjuvant are completed, ixabepilone complements our current arma- setting, but an important consideration is neurotoxicity. Similar mentarium of chemotherapy. Future studies will define the to other microtubule agents, neuropathy is the most significant optimal position of ixabepilone in the treatment of early and side effect (Table 1). In the phase III trial, grade 2 peripheral advanced breast cancer. sensory neuropathy occurred in 27% of patients on the combination versus 4% with single agent capecitabine. Grade z3 neuropathy occurred in f20% of patients receiving the Disclosure of Potential Conflicts of Interest combination versus 0% with capecitabine alone. This was cumulative, but reversible with a median resolution time to A.R. Tan: Bristol-Myers Squibb, research funding. The other author disclosed no grade 1 in 6 weeks after dose reduction. In the phase II trials, potential conflicts of interest.

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Antoinette R. Tan and Deborah L. Toppmeyer

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