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Originally published as JCO Early Release 10.1200/JCO.2008.21.6481 on May 18 2009 © 2009 American Society of Clinical Oncology.
Epothilones: Better or More of the Same?Memorial Sloan-Kettering Cancer Center, New York, NY Agents that interfere with microtubule structure and function continue to play a major role in cancer treatment. The vinca alkaloids represent the oldest class of drugs traditionally characterized as having a microtubule destabilizing function, whereas the taxanes—notably paclitaxel and docetaxel—are considered microtubule stabilizers.1 The wide use of both classes of therapy is directly related to their broad activity and acceptable safety profile in most patients. The goals of improving efficacy and reducing toxicity of paclitaxel have resulted in the development of modified taxanes such as docetaxel, nanoparticle albumin-bound paclitaxel, and paclitaxel poliglumex. A series of analogs, such as larotaxel, milataxel, TPI-287, BMS-275183, and others, have also been investigated.2 To date, there has been significant overlap between spectrums of activity and toxicities of these agents. None has clearly distinguished itself from paclitaxel, the first-in-class compound. However, nontaxane microtubule-targeting agents such as the epothilones are also on the rise.3 Epothilones as a class have shown increased antiproliferative activity in vitro when compared with taxanes and shown activity in cell lines with natural taxane resistance indicated by multidrug resistance4 or tubulin mutation.5 Epothilone B (patupilone) and four of its synthetic derivatives (including ixabepilone) and epothilone D and one of its derivatives (KOS-1584) are under active investigation in many solid tumors.3 Ixabepilone, the semisynthetic analog of epothilone B, was the first epothilone to get a US Food and Drug Administration indication in 2007 as monotherapy for patients with metastatic or locally advanced breast cancer whose tumors were resistant to anthracyclines and taxanes.6 This approval was issued on the basis of two trials. The first was a single-arm phase II study7 of 126 patients whose disease progressed within 6 months of prior chemotherapy, resulting in an independent radiology review response rate of 11.5% (95% CI, 6.3% to 18.9%). Treatment-related grade 3 to 4 toxicities included neuropathy (14%), asthenia (13%), and neutropenia (54%), with alopecia in 48% of patients. The second was a randomized phase III trial8 comparing capecitabine with or without ixabepilone in 752 patients resistant to anthracyclines and taxanes. A statistically significant improvement in progression-free survival of 4.2 to 5.8 months (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003) in favor of the combination was reported. Treatment-related grade 3 to 4 toxicities were similar and included neuropathy (21%), asthenia (16%), and neutropenia (68%), with alopecia in 31% of patients. The overall toxicity of ixabepilone, notably neuropathy, was not improved relative to paclitaxel, and responses in breast cancer were modest, albeit in patients clinically considered to be paclitaxel resistant. The relative efficacy of epothilone B when compared with paclitaxel or docetaxel in taxane-naïve patients is not yet well characterized. As epothilones are evaluated in other tumor types, particularly for gynecologic cancers in which taxanes have major activity, paclitaxel remains the benchmark with which these agents must be compared. The questions are straightforward: first, is a particular epothilone more efficacious than paclitaxel in taxane-naïve patients; second, is it significantly active in clinically defined taxane-resistant patients; third, does it have a favorable toxicity profile when compared with paclitaxel; and fourth, is it possible to predict who might respond? It is fair to say that preclinical attributes should drive the design of clinical trials, but the predictive value of some preclinical models has proven to be limited.9 In this issue of Journal of Clinical Oncology, two trials evaluating epothilones in patients with gynecologic cancers are presented. These studies should be considered in the context of the aforementioned questions. First, the phase II study by Dizon et al10 evaluated ixabepilone in a group of 52 patients with recurrent or persistent endometrial cancer with one prior chemotherapeutic regimen. The vast majority (94%) had received prior paclitaxel. The second-line response rate in these patients was 12%, falling short of the predefined benchmark in the study, and progression-free survival was only 2.9 months. Treatment-related grade 3 to 4 toxicities included neuropathy (18%), asthenia (13%), and neutropenia (52%), with alopecia in 46% of patients. This response rate was, as expected, less than that seen in the second-line setting with paclitaxel in taxane-naïve patients (26%), but it was slightly improved when considered in the context of other agents in taxane-pretreated patients, including topotecan (9%), liposomal doxorubicin (9.5%), and docetaxel (7.7%).11–14 The toxicity profile has remained remarkably similar across ixabepilone studies. However, the 18% incidence of grade 3 neuropathy in the Dizon et al study is higher than the 11% rate seen in the prior study of docetaxel in this group.14 Ixabepilone monotherapy is not likely to provide a sustained, clinically meaningful benefit in most patients with taxane-treated endometrial cancer. But it is likely that many of the primary taxane responders would have also responded to ixabepilone if used initially, and the question of its possible superiority can only be addressed in comparative trials. Because paclitaxel is a good agent, the bar for primary responses must be set high. Given the growing interest in antivascular agents and targeted strategies such as mammalian target of rapamycin inhibitors in endometrial cancer,15,16 it is hoped that a multiarm first-line trial will be considered that includes these or similar novel approaches in addition to ixabepilone (or another epothilone) to evaluate the broadest array of strategies with the potential to improve outcome in the shortest time. Historically, we have fallen short of desired progress by simply combining various standard cytotoxic agents—such as ixabepilone—without employing other novel strategies. The second report describes the phase I study by ten Bokkel Huinik et al17 evaluating 6.5 to 11.0 mg/m2 of patupilone every 3 weeks administered to 45 patients with ovarian cancer and supporting a 10 mg/m2 dose for additional development. The objective of this study was to confirm the dose for additional study using a standardized diarrhea control algorithm on the basis of previous data showing diarrhea (as opposed to neuropathy in ixabepilone) as dose-limiting toxicity. Grade 3 diarrhea was still present in 16% of patients, but incidence of grade 3 to 4 neuropathy was only 4%. Although it was not the study end point, a response rate of 19.5% was documented, with a median duration of disease stabilization at 15.8 months. It should be noted that this response rate is encouraging in a population with a median of six prior regimens, along with a median time from prior chemotherapy of 4.2 months. On the other hand, relapse less than 6 months after primary therapy was required for eligibility, but there was no requirement regarding time from prior taxane therapy. We know that a wide variety of taxane responses exist for patients with recurrent disease. For example, response rates of 44% have been reported with paclitaxel in selected patients treated in the second-line setting with partial or complete response to prior taxane exposure and with a prolonged treatment-free interval.18 More heavily pretreated patients have had response rates of 22%,19 and an objective response rate of only 4% was seen in a heavily pretreated cohort on the initial National Cancer Center Referral Protocol.20 The toxicity profile of patupilone differs from that of ixabepilone, illustrating different toxicities among the class. The peripheral neuropathy rate is clearly reduced with patupilone, and this may be a welcome addition to ovarian cancer treatment after initial taxane-based therapy. Patupilone is being investigated in an important phase III, multicenter, randomized trial (clinical trials No. NCT00262990 [ClinicalTrials.gov] ) evaluating patupilone versus liposomal doxorubicin in patients with traditionally defined platinum- and taxane-resistant disease. It is nearing completion, with preliminary results expected soon. It is certain that not all of the taxane analogs and nontaxane microtubule targeting agents will find room at the inn. They come at the end of development of a series of cytotoxic agents evaluated in "all comers" rather than in specific subgroups of patients. The strength of the epothilones lies in the modest activity shown by some in clinically defined taxane-resistant tumors; their toxicity profiles vary, with some adverse events more or less bothersome than those seen with paclitaxel. Success will be predicated on either superiority to paclitaxel in taxane-naïve patients or clinically meaningful responses in taxane-resistant patients, combined with at least a neutral toxicity profile when compared with a traditional taxane. Perhaps the most important question remains largely unanswered. There are preclinical data to suggest a correlation between various biomarkers and response to microtubule targeted agents. For example, mutations in B tubulin have been linked to resistance to taxanes in vitro but have not been linked to epothilones, and low expression of the microtubule-associated protein tau has been observed to correlate with heightened sensitivity to taxanes.21,22 By evaluating these or other predictive biomarkers clinically to determine if we can enrich the population weighted toward response to one class of drugs or another, we may facilitate successful development of these agents. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Collection and assembly of data: Paul Sabbatini, David R. Spriggs Data analysis and interpretation: Paul Sabbatini, David R. Spriggs Manuscript writing: Paul Sabbatini, David R. Spriggs Final approval of manuscript: Paul Sabbatini, David R. Spriggs REFERENCES
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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