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Originally published as JCO Early Release 10.1200/JCO.2007.10.9504 on July 2 2007 © 2007 American Society of Clinical Oncology.
Ixabepilone and the Narrow Path to Developing New Cytotoxic Drugs
Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Medical Oncology, Milano, Italy During the last decade, the focus of attention in the field of new drug development has drifted away from the uninterrupted quest of new and better cytotoxic drugs to the newer and more glamorous grounds of targeted therapy, proof of principle and proof of concept, and sophisticated pharmacodynamic investigations. After years of relentless work behind the scenes, ixabepilone is emerging from the somewhat neglected list of cytotoxic compounds to stand on stage as something more than an apprentice, as reported in this issue of the Journal of Clinical Oncology (JCO). There are reports of five phase II studies of the drug, four in metastatic breast cancer (MBC) and one in non–small-cell lung cancer (NSCLC).1-5 Ixabepilone (BMS-247550) is an analog of epothilone B and a reference compound of a novel class of tubulin-active drugs that blocks tubulin polymerization in a way similar to that of the taxanes.6,7 Ixabepilone binds to a different site of the tubulin molecule than the taxanes6; such a feature may be relevant to the reported lack of complete cross resistance with paclitaxel and docetaxel in preclinical models.8 The data presented in this issue deserve attention for multiple reasons, forcing us to reconsider the role of the development of old-fashioned chemotherapy to complement the current armamentarium of drugs for cancer treatment in the era of targeted therapies. Ixabepilone enters with the almost mandatory ambition of challenging the still undisputed role of the taxanes. The data presented in this issue of JCO, as summarized in Table 1, support such ambition: ixabepilone worked well as first-line therapy in women with MBC,1 and had clear antitumor activity in tumors resistant to or even refractory to multiple other classes of cytotoxic drugs and—most important—to paclitaxel or docetaxel.2-4 For NSCLC, the activity was observed despite progression within 4 months from treatment with cisplatin or carboplatin.5 Such therapeutic activity is an encouraging start to widening the range of therapeutic options after failure of the taxanes, prompting the testing of ixabepilone in early stages of disease. But ixabepilone treatment comes at a price: neurotoxicity.
Tubulin-active drugs almost invariably cause neurologic adverse effects. Ixabepilone, which was well tolerated regarding bone marrow and other organ toxicities,1-5 is not an exception, causing a paclitaxel-like neuropathy that was primarily sensory in nature, cumulative, and slowly reversible in the majority of patients.9 The neuropathy associated with ixabepilone had much to do with the uneven and slower than expected clinical development of the drug. Table 1 reveals a situation that points to the differences of dose and schedule of ixabepilone in the different trials reported in this issue of JCO. The difference is indeed larger than it appears from the table, due to the extent and severity of the neuropathy initially observed in four of the studies2-5 that forced a lowering of the dose from 50 to 40 or even to 32 mg/m2 per cycle to make treatment feasible with the schedule of administration once every 3 weeks. The only exception to the remedy of amending the dose was the study in women who never received taxanes before ixabepilone, in which daily administration for 5 consecutive days was adopted.1 One may be tempted to conclude that the daily schedule was less neurotoxic. However, after dose titration to feasibility of the once-per-cycle dosing, there was no obvious pattern of different tolerability in patients with NSCLC, allowing a choice between the two schedules.5 In considering neurotoxicity, some better quantification and uniformity of the data would have been welcome. In two of the studies, a toxicity of grade less than 3 is almost discounted as of little relevance, although grade 2 neuropathy may be very clinically relevant. The possibility should be considered that prior exposure to neurotoxic drugs increased the likelihood or severity of the adverse effect. In this respect, it should be noted that the same group of investigators here describing a 13% incidence of grade 2/3 toxicity in women at their first line of therapy for MBC1 earlier reported an almost double incidence of neuropathic problems when ixabepilone was administered to patients pretreated with taxanes.10 It is therefore possible that use of ixabepilone in earlier stages of disease for patients not previously exposed to neurotoxic drugs was associated with better tolerance. Also relevant is the consideration that in patients developing neuropathy, the median time to grade 2/3 toxicity was six cycles with the 3-hour-long infusion every 3 weeks2 and with the daily schedule,9 whereas the median time to partial response was two cycles.2 The difference defines a benefit-to-toxicity ratio in clear favor of the therapeutic potential of ixabepilone that can be exploited in patients with metastatic disease. The jumpy course of dose adjustments that occurred in many studies of ixabepilone is a testimony that the classical design of phase I trials is inadequate to take into account the risk of cumulative or late-onset adverse effects that show up later during phase II studies. Adaptive designs may overcome such a limitation,11,12 would have likely simplified the finding of a correct dose for multiple cycles, and consequently may have greatly accelerated the conduct of phase II studies of ixabepilone. Ixabepilone is clinically useful because of its demonstrated antitumor activity, lack of complete clinical cross resistance with most commonly used chemotherapy drugs including the taxanes, and an acceptable tolerability, which could be made even better in the setting of adjuvant therapy in which a fixed number of four to six cycles are commonly planned in patients who never received chemotherapy. How can ixabepilone be positioned in the crowded arena of treatments for breast, lung, and other cancers? Is it a substitute or a complement of paclitaxel and docetaxel? The comparison of ixabepilone with the taxanes is as obvious as it is unavoidable in the light of the role that taxoids play in several widely used regimens and considering the common biochemical target of tubulin. However, it is unlikely that anything less than a very large efficacy advantage over paclitaxel and docetaxel can shift the standard of care toward ixabepilone or any other epothilone, such as patupilone,13 epothilone-D, or ZK-EPO.7 For lung cancer, the problem of how to position an epothilone is still unpredictable, because the activity observed in patients with tumors resistant to cisplatin requires confirmation.5 For breast tumors, the comparison will most likely start soon, and a key element of such comparison, in early as well as in later stages of breast cancer, will be to test for therapeutic features of the two classes of tubulin-active drugs and eventually to define distinct areas of applicability of the epothilones and the taxanes. One course will likely be that of making good value of one aspect that characterized the development of ixabepilone in the era of human epidermal growth factor receptor–targeted drugs. Most patients with breast cancer undergoing ixabepilone therapy had human epidermal growth factor receptor–negative disease, and many of them also estrogen receptor–negative and progesterone receptor–negative tumors.2,4 This patient selection led to more clearly observed antitumor activity in so-called triple-negative tumors, a characteristic that could not go unnoticed and forms the basis for a rational test of ixabepilone in this subset of patients.14 However, the triple-negative hypothesis is only a corollary of a more general attitude that should be applied to the development of ixabepilone in breast cancer and, eventually, in other tumor types. The epothilones were tested using conventional approaches of empirical screening, and are undergoing empirical development. Such an empirical approach should not let us forget that cytotoxic compounds do have a target, and new molecular tools may allow for testing to identify specific tumor or patient characteristics that predict for sensitivity or resistance.15 In a recently completed trial of ixabepilone as neoadjuvant chemotherapy in women with breast cancer, a major investment in genomic studies addresses the challenge of defining a useful predictor of sensitivity to the drug.16 Any classifier of response will need a prospective validation that should include the assessment of its applicability to predict efficacy in the adjuvant setting rather than simply antitumor activity in the neoadjuvant setting. Ideally, the classifier should not only be capable of predicting patterns of efficacy with high sensitivity, but also with high specificity for ixabepilone. Such high specificity and sensitivity are not easy to achieve for any test and for any drug, as recently pointed out,17,18 but it will be key to explore whether there are distinctive features that discriminate tumors for which ixabepilone, instead of taxanes, are indicated. The challenge of this type of development is of major magnitude, but it is through such a narrow path that new chemotherapy agents will move from apprentice to master, as is rightly the ambition for ixabepilone. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Luca Gianni, Bristol-Myers Squibb Stock: N/A Honoraria: Luca Gianni, Novartis, Berlex-Shering Research Funds: N/A Testimony: N/A Other: N/A
NOTES published online ahead of print at www.jco.org on July 2, 2007. REFERENCES
1. Denduluri N, Low JA, Lee JJ, et al: Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. J Clin Oncol 25:3421-3427, 2007 2. Roché H, Yelle L, Cognetti F, et al: Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol 25:3415-3420, 2007 3. Thomas E, Tabernero J, Fornier M, et al: Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 25:3399-3406, 2007 4. Perez EA, Lerzo G, Pivot X, et al: Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 25:3407-3414, 2007 5. Vansteenkiste JF, Lara PN Jr, Le Chevalier T, et al: Phase II clinical trial of the epothilone B analog, ixabepilone, in patients with non–small-cell lung cancer whose tumors have failed first-line platinum-based chemotherapy. J Clin Oncol 25:3448-3455, 2007 6. He L, Orr GA, Horwitz SBL Novel molecules that interact with microtubules and have functional activity similar to Taxol. Drug Discov Today 15:1153-1164, 2001 7. Larkin JM, Kaye SB: Epothilones in the treatment of cancer. Expert Opin Investig Drugs 15:691-702, 2006[CrossRef][Medline] 8. Lee FY, Borzilleri R, Fairchild CR, et al: BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7:1429-1437, 2001 9. Lee JJ, Low JA, Croarkin E, et al: Changes in neurological function tests may predict neurotoxicity caused by ixabepilone. J Clin Oncol 24:2084-2091, 2006 10. Low JA, Wedam SB, Lee JJ, et al: Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 23:2726-2734, 2005 11. Schmidt C: Adaptive design may hasten clinical trials. J Natl Cancer Inst 99:108-109, 2007 12. Rogatko A, Babb JS, Tighiouart M, et al: New paradigm in dose-finding trials: Patient-specific dosing and beyond phase I. Clin Cancer Res 11:5342-5346, 2005 13. Rubin EH, Rothermel J, Tesfaye F, et al: Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol 23:9120-9129, 2005 14. Roché H, Perez EA, Llombart-Cussac A, et al: Ixabepilone, an epothilone B analog, is effective in ER, PR, HER-2 negative (triple negative) patients (pts): Data from neoadjuvant and metastatic breast cancer (MBC) trials. Ann Oncol 17:S9, 2006 (abstr 256P) 15. Pusztai L, Gianni L: Technology insight: Emerging techniques to predict response to preoperative chemotherapy in breast cancer. Nat Clin Pract Oncol 1:44-50, 2004[CrossRef][Medline] 16. Baselga J, Gianni L, Llombart A, et al: Predicting response to ixabepilone: Genomics study in patients receiving single agent ixabepilone as neoadjuvant treatment for breast cancer (BC). Proceedings of the 28th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005 (abstr 305) 17. Pusztai L: Chips to bedside: Incorporation of microarray data into clinical practice. Clin Cancer Res 12:7209-7214, 2006 18. Hess KR, Anderson K, Symmans WF, et al: Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol 24:4236-4244, 2006
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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