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Eribulin Mesylate (E7389): Review of Efficacy and Tolerability

This article reviews the efficacy and tolerability of eribulin mesylate (E7389), a microtubule inhibitor indicated for the treatment of metastatic breast cancer. It discusses the indications, structure of the molecule, mechanism of action, and the results of clinical trials.

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Eribulin Mesylate (E7389): Review of Efficacy and Tolerability

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  1. Locally advanced and metastatic disease Eribulin mesylate (E7389): review of efficacy and tolerability Jennifer Foglietta Ospedale Santa Maria della Misericordia Perugia

  2. - Indications- Structure of molecule- Mechanism of action- Clinical trials (phase II and III) - efficacy outcomes - safety Eribulin mesylate (E7389)

  3. Indications of eribulin Eribulin is a microtubule inhibitor indicated for the treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

  4. Eribulin: structure of molecule - Synthetic analogue of halichondrin B; natural product from marine sponge Halichondriaokadai - Tubulin-targeting agent - Eribulin could be effective in patients with disease that is resistant to other tubulin-targeting-agents Halichondria okadai Jordan MA, et al. Mol Cancer Ther. 2005;4:1086-1095.

  5. Mechanism of action Polimerizzazione tubulina 1 Eribulin Blocks microtubule polymerization 3 Growth of microtubules • Sequesters tubulin into non functional aggregates Spindle Pole Eribulin Eribulin Eribulin No effect on depolymerization 2 Shortening of microtubules Eribulin Jordan MA, et al. Mol Cancer Ther. 2005;4:1086-1095. Jordan MA et al. Current Cancer Drug Targets. 2007; 7:730-742.

  6. Different sites of action Paclitaxel, docetaxel e epothilone B Eribulina Vinblastina • Eribulina lega solo all’estremità in crescita, (+) ends • Legano le subunitàβall’internodeimicrotubuli • Si lega lungo il lato esterno e lega le (+) ends • Inibiscono l’allungamento e l’accorciamento dei microtubuli • Inibisce solo l’allungamento Modified from Jordan MA and Wilson L. Nat Rev Cancer. 2004; 4:253-265. and Smith J. Biochemistry. 2010; 49:1331-1337.

  7. Phase II trials

  8. Study 201: trial design Vahdat LT, et al. J Clin Oncol. 2009;27:2954-2961. • Patients (N=103) • Advanced breast cancer • Prior anthracyclineand taxane • Progression <6 months of last chemotherapy • ECOG PS: 0-1 • Pre-existing neuropathy Grade ≤2 Eribulin mesylate 1.4 mg/m2 administered by IV for up to 5 min 28-day cohort (n=70) Initial schedule Dosing days1, 8, and 15q28 days Alternative schedule 21-day cohort(n=33) Days 1, 8 q21 days Neutropenia day 15

  9. Study 211: trial design • Patients (N=299) • Advanced breast cancer • Prior anthracycline, taxane, capecitabine • Progression on or within 6 months of last chemotherapy • ECOG PS: 0-2 • Pre-existing neuropathy Grade <2 • Primary endpoint • ORR by IRR • Other endpoints • Duration of response • ORR by investigator • PFS, OS • EORTC QoL • Safety Eribulinmesylate 1.4 mg/m2 2-5 minute IV Days 1,8 q21 days Cortes J, et al. J ClinOncol 2010;28:3922–3928.

  10. Phase II trials: 201 and 211 study • ORR: 11.5% • Median DOR: 5.6 months • Median PFS: 2.6 months • 6-month PFS 25.9% [95% CI, 15.5, 36.3] • Median OS: 9 months (range 15–826 days) • 6-month survival 67.8% [95% CI, 58.0, 77.6) • 1-year survival 45.7% [95% CI, 35.2, 56.2] 201 Study1 (n = 103): Prior taxane & anthracycline* • Primary Endpoint: • ORR with independent review Secondary Endpoints: • DOR, PFS, OS, Adverse events • ORR: 9.3% • Median DOR: 4.1 months • Median PFS: 2.6 months • 6-month PFS 15.6% (95% CI, 10.7, 20.5) • Median OS: 10.4 months • 6-month survival 72.3% (95% CI, 66.9, 77.6) • 1-year survival 45.7% [95% CI, 35.2, 56.2] 211 Study2 (n = 299): Prior taxane, anthracycline, & capecitabine* ORR, overall response rate; DOR, duration of response; PFS, progression-free survival; OS, overall survival *MBC patients with progression of disease ≤6 months of last chemotherapy and, if present, preexisting neuropathy ≤ grade 2 1. Vahdat L, et al. J ClinOncol. 2009;27:2954-2961. 2. Cortes J, et al. J ClinOncol. 2010;28:3922-3928.

  11. Safety: Hematologic adverse events Cortes J, et al. J ClinOncol. 2010;28:3922-3928 Vahdat L, et al. J ClinOncol. 2009;27:2954-2961

  12. Safety: Not hematologic adverse events Cortes J, et al. J ClinOncol. 2010;28:3922-3928 Vahdat L, et al. J ClinOncol. 2009;27:2954-2961

  13. Eribulin+trastuzumabas first line MBC:trial design Vahdat L et al. SABCS2012 poster P5-20-04

  14. Eribulin+trastuzumab: characteristics of patients Vahdat L et al. SABCS2012 poster P5-20-04

  15. Eribulin+trastuzumab: primaryoutcome Vahdat L et al. SABCS2012 poster P5-20-04

  16. Eribulin+trastuzumab:Secondaryefficacyoutcomes Final results are expected by December 2013 Vahdat L et al. SABCS2012 poster P5-20-04

  17. Eribulin+trastuzumab:safety Vahdat L et al. SABCS2012 poster P5-20-04

  18. Phase III trials

  19. EMBRACE: Physician’s Choice (TPC) vs Eribulin • Patients (n=762) • Locally recurrent or MBC • 2–5 prior chemotherapies • ≥ 2 for advanced disease • Prior anthracycline and taxane • Progression ≤ 6 months of last chemotherapy • Neuropathy ≤ grade 2 • ECOG ≤ 2 • Primary Endpoint: • OS Secondary Endpoints: • PFS • ORR • Safety Eribulinmesylate (n=508) 1.4 mg/m2* IV over 2-5 minutes on Day 1,8 q21 days RANDOMISATION 2:1 • TPC (n=254): • Any monotherapy (cytotoxic, hormonal, biological); or • Palliative treatment; or • Radiotherapy • Stratification: • Geographical region • Prior capecitabine • HER2 status • *Equivalent to 1.23 mg/m2eribulin • Exploratory subgroups: Hormone receptor expression status (ER, PgR, HER2, triple-negative); number of organs involved; sites of disease Cortes J, et al. Lancet 2011;377:914-923.

  20. EMBRACE: main characteristics of patients Cortes J, et al. Lancet 2011;377:914-923.

  21. EMBRACE: Priorantitumourtherapies Cortes J, et al. Lancet 2011;377:914-923.

  22. EMBRACE: TPC 96% pts treated with chemotherapy Total patients = 247 N= 61 N= 46 % of Patients N= 44 N= 38 N= 25 N= 24 N= 9 None of patientsreceivedonlysupportive care or immunotherapy **Include: paclitaxel, docetaxel, abraxane, (ixabepilone) Cortes J, et al. Lancet 2011;377:914-923.

  23. EMBRACE: Overall Survival Eribulin TPC p-value= 0.041 HR (95CI) = 0.81 Cortes J, et al. Lancet 2011;377:914-923.

  24. 1-year survival Eribulin (n=508) 54.5% TPC (n=254) 42.8% EMBRACE: OS (ITT Population) Updated 3 March 2010 1.0 0.8 EribulinMedian 13.2 months 0.6 HR* 0.81 (95% CI 0.68, 0.96)Nominal p value=0.014 Overall survival (%) TPCMedian 10.6 months 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months)

  25. EMBRACE: Overall Survival by Stratification Factor* HER2, human epidermal growth factor receptor type 2.*Intent-to-treat population; Based upon a stratified Cox analysis including geographic region, HER-2/neu status, and prior capecitabine therapy as strata. Cortes J, et al. Lancet 2011;377:914-923.

  26. EMBRACE: secondary endpoint PFS Cortes J, et al. Lancet 2011;377:914-923.

  27. EMBRACE: secondary endpoint ORR Cortes J, et al. Lancet 2011;377:914-923.

  28. EMBRACE: safety Cortes J, et al. Lancet 2011;377:914-923.

  29. Embrace: hematologic adverse events Cortes J, et al. Lancet 2011;377:914-923.

  30. Embrace: not hematologic adverse events Cortes J, et al. Lancet 2011;377:914-923.

  31. Study 301: eribulin vs capecitabinetrialdesign * Stratification: - geographicregion - HER2 status Co-primary end-points: OS and PFS Secondaryendpoints: ORR, QoL, DOR, 1-, 2-, 3-year survival and safety * ≤ 2 for advanceddisease Kaufman PA et al. SABCS 2012 S6-6

  32. Study 301: eribulin vs capecitabinecharacteristics of patients Kaufman PA et al. SABCS 2012 S6-6

  33. Study 301: eribulin vs capecitabine Co-primaryendpoints Kaufman PA et al. SABCS 2012 S6-6

  34. Study 301: eribulin vs capecitabine OS Pre-specifiedSubgroup Analysis Author conclusions: “particular patient subgroups may have greater therapeutic benefit with eribulin and this may warrant further study” Kaufman PA et al. SABCS 2012 S6-6

  35. Study 301: eribulin vs capecitabine Response Rate Kaufman PA et al. SABCS 2012 S6-6

  36. Study 301: eribulin vs capecitabine Toxicity Kaufman PA et al. SABCS 2012 S6-6

  37. Conclusions • Efficacy of eribulin in MBC pts • Combination with other agents? • Manageable toxicity • Common EAs: neutropenia, fatigue, neuropathy • Low incidence of neuropathy grade 3/4 • Trials ongoing in early breast cancer (adjuvant and neoadjuvant setting) • Trials in other solid tumours (sarcoma, NSCLC, pancreatic cancer…)?

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