Indication

IXEMPRA is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.

  • Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting
  • Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting

Study 046: IXEMPRA
in combination with capecitabine

Study objective

To evaluate the safety and efficacy of IXEMPRA® (ixabepilone) plus capecitabine vs capecitabine alone in metastatic or locally advanced breast cancer resistant to both an anthracycline and a taxane.1

Study design

Study design and baseline characteristics

Study 046 design1,2

Study 046 was a phase 3, open-label, multicenter, randomized trial of non-taxane IXEMPRA® (ixabepilone) in combination with capecitabine (N=752)

IRR, independent radiologic review; ORR, objective tumor response rate; PFS, progression-free survival; PO, by mouth; RECIST, Response Evaluation Criteria in Solid Tumors.

* For anthracyclines, patients who received a minimum cumulative dose of 240 mg/m2 of doxorubicin or 360 mg/m2 of epirubicin were also eligible.2

PFS was defined as time from randomization to radiologic progression, based on IRR of intent-to-treat population.1,2

Patients were censored for PFS at the last date of tumor assessment prior to the start of subsequent therapy. In patients where independent review was not available, PFS was censored at the randomization date.2

Study 046 baseline patient demographics and clinical characteristics1,2

IXEMPRA® (ixabepilone) combination Study 046 baseline patient demographics and clinical characteristics

ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.

* Percentages may not add to 100% due to rounding and/or unknown data for some patients.1

Defined as positive by fluorescence in situ hybridization or 3+ by immunohistochemistry.1

Resistance is defined as recurrence within 6 months in the adjuvant or neoadjuvant setting or progression within 3 months of the last anthracycline dose in the metastatic setting.1

§ Resistance is defined as recurrence within 12 months in the adjuvant or neoadjuvant setting or progression within 4 months of the last taxane dose in the metastatic setting.1

Efficacy

In combination with capecitabine, IXEMPRA® (ixabepilone) significantly improved progression-free survival (PFS) and more than doubled the objective tumor response rate (ORR) vs capecitabine alone2

  • IXEMPRA in combination with capecitabine demonstrated statistically significant improvement in PFS vs capecitabine alone in patients with metastatic or locally advanced breast cancer whose tumors were resistant to an anthracycline (or for whom further use was contraindicated) and a taxane2

Study 046 results (N=752)2

In combination with capecitabine, IXEMPRA® (ixabepilone) significantly improved progression-free survival (PFS) and more than doubled the objective tumor response rate (ORR) vs capecitabine alone

CI, confidence interval; HR, hazard ratio.

* For the hazard ratio, a value less than 1.00 favors combination treatment; CI adjusted for interim analysis.2,3

Stratified by visceral metastases in the liver/lung, prior chemotherapy in the metastatic setting, and anthracycline resistance.2

Calculated for all patients who achieved an objective tumor response (IXEMPRA + capecitabine, n=130; capecitabine, n=54).3

  • Patients received a median of 5 cycles and 4 cycles in the combination and capecitabine groups, respectively2
  • In patients who progressed on an anthracycline and a taxane, approximately 70% received IXEMPRA plus capecitabine after initial taxane failure3
  • There was a statistically significant improvement in median PFS: 5.7 months vs 4.1 months, respectively (P<0.0001)2
  • There was a statistically significant improvement in median ORR: 34.7% vs 14.3%, respectively (P<0.0001)2
  • There was no statistically significant difference in overall survival between treatment arms in this and a similarly designed study2
    • In the study described above, median overall survival was 12.9 months (95% CI, 11.5-14.2) in the combination therapy arm and 11.1 months (95% CI, 10.0-12.5) in the capecitabine alone arm (HR=0.90; 95% CI, 0.77-1.05; P=0.19)2
    • In the second trial comparing IXEMPRA in combination with capecitabine versus capecitabine alone, conducted in 1,221 patients pretreated with an anthracycline and a taxane, the median overall survival was 16.4 months (95% CI, 15.0-17.9) in the combination therapy arm and 15.6 months (95% CI, 13.9-17.0) in the capecitabine alone arm (HR=0.90; 95% CI, 0.78-1.03; P=0.12)2
In combination with capecitabine, IXEMPRA® (ixabepilone) significantly improved progression-free survival (PFS)

CI, confidence interval; PFS, progression-free survival.

* PFS was defined as time from randomization to radiologic progression, based on independent radiologic review of intent-to-treat population.1,2

Patients were censored for PFS at the last date of tumor assessment prior to the start of subsequent therapy. In patients where independent review was not available, PFS was censored at the randomization date.2

Stratified by visceral metastases in the liver/lung, prior chemotherapy in the metastatic setting, and anthracycline resistance.2

§ For the hazard ratio, a value less than 1.00 favors combination treatment; CI adjusted for interim analysis.2,3

In combination with capecitabine, IXEMPRA® (ixabepilone) more than doubled the objective tumor response rate (ORR) vs capecitabine alone

CI, confidence interval; ORR, objective tumor response rate.

* Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST).2

Stratified by visceral metastases in the liver/lung, prior chemotherapy in the metastatic setting, and anthracycline resistance.2

Calculated for all patients who achieved an objective tumor response (IXEMPRA + capecitabine, n=130; capecitabine, n=54).3

  • More than double the ORR in the combination group in patients with metastatic or locally advanced breast cancer as evaluated using RECIST2
  • Median duration of response: 6.4 months (95% CI, 5.6-7.1) vs 5.6 months (95% CI, 4.2-7.5), respectively2

Patient profiles

Trina

IXEMPRA® (ixabepilone) patient profile Trina* | Age: 45 years—perimenopausal

DIAGNOSIS

Initial stage

  • Palpable mass in the right breast
  • Mammography revealed 3.5-cm mass
  • Ultrasound-guided biopsy confirmed presence of invasive ductal carcinoma
  • Chest X-ray, bone scan, and CT scan were negative for metastatic disease

Receptor status

  • ER−, PR−, HER2/neu−

TREATMENT HISTORY

  • Underwent a mastectomy with axillary node dissection performed approximately 1 month after initial presentation
  • 6 of 12 axillary nodes contained macrometastases, and 1 contained 2-mm micrometastasis (pT2N2)

Adjuvant

  • Adjuvant therapy (AC–>T) initiated
  • Patient subsequently received radiation therapy

PRESENTATION

General

  • 9 months after completion of adjuvant therapy, patient complained of abdominal pain and shortness of breath on mild exertion; unable to work a full day due to severe fatigue

Sites of metastases

  • Multiple liver and lung lesions

Pertinent labs

  • CT-guided biopsy of one of the liver nodules was consistent with invasive ductal carcinoma
  • Receptor status confirmed as ER−, PR−, and HER2/neu−
  • LFT (AST/ALT) values were normal
  • Neutrophil and platelet counts were within normal limits

FIRST-LINE METASTATIC CHEMOTHERAPY

  • 16 months after surgery, patient was started on docetaxel plus capecitabine
  • Further anthracycline therapy was contraindicated
  • Patient progressed within 4 months
Trina reached the IXEMPRA® (ixabepilone) Zone for combination therapy

AC–>T, doxorubicin and cyclophosphamide followed by taxane (docetaxel or paclitaxel); ALT, alanine aminotransferase; AST, aspartate aminotransferase; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LFT, liver function test; PR, progesterone receptor; Tx, treatment.

* Hypothetical patient profile. Photo not of actual patient.

Further anthracycline therapy was contraindicated.

Reflects approved indications for IXEMPRA.

Jennifer

IXEMPRA patient profile Jennifer* | Age: 55 years—postmenopausal

DIAGNOSIS

Initial stage

  • 2.5-cm mass in the upper outer quadrant of the left breast; mass was dense with abundant speculation
  • Stranding around the mass and architectural distortion were also present
  • Mass was palpable, shotty, non-tender, and soft; mobile axillary lymph nodes were observed (stage IIA)

Receptor status

  • ER+, PR+, HER2/neu−

TREATMENT HISTORY

  • Lumpectomy and axillary staging; 2 of 11 axillary nodes contained micrometastases, and 1 contained 3-mm metastasis (stage IIB)

Adjuvant

  • Docetaxel + doxorubicin (cumulative dose of 300 mg/m2) + cyclophosphamide; G-CSF support
  • Additional doxorubicin therapy was contraindicated
  • Patient was started on an aromatase inhibitor and radiation therapy after completion of adjuvant chemotherapy

PRESENTATION

General

  • 13 months after completion of TAC, patient complained of persistent back pain that was not relieved despite taking an NSAID

Sites of metastases

  • Multiple liver and bone lesions

Pertinent labs

  • An MRI scan of patient’s spine showed lytic lesions on L4 and L5
  • Subsequent bone scans and CT scan revealed numerous skeletal lesions, as well as 3 hepatic lesions, each measuring 1 x 2 cm
  • Liver biopsy confirmed receptor status changed to ER−, PR+, and HER2/neu−
  • LFT (AST/ALT) values were normal
  • Neutrophil and platelet counts were within normal limits

FIRST-LINE METASTATIC CHEMOTHERAPY

  • Started on another taxane therapy (progressed within 3 months of starting therapy)
Jennifer reached the IXEMPRA® (ixabepilone) Zone for combination therapy

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ER, estrogen receptor; G-CSF, granulocyte colony-stimulating factor; HER2, human epidermal growth factor receptor 2; LFT, liver function test; PR, progesterone receptor; TAC, docetaxel, doxorubicin, and cyclophosphamide.

* Hypothetical patient profile. Photo not of actual patient.

Further anthracycline therapy was contraindicated.

Safety profile

Safety profile of IXEMPRA® (ixabepilone) in combination with capecitabine

Study 046 peripheral neuropathy2

Safety profile of IXEMPRA® (ixabepilone) in combination with capecitabine * Sensory and motor neuropathy combined.
  • Prior therapy with neurotoxic chemotherapy agents did not predict the development of neuropathy
  • Peripheral neuropathy was common and primarily sensory
  • Neuropathy is cumulative and generally reversible and should be managed with dose adjustments and delays
    • The median time to improvement of grades 3/4 neuropathy to baseline or grade 1 was 6.0 weeks
    • Following dose reduction, 80% of patients had improvement or no worsening of their neuropathy
    • Discontinuation due to neuropathy was 21%

Study 046 hematologic abnormalities1,2

Continued safety profile of IXEMPRA® (ixabepilone) in combination with capecitabine

Hgb, hemoglobin; WBC, white blood cell count.

* Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) was used in 20% of patients who received IXEMPRA in Study 046.2

In clinical trials, febrile neutropenia was classified as a nonhematologic adverse reaction.2

National Cancer Institute Common Terminology Criteria (NCI CTC) grading for febrile neutropenia ranges from grade 3 to grade 5. Three patients (1%) experienced grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia.2

  • Neutropenia-related deaths occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with XEMPRA in combination with capecitabine2
  • Infection with neutropenia was reported in 6% of patients treated with IXEMPRA in combination with capecitabine2

Study 046 nonhematologic drug-related adverse reactions occurring in ≥5% of patients2

IXEMPRA® (ixabepilone) in combination with capecitabine Study 046 nonhematologic drug-related adverse reactions occurring in ≥5% of patients

* System organ class presented as outlined in Guidelines for Preparing Core Clinical-Safety Information on Drugs by the Council for International Organizations of Medical Sciences (CIOMS).

National Cancer Institute Common Terminology Criteria (NCI CTC) grading for febrile neutropenia ranges from grade 3 to grade 5. Three patients (1%) experienced grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia.

No grade 4 reports.

§ A composite of multiple MedDRA Preferred Terms.

|| Peripheral sensory neuropathy (graded with the NCI CTC scale) was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, pallanesthesia, paresthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic, and sensorimotor disorder.

Peripheral motor neuropathy (graded with the NCI CTC scale) was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.

# Palmar-plantar erythrodysesthesia (hand-foot) syndrome was graded on a 1-3 severity scale in Study 046.

Indications and Important Safety Informationexpand

Indications

IXEMPRA® (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.

  • Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting
  • Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting

IXEMPRA is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

Important Safety Information
WARNING: Toxicity in hepatic impairment

Contraindications

Peripheral neuropathy

Myelosuppression

Hypersensitivity reaction

Pregnancy

Cardiac adverse reactions

Potential for cognitive impairment from excipients

Adverse reactions

Monotherapy

Combination with capecitabine

Cremophor is a registered trademark of BASF AG.

AST = aspartate aminotransferase; ALT = alanine aminotransferase; ULN = upper limit of normal; CTC = common terminology criteria.

Indications

IXEMPRA® (ixabepilone) is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.

  • Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant setting or 3 months in the metastatic setting
  • Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting

IXEMPRA is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

Please see US Full Prescribing Information, including boxed WARNING regarding hepatic impairment.

References: 1. Thomas ES, Gomez HL, Li RK, et al. lxabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007;25(33):5210-5217. 2. IXEMPRA (ixabepilone) Prescribing Information; January 2016. 3. Data on file: IXEM003. R-Pharm US: Princeton, NJ; 2007.

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