IXEMPRA

【Function and Indications】

Ixempra (Ixabepilone) is a new anti-tumor chemotherapy drug of the epothilone class that is similar to paclitaxel in tubulin polymerization and inhibits microtubule depolymerization activity. It was developed and produced by Bristol-Myers Squibb. In October 2007, the FDA approved Ixempra as a single agent or in combination with capecitabine for the treatment of metastatic or locally advanced breast cancer that is refractory to anthracyclines, taxane derivatives, and capecitabine.
Epothilones: a class of sixteen-membered macrolide drugs, first isolated by Holfe and Reichenbach from the myxobacterium Sorangium cellulosum in 1992

Ixabepilone Ixempra (BMS-247550) is a semi-synthetic epothilone β-lactam analogue, a new generation of anti-mitotic drugs, with a mechanism of action similar to that of taxanes, which can bind to tubulin to prevent cancer cells from undergoing mitosis smoothly, thereby causing apoptosis of cancer cells. It is superior to paclitaxel in terms of anti-tumor spectrum, anti-tumor activity, safety, water solubility and synthesis method.

[Usage and Dosage]

1. Ixempra monotherapy

In a Phase II clinical trial of Ixempra monotherapy for anthracycline, taxane and capecitabine-resistant metastatic breast cancer, breast cancer patients received an intravenous infusion of Ixempra 40mg/m2 for 3 hours, one course every 3 weeks until disease progression (PD). The results showed that among 113 evaluable patients, the ORR was 11.5%, the disease stability (SD) rate was 50.0%, and the median progression-free survival (PFS) was 3.1 months. Among grade 3-4 toxic reactions, the highest incidence of neutropenia (54%) was observed, and peripheral neuropathy, weakness, myalgia, mucositis, etc. were also observed.

2. Ixempra combination therapy

The CA163046 study is a randomized Phase III clinical trial. The study included 752 patients with metastatic or locally advanced breast cancer resistant to anthracyclines and taxanes. Patients were randomly divided into a combination therapy group (n=375) and a monotherapy group (n=377), receiving Ixempra (40 mg/m2, intravenous infusion >3 hours, d1, q3w) + capecitabine (2000 mg/m2 daily, divided into 2 oral doses, d1-d14, q3w) or capecitabine monotherapy (2500 mg/m2 daily, divided into 2 oral doses, d1-d14, q3w). The researchers strictly defined previous treatment resistance as metastatic breast cancer with rapid tumor progression after adjuvant anthracycline and taxane chemotherapy or metastatic disease treatment. The primary endpoint of the study was PFS [using blinded independent radiographic assessment (IRR)]; secondary endpoints were ORR, time to response, duration of response, and overall survival (OS).

The results showed that the baseline characteristics of the two groups of patients, such as age, KPS score, previous treatment regimens for metastatic disease, and previous treatments, were similar and comparable. In addition, the disease and tumor characteristics of the two groups of patients, such as the number of lesions, visceral metastasis, hormone receptor status, and Her-2 status, were also similar. Based on IRR evaluation, the ORR of the two groups was 35% and 14%, respectively (P<0.0001), while the median PFS of patients in the combination and monotherapy groups were 5.8 months and 4.2 months, respectively (HR: 0.75, P=0.0003).

Subgroup analysis confirmed that compared with capecitabine monotherapy, Ixempra ixabepilone combined with capecitabine showed PFS benefits in all treatment subgroups. Further subgroup analysis (55 cases) showed that Ixempra ixabepilone combined with capecitabine as the first-line treatment of resistant metastatic breast cancer significantly improved the patient’s PFS compared with capecitabine monotherapy (7.0 months vs. 2.1 months; HR: 0.46, P=0.0109).

The incidence of grade 3-4 hematological toxicity in the combination therapy group was higher than that in the monotherapy group, mainly including leukopenia (57% vs. 6%), neutropenia (68% vs. 11%), anemia (10% vs. 4%), thrombocytopenia (8% vs. 4%), and neutropenia with fever (4% vs. <1%). The grade 3-4 non-hematological toxicity that was more common in the combination therapy group than in the monotherapy group included peripheral neuropathy (mainly sensory neuropathy, which was cumulative toxicity, reversible, and the median time to return to baseline or grade 1 was 6 weeks), fatigue, myalgia, mucositis, arthralgia, etc., and the incidence of diarrhea in the monotherapy group was higher than that in the combination therapy group.

Studies have confirmed that for metastatic breast cancer resistant to anthracyclines and taxanes, the efficacy of Ixempra ixabepilone combined with capecitabine is better than that of capecitabine monotherapy: prolonging PFS (HR: 0.75), increasing ORR by 2.5 times (35% vs. 14%), and patients in all subgroups showed survival benefits. The incidence of hematologic toxicity was higher in the Ixempra plus capecitabine group, and neuropathy (a known toxicity of microtubule-stabilizing drugs) was cumulative and reversible. Ixempra plus capecitabine is an effective treatment option for anthracycline- and taxane-resistant metastatic breast cancer.