"The U.S. Food and Drug Administration today approved Kadcyla (ado-trastuzumab emtansine), a new therapy for patients with HER2-positive, late-stage (metastatic) breast cancer.
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Mechanism Of Action
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use.
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m² to 115 mg/m² in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m² to 115 mg/m² with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hour, respectively. Mean total body clearance was 21 L/h/m² .
The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.
In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 [see DRUG INTERACTIONS].
A study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug.
Effect of Age
A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m². Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel were not influenced by age.
Effect of Gender
The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel.
The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT > 1.5 times ULN concomitant with alkaline phosphatase > 2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with DOCEFREZ. Patients with severe hepatic impairment have not been studied. [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].
Effect of Race
Mean total body clearance for Japanese patients dosed at the range of 10 mg/m² to 90 mg/m² was similar to that of European/American populations dosed at 100 mg/m², suggesting no significant difference in the elimination of docetaxel in the two populations.
Effect of Ketoconazole
The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m² intravenous) alone or docetaxel (10 mg/m² intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was co-administration with ketoconazole [see DOSAGE AND ADMINISTRATION and Drug-Drug Interactions].
Effect of Combination Therapies:
- Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone.
- Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that previously observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone.
- Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with hormone-refractory metastatic prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone.
Locally Advanced Or Metastatic Breast Cancer
The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens).
In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m² every 3 weeks) or the combination of mitomycin (12 mg/m² every 6 weeks) and vinblastine (6 mg/m² every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results (See Table 8).
Table 8 : Efficacy of Docetaxel in the Treatment of
Breast Cancer Patients Previously Treated with an Anthracycline-Containing
Regimen (Intent-to-Treat Analysis)
|Median Survival||11.4 months||8.7 months||p=0.01|
|Risk Ratio*, Mortality (Docetaxel: Control)||0.73||Log Rank|
|95% CI (Risk Ratio)||0.58-0.93|
|Median Time to Progression||4.3 months||2.5 months|
|Risk Ratio*, Progression (Docetaxel: Control)||0.75||p=0.01 Log Rank|
|95% CI (Risk Ratio)||0.61-0.94|
|Overall Response Rate Complete Response Rate||28.1% 3.4%||9.5% 1.6%||p < 0.0001 Chi Square|
|*For the risk ratio, a value less than 1.00 favors docetaxel.|
In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m²) or doxorubicin (75 mg/m² ) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below (See Table 9).
Table 9 : Efficacy of Docetaxel in the Treatment of
Breast Cancer Patients Previously Treated with an Alkylating-Containing Regimen
|Efficacy Parameter||Docetaxel (n=161)||Doxorubicin (n=165)||p-value|
|Median Survival||14.7 months||14.3 months|
|Risk Ratio*, Mortality (Docetaxel: Control)||0.89||p=0.39 Log Rank|
|95% CI (Risk Ratio)||0.68-1||.16|
|Median Time to Progression||6.5 months||5.3 months|
|Risk Ratio*, Progression (Docetaxel: Control)||0.93||p=0.45 Log Rank|
|95% CI (Risk Ratio)||0.71-1||.16|
|Overall Response Rate||45.3%||29.7%||p=0.004|
|Complete Response Rate||6.8%||4.2%||Chi Square|
|*For the risk ratio, a value less than 1.00 favors docetaxel.|
In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m² (n=151), 75 mg/m² (n=188) or 100 mg/m² (n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with docetaxel dose: 19.9% for the 60 mg/m² group compared to 22.3% for the 75 mg/m² and 29.8% for the 100 mg/m² group; pair-wise comparison between the 60 mg/m² and 100 mg/m² groups was statistically significant (p=0.037).
Single Arm Studies
Docetaxel at a dose of 100 mg/m² was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31.0% to 44.8%) and the complete response rate was 2.1%.
Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m², in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2% to 55.7%), similar to the response rate in single arm studies of 100 mg/m² .
Non-Small Cell Lung Cancer (NSCLC)
The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve.
Monotherapy with Docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy
Two randomized, controlled trials established that a docetaxel dose of 75 mg/m² was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m², however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used [see BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤ 2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m² or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m². A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m² or best supportive care.
In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤ 2 were randomized to docetaxel 75 mg/m², docetaxel 100 mg/m² and a treatment in which the investigator chose either vinorelbine 30 mg/m² days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m² days 1-3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the docetaxel 75 mg/m² arm and the comparator arms are summarized in Table 10 and Figures 1 and 2 showing the survival curves for the two studies.
Table 10 : Efficacy of Docetaxel in the Treatment of
Non-Small Cell Lung Cancer Patients Previously Treated with a Platinum-Based
Chemotherapy Regimen (Intent-to-Treat Analysis)
|Docetaxel 75 mg/m²
|Best Supportive Care
|Docetaxel 75 mg/m²
|Overall Survival Log-rank Test||p=0.01||p=0.13|
|Risk Ratio††, Mortality (Docetaxel: Control)||0.56||0.82|
|95% CI (Risk Ratio)||(0.35, 0.88)||(0.63, 1.06)|
|Median Survival 95% CI||7.5 months (5.5, 12.8)||4.6 months (3.7, 6.1)||5.7 months (5.1, 7.1)||5.6 months (4.4, 7.9)|
|% 1-year Survival 95% CI||37%**† (24, 50)||12% (2.0, 23)||30%**† (22, 39)||20% (13, 27)|
|Time to Progression 95% CI||12.3 weeks** (9.0, 18.3)||7 weeks (6.0, 9.3)||8.3 weeks (7.0, 11.7)||7.6 weeks (6.7, 10.1)|
|Response Rate 95% CI||5.5% (1.1, 15.1)||Not Applicable||5.7% (2.3, 11.3)||0.8% (0.0, 4.5)|
**p ≤ 0.05;
† uncorrected for multiple comparisons;
†† a value less than 1.00 favors docetaxel.
Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m² .
Figure 1 :TAX317 Survival K-M Curves -Docetaxel 75
mg/m² vs. Best Supportive Care
Figure 2 :TAX320 Survival K-M Curves – Docetaxel 75
mg/m² vs. Vinorelbine or Ifosfamide Control
Patients treated with docetaxel at a dose of 75 mg/m² experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.
Combination Therapy with Docetaxel for Chemotherapy-Naïve NSCLC
In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m² as a 1 hour infusion immediately followed by cisplatin 75 mg/m² over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m² administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m² administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin.
The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 11.
Table 11 :Survival Analysis of Docetaxel in
Combination Therapy for Chemotherapy-Naïve NSCLC
|Comparison||Docetaxel + Cisplatin
|Vinorelbine + Cisplatin
|Kaplan-Meier Estimate of Median Survival||10.9 months||10 months|
|Estimated Hazard Ratiob||0.88|
|Adjusted 95% CIc||(0.74, 1.06)|
|aFrom the superiority test (stratified log
rank) comparing docetaxel+cisplatin to vinorelbine+cisplatin
bHazard ratio of docetaxel+cisplatin vs. vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that docetaxel+cisplatin is associated with a longer survival.
cAdjusted for interim analysis and multiple comparisons.
The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 12).
Table 12 :Response and TTP Analysis of Docetaxel in
Combination Therapy for Chemotherapy-Naïve NSCLC
|Endpoint||Docetaxel + Cisplatin||Vinorelbine + Cisplatin||p-value|
|Objective Response Rate (95% CI)a||31.6%
|Median Time to Progressionb (95% CI)a||21.4 weeks
|aAdjusted for multiple comparisons.
Hormone Refractory Prostate Cancer
The safety and efficacy of docetaxel in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial.
A total of 1006 patients with Karnofsky Performance Status (KPS) ≥ 60 were randomized to the following treatment groups:
- Docetaxel 75 mg/m² every 3 weeks for 10 cycles.
- Docetaxel 30 mg/m² administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
- Mitoxantrone 12 mg/m² every 3 weeks for 10 cycles.
All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.
In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 13 and Figure 3.
Table 13: Efficacy of Docetaxel in the Treatment of
Patients with Androgen Independent (Hormone Refractory) Metastatic Prostate
Cancer (Intent-to-Treat Analysis)
|Docetaxel + Prednisone every 3 weeks||Mitoxantrone + Prednisone every 3 weeks|
|Number of patients||335||337|
|Median survival (months)95% CI||18.9 (17.0-21.2)||16.5 (14.4-18.6)|
|*Stratified log rank test. Threshold for statistical significance = 0.0175 because of 3 arms.|
Figure 3 : TAX327 Survival K-M Curves
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.
3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm. 2006;63:1172-11934. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.
Last reviewed on RxList: 5/21/2015
This monograph has been modified to include the generic and brand name in many instances.
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