Combination Docetaxel/Vinorelbine for Metastatic Breast Cancer and Non-Small-Cell Lung Cancer

ABSTRACT: Docetaxel (Taxotere) andvinorelbine (Navelbine) have both demonstrated activity as single agentsfor the treatment of patients with metastatic breast cancer and non-small-celllung cancer. With 100 mg/m² of docetaxel administered as a 1-hourintravenous infusion once every 3 weeks, projected median survival in previouslyuntreated and treated patients with non-small-cell lung cancer is reportedto be approximately 9 months. In addition, response rates have ranged from23% to 36% and 17% to 21% in these respective patient populations. Preliminarystudies indicate that in previously untreated patients with non-small-celllung cancer, vinorelbine provides a survival benefit that is greater thanbest supportive care and similar to that of platinum-based chemotherapeuticregimens. Investigation into the use of these agents in combination issupported by synergy shown in preclinical models, nonoverlapping side-effectprofiles, and the schedule independence of docetaxel. Preliminary resultsfrom phase I and II combination studies are encouraging, and no neurotoxicityhas been observed. Based on these data, further study into the combineduse of docetaxel and vinorelbine in patients with non-small-cell lung canceris warranted. [ONCOLOGY 11(Suppl 8):46-49, 1997]

Introduction

The rationale for the use of docetaxel (Taxotere) and vinorelbine (Navelbine)in combination chemotherapy regimens is based on a number of factors. Oneis attributable to their mechanisms of action, because both of these agentsexert complementary effects on microtubules. Docetaxel promotes abnormalpolymerization of tubulin into stable microtubule bundles by binding specificallywith the b-tubulin subunit of microtubules, thereby leading to the inhibitionof microtubule depolymerization.[1-3] Vinorelbine, on the other hand, bindsspecifically to the a- and b-tubulin subunits and blocks the ability ofthe protein to polymerize into microtubules. This action leads to the inabilityof chromosomes to segregate correctly during mitosis, thereby inducingapoptosis.[4,5]

The interest in these two compounds is also generated by specific characteristicswithin their respective chemical classes--ie, the taxoids and Vinca alkaloids.For example, docetaxel possesses greater potency as an inhibitor of microtubulardepolymerization, estimated as twice that of paclitaxel (Taxol).[2,3] Otherdifferentiating in vitro characteristics of docetaxel include higher bindingaffinities for microtubules, higher intracellular concentrations, and prolongedretention in tumor cells as compared with paclitaxel.[6,7]

It is believed that vinorelbine is less neurotoxic than other Vincaalkaloids because of the selectivity of vinorelbine for mitotic microtubules.[5]Moreover, results from preclinical tests[8] demonstrate that depolymerizationof axonal microtubules with vinorelbine occurs at a concentration of 40µM/L as compared with 5 and 30 µM/L for vincristine and vinblastine,respectively. Thus, the therapeutic index of vinorelbine can potentiallybe greater than that of either vincristine or vinblastine, as indicatedby its actions on mitotic and axonal activity.

Preclinical tests conducted by Bissery and colleagues[6] revealed thatdocetaxel and vinorelbine produce a synergistic response in the MA 16/Cmammary adenocarcinoma model. Synergy was demonstrated whether both agentswere administered simultaneously or 24 hours apart at 80% of the highestnontoxic dose.[6,9] Additional toxicity at these doses was not observed.In contrast, synergy was not demonstrated with either vincristine or vinblastine.[6]Thus, the results from preclinical studies and the well-established antitumoractivity as first-line single agents in metastatic breast cancer, non-small-celllung cancer, and a variety of other cancers support the use of docetaxeland vinorelbine in combination regimens.

ClinicalTrials with Docetaxel and Vinblastine

Phase I/II Studies in Metastatic Breast Cancer

A phase I/II dose-finding study by Fumoleau and colleagues[10] establishedthe maximum tolerated doses for the combination of docetaxel and vinorelbine,determined major pharmacokinetic parameters, and identified a recommendeddose for future phase II studies. Dose-limiting toxicity was defined asfebrile neutropenia of more than 3 days' duration and/or grade 4 neutropenialasting more than 7 days and/or grade 3 to 4 nonhematologic toxicity. Patientsentered in this trial had metastatic breast cancer, a World Health Organizationperformance status of 2 or less, and no prior chemotherapy for advanceddisease.

The treatment plan included vinorelbine administered as a 30-minuteintravenous infusion on days 1 and 5 followed immediately by a 1-hour intravenousinfusion of docetaxel on day 1 of a 21-day cycle. The dose levels of vinorelbine/docetaxeladministered were 20/60, 20/75, 22.5/ 75, 20/85, and 20/100 mg/m².All patients received premedication with 8 mg/day of dexamethasone for3 days starting 1 day prior to chemotherapy. Because of the potential forneurotoxicity with the use of vinorelbine, neurological examinations includingnerve conduction studies were performed at baseline, and then followingevery 2 cycles thereafter.

Overall, responses were observed at each dose level. Two maximum tolerateddoses were reached: 22.5 mg/m² of vinorelbine followed by 75 mg/m²of docetaxel and 20 mg/m² of vinorelbine followed by 100 mg/m²of docetaxel. Febrile neutropenia was observed in 37% and 11% of the cyclesat the 2 dose levels. Based on these results, the authors concluded that20 mg/m² of vinorelbine (days 1 and 5) followed by either 75 or 85mg/m² of docetaxel on day 1 was recommended for phase II studies.At the recommended doses, 11 of 16 patients had an objective response.

Based on the results of the phase I study,[10] a multicenter phase IItrial was initiated to evaluate the combination of docetaxel and vinorelbineas first-line therapy in patients with metastatic breast cancer. Patientsin this ongoing trial will receive 20 mg/m² of vinorelbine administeredas a 30-minute intravenous infusion on days 1 and 5 followed immediatelyby 85 mg/m² of docetaxel on day 1 of a 21-day cycle.

Phase I/II Studies in Non-Small-Cell Lung Cancer

Although the initial studies of docetaxel and vinorelbine combinationswere performed in patients with metastatic breast cancer, subsequent studieshave concentrated on non-small-cell lung cancer. Douillard and co-workers[11]conducted a phase I dose-escalation trial to determine the dose-limitingtoxicity, maximum tolerated dose, and the recommended dose of docetaxelplus vinorelbine for future trials. Inclusion criteria included previouslyuntreated patients with histologically proven advanced or metastatic non-small-celllung cancer with at least one bidimensionally measurable lesion and whohad a World Health Organization performance status less than or equal to2.

During the 3-week cycle, vinorelbine was administered as a 30-minuteintravenous infusion on days 1 and 8 followed immediately by a 1-hour intravenousinfusion of docetaxel on day 8. The dose levels are shown in Table1. Patients were premedicated with 8 mg of dexamethasone twice dailyfor 3 days, beginning 1 day prior to the administration of docetaxel.

To date, 26 patients have entered this ongoing trial, with evaluabledata on 23 patients (Table 2). The medianage is 52 years (range: 39 to 68 years) with a median World Health Organizationperformance status of 1. The maximum tolerated dose was 25 mg/m² ofvinorelbine on days 1 and 8 and 100 mg/m² of docetaxel on day 8. Atthis dose, 3 patients developed dose-limiting toxicities (1 incidence offebrile neutropenia, 1 neurosensory, and 1 neutropenia with infection).Data are not yet available for patients receiving 25 and 20 mg/m²of vinorelbine on days 1 and 8, and 100 mg/m² of docetaxel on day8. The authors concluded that the maximum tolerated dose found in thisstudy was close to the recommended dose of each drug as a single agent.

Use of a 2-Week Cycle

Investigators at Memorial Sloan-Kettering Cancer Center[12] evaluatedan every-2-week dose schedule in a phase I/II trial of docetaxel and vinorelbinein previously untreated patients with advanced non-small-cell lung cancer.Based on preliminary observations, the authors noted that the toxicityof this combination appears to be minimized when docetaxel and vinorelbineare administered at approximately the same time.

Using a 2-week cycle, patients in this ongoing study receive either15, 20, 25, 30, or 37.5 mg/m² of vinorelbine as a 10-minute intravenousinfusion followed immediately by a 1-hour IV infusion of 50 mg/m²of docetaxel. Patients are also receiving granulocyte colony-stimulatingfactor (G-CSF) (filgrastim [Neupogen]) support, and premedication withdexamethasone.

Preliminary data are available on 17 patients who have received a totalof 83 cycles (Table 2). The median ageof patients was 56 years. Overall, partial response was achieved in 29%of patients (range: 10% to 56%; 95% confidence interval). As with Douillardand colleagues,[11] no cases of neurotoxicity were noted. Only 2 episodesof febrile neutropenia were observed. Other nonhematologic toxicities (grade1 to 2) included mucositis (2/17), diarrhea (1/17), bacteremia (1/17),and upper extremity thrombosis (1/17). Patient accrual is ongoing and moredata are needed before a identifying the maximum tolerated dose and thedose-limiting toxicity.

Schiller et al[13] performed a phase I study evaluating the maximumtolerated dose of docetaxel and vinorelbine in patients with advanced non-small-celllung cancer who had failed platinum-based chemotherapy. Dose-limiting toxicitywas defined as grade 4 neutropenia of at least 5 days' duration, febrileneutropenia, a 2-week or greater delay in the administration of vinorelbine,and/or a grade 3 or greater nonhematologic toxicity in the first cycle.

Patients received 15 mg/m² of vinorelbine administered by intravenousinfusion on a weekly basis followed immediately by varying doses of docetaxel(45, 60, and 75 mg/m²) on day 1, once every 3 weeks. This schedulewas implemented after an initial trial of vinorelbine on days 1, 2, and3 was believed by the authors to be too myelosuppressive for the first2 patients.

Preliminary data are available for 11 patients (Table2). The median age is 63 years with a World Health Organization performancestatus between 0 and 1. Patient accrual continues in this study. Resultsfrom the first 11 patients suggest that 15 mg/m² of vinorelbine administeredby intravenous infusion once weekly followed immediately by 60 mg/m²of docetaxel as a 1-hour intravenous infusion once every 3 weeks is welltolerated.

The recommended dose of docetaxel and vinorelbine reported by Fumoleauand colleagues[10] in patients with metastatic breast cancer was adoptedby Trillet-Lenoir and colleagues[14] in a multicenter phase II trial of39 previously untreated patients with locally advanced or metastatic non-small-celllung cancer. Inclusion criteria included patients with histologically provenlocally or advanced metastatic non-small-cell lung cancer with at leastone bidimensionally measurable lesion. Seventy-nine percent of patientshad a World Health Organization performance status of 1 and 21% had a WHOperformance status of 2.

The initial dose was 20 mg/m² of vinorelbine administered as a30-minute intravenous infusion on days 1 and 5 followed immediately bya 1-hour intravenous infusion of 75 mg/m² of docetaxel on day 1, onceevery 3 weeks. Patients also received premedication with prednisone, diosmine,and antiemetics on an outpatient basis. Prophylactic growth factor supportwas not provided in this study.

Partial responses were achieved in 27% of the patients and the medianduration of response was 4 months (Table2). The dose-limiting toxicity was grade 4 neutropenia, which was seenin 85% of the patients.[14] Febrile neutropenia was experienced by 41%of patients. Grade 3 to 4 stomatitis occurred in 11% of the patients. Approximately18% of the patients experienced grade 1 to 2 neurosensory toxicity. Fluidretention was not observed in any patient. The authors concluded that thecombination of 75 mg/m²of docetaxel and 20 mg/m² of vinorelbineis a feasible combination with promising activity. Additional studies areneeded to determine if the activity documented in this study is similarto that of docetaxel alone. In addition, future studies incorporating G-CSFmay decrease the incidence of febrile neutropenia.[14]

One such trial incorporating the use of G-CSF support was that conductedby Kourousis and colleagues.[15] In 41 previously untreated patients withstage IIIB or IV non-small-cell lung cancer, 25 mg/m² of vinorelbinewas administered as a 15-minute intravenous infusion followed immediatelyby a 1-hour intravenous infusion of 100 mg/m² of docetaxel once every3 weeks. Patients in this phase II study also received 5 µg/kg ofG-CSF beginning on day 4 and continuing through day 15. The majority ofpatients had stage IV disease (70%) and had a World Health Organizationperformance status of 0 to 1 (80%).[15]

Partial response was documented in 41% of the 37 evaluable patients(range: 25% to 56%; 95% confidence interval), with a median survival ofover 5 months (range: 2 to 13 months) (Table2). The addition of G-CSF support minimized the magnitude of grade3 or 4 neutropenia, which was noted in 49% of patients. Febrile neutropeniawas noted in 24% of patients. Neurotoxicity of grade 3 severity was alsolow, at 2%, with no cases of grade 4 neurotoxicity. The authors noted thatthe addition of G-CSF support to docetaxel and vinorelbine was a well-toleratedregimen that provided significant antitumor activity.[15]

Commentary

The combination of docetaxel and vinorelbine is an active and well-toleratedregimen, based on the preliminary results from phase I and II trials inboth patients with metastatic breast cancer and non-small-cell lung cancer.Identifying a standard dosage and schedule for this combination continuesto be refined, most notably in patients with non-small-cell lung cancerwho, as expected, appear to have a different tolerability for such schedules.The majority of studies have used various dosages of vinorelbine that requiredvarious dosages of docetaxel (see Table 2).

For docetaxel, it is becoming clear that doses near those recommendedfor single-agent use (75 to 100 mg/m², 1-hour intravenous infusion,once every 3 weeks) are appropriate. However, defining a dose schedulefor vinorelbine has been more difficult, especially in the non-small-celllung cancer setting. Based on the preliminary data, promising antitumoractivity and acceptable safety profile have been noted with 2 regimens:75 mg/m² of docetaxel on day 1 and 20 mg/m² of vinorelbine ondays 1 and 5, once every 3 weeks; 25 mg/m² of vinorelbine on days1 and 8 and 85 mg/m² of docetaxel on day 8, once every 3 weeks. Itis hoped that results from future studies will further define the optimaldose schedules of this combination in both metastatic breast cancer andnon-small-cell lung cancer.

References:

1. Diaz JF, Andreu JM: Assembly of purified GDP-tubulin into microtubulesinduced by Taxol and Taxotere: Reversibility, ligand stoichiometry, andcompetition. Biochemistry 32:2747, 1993.

2. Gueritte-Voegelein F, Guenard D, Lavelle F, et al: Relationshipsbetween the structure of taxol analogues and their antimitotic activity.J Med Chem 34:992-998, 1991.

3. Ringel I, Horwitz SB: Studies with RP 56976 (Taxotere): A semisyntheticanalogue of taxol. J Natl Cancer Inst 83:288-291, 1991.

4. Burris HA, Fields S: Summary of data from in vitro and phase I vinorelbine(Navelbine) studies. Semin Oncol 21(suppl 10):14-21, 1994.

5. Binet S, Fellows A, Meininger V: In situ analysis of the action ofNavelbine on various types of microtubules using immunofluorescence. SeminOncol 16(suppl 4):5-8, 1989.

6. Lavelle F, Bissery MC, Combeau C, et al: Preclinical evaluation ofdocetaxel (Taxotere). Semin Oncol 22(suppl 4):3-16, 1995.

7. Riou J-F, Petitgenet O, et al: Cellular uptake and efflux of docetaxel(Taxotere) and paclitaxel (Taxol) in P388 cell line (abstract 2292). ProcAm Assoc Cancer Res 35:385, 1994.

8. Binet S, Chineau E, Fellows A, et al: Immunofluorescence of the actionof Navelbine,

vincristine, and vinblastine on mitotic and axonal microtubules. IntJ Cancer 46:262-266, 1990.

9. Bissery MC, Azli N, Fumoleau P: Docetaxel in combination with vinorelbine:Preclinical-clinical correlation (abstract 1550). Proc Am Soc Clin Oncol15:487, 1996.

10. Fumoleau P, Delecroix V, Perrocheau G, et al: Final results of aphase I dose finding and pharmacokinetic study of docetaxel in combinationwith vinorelbine in metastatic breast cancer (abstract 606P). Ann Oncol7(suppl 5):126, 1996.

11. Douillard JY, Monnier A, Le Chevalier, et al: Docetaxel in combinationwith vinorelbine in chemotherapy naive patients with metastatic or unresectablenon-small-cell lung cancer (NSCLC): Preliminary results of a phase I study(abstract). Proc Am Soc Clin Oncol 16, 1997.

12. Early E, Miller, VA, Grant SC, et al: Phase I/II trial of docetaxeland vinorelbine with filgrastim (G-CSF) in patients with advanced non-smallcell lung cancer (abstract 1678). Proc Am Soc Clin Oncol 16, 1997.

13. Schiller JH, Larson M, et al: Phase I trial of docetaxel and vinorelbinein patients with advanced non-small-cell lung cancer previously treatedwith platinum-based chemotherapy (abstract 1733). Proc Am Soc Clin Oncol16, 1997.

14. Trillet-Lenoir V, Monnier A, Douillard JY, et al: Interim resultsof a phase II study of docetaxel (Taxotere) and vinorelbine in chemotherapynaive patients with advanced non-small-cell lung carcinoma (NSCLC) (abstract450P). Ann Oncol 7(suppl 5):95, 1996.

15. Kourousis C, Androullakis N, Kakolyris S, et al: First line treatmentof non-small-cell lung carcinoma (NSCLC) with docetaxel and vinorelbine:A phase II study(abstract 1441P). Ann Oncol 7(suppl 5):93, 1996.