Drugs 44 (Suppl . 4): 29-35, 199200 12-6667/92/0400-0029/$3 .50/0© Adis International Limited. All rights reserved.

DRSUP3419

A Review of the Antitumour Activity of Vinorelbinein Breast Cancer

M. Marty, J.M. Extra, V. Dieras, S. Giacchetti, S. Ohana and M. EspieDepartment of Medical Oncology, Hopital Saint Louis, Paris, France

Summary The use of vinorelbine 30 mg/m2/week as a single-agent treatment in advanced breast cancerhas achieved response rates of > 20% as second-line treatment and 40 to 50% as first-line treat­ment. The major toxicity of the drug is reversible neutropenia; 35 to 50% of treated patients havegrade IV neutropenia. The agent did not induce thrombocytopenia and proved mildly emetogenicand neurotoxic . Activity was confirmed in combination with fluorouracil or doxorubicin, whenresponse rates ranging from 60 to 74%were achieved. Thus , vinorelbine appears to be a promisingagent in the treatment of advanced breast cancer.

For many years, it was considered that the ca­tharanthine moiety of the vinca alkaloids was theinert part of this class of molecules. The ability tomodify this moiety through hemisynthesis (Man­geney et al. 1979) has led to the development ofnew compounds with specific binding to mitotictubulin, distinctive pharmacokinetic properties,specific adverse effects and an enlarged spectrumof activity compared with the previously studiedvinca alkaloids. Vinorelbine is the most represent­ative of these molecules, as it possesses both spe­cific toxicity and activity profiles. In the field ofadvanced breast cancer (ABC), available studiesshowed that the activity of this agent was similarto that observed with anthracyclines - the mostactive agents known so far. Such an activity hasled to the approval in France ofvinorelbine in ABC.

1. In Vitro Antltumour Activity

The antitumour activity ofvinorelbine has beenstudied in more than 30 malignant cell lines (tableI). In all but one case (a breast cancer cell line re-

sistant to doxorubicin), concentrations required toinhibit 50% of malignant cells (ICso) were in therange of 10-9 to 10-7 mol/L, Such concentrationsare readily achieved in human subjects with a doseof30 mg/rn-'. The activity ofvinorelbine comparesfavourably with that of other vinca alkaloids (P388and LI21O: leukaemia and ovarian carcinoma;A2780: breast cancer) [Cros et al. 1989a,bl, and issimilar to that observed with the most active vincaalkaloid. If doses used in vivo in human subjectswere taken into account, the therapeutic index couldbe 10 to 40 times that of other vinca alkaloids.However, few breast cancer cell lines have beenstudied and the relevance of such in vitro screeningto clinical activity is far from being established.

2. In Vivo Antitumour Activity

Vinorelbine, given as a single intravenous dose,has demonstrated activity against 5 human tumourxenografts in nude mice: MX-l (breast cancer), LX­I and QG-56 (lung, squamous carcinoma), QG-36

30

Table I. Antitumour activity of vinorelbine in malignant cell lines

Cell line Origin Vinorelbine

ICso(nmoI/L)

L1210 LA. murine 7.15A2780 Ovarian Ca 47

A278000x 450NSCLC N6L2 Lung. sq. 1.4MOLT-4 LA. murine 1.59K-562 LA. murine 9.38H522 NSCLC 1.74H23 NSCLC 3.02H125 NSCLC 3.09H358 NSCLC 2.59H460 NSCLC 19.0A549 NSCLC 6.57H322 NSCLC 11.0EKVX NSCLC 2.95DMSl14 SCLC 4.82LoVo Colon Ca 2.25WIDR Colon Ca 9.20SW620 Colon Ca 2.44

DLD-l Colon Ca 49.3HT29 Colon Ca 2.66MCF7 Breast Ca 19.1

MCF700x Breast Ca 4000TE671 CNS 4.6

U251 CNS 2.06SK-MEL-5 Melanoma 1.6LOX Melanoma 24.0RPMI-7951 Melanoma 4.53Malme-3M Melanoma 3.47SK-MEL-2 Melanoma 7.1

Abbreviations : ICso = concentration required to inhibit 50% ofmalignant cells ; LA = leukaemia ; Ca = carcinoma; NSCLC =non-small cell lung cancer ; SCLC = small cell lung cancer ;CNS = central nervous system .

(lung, small cell carcinoma), and 04-I -ST (gastric,adenocarcinoma).

3. Clinical Trials with Vinorelbine inAdvanced Breast Cancer

A number of clinical trials have demonstrateda high level of activity of vinorelbine in ABC.

3.1 Single-Agent Treatment

In all of these studies, a common protocol wasused: patients with recurrent breast cancer, eitherafter they had failed I prior chemotherapy regimen

Drugs 44 (Suppl. 4) 1992

(second-line treatment) or without prior chemo­therapy for the treated progression, were eligible ifthey had a good performance status (0 to 2; WHOscale), normal blood cell counts, no significant or­gan dysfunction, and had given their informedconsent. Vinorelbine was administered as a weekly20-minute infusion at a dose of 30 mg/m-', In caseof grade 3 to 4 leucopenia and/or other adverseevents, it was possible to postpone the infusion by7 days and/or reduce the dose to 25 mg/m-'. WHOresponse criteria were used for evaluation.

3.1.1 Initial Phase II Study in ABCOf the 36 patients with ABC who entered an

initial phase II study, 14 had previously receivedadjuvant chemotherapy, 10 had received chemo­therapy as treatment of metastatic progression, and13 had previously received hormone therapy (Can­obbio et at. 1988). Dominant sites of disease wereviscera (n = 13), bone (n = 13), and soft tissue (n= 10).32 patients were evaluable for response (438cycles). Objective responses (partial and complete)were achieved in 17 patients (53 ± 17%), with 4achieving complete response (CR). Of 7 evaluablepatients previously treated with palliative chemo­therapy, 2 experienced a partial response (PR). Al­though preliminary, these results suggested a strik­ing activity of vinorelbine in ABC.

3.1.2 Vinorelbine as a Single Agent inSecond-Line TherapyThe efficacy and safety of vinorelbine was eval­

uated using a 2-stage design with a predefined lowerresponse rate of 20% (Lee et at. 1979; table II). All33 patients included in the study were evaluablefor response and toxicity, and all had previouslyreceived at least I chemotherapy regimen with ananthracycline and/or mitoxantrone. A median of 6cytotoxic agents had previously been received. Tar­get lesions were as follows: skin (II patients; 33%);liver (11 patients; 33%); lung (5 patients; 16%);nodes (3 patients; 9%); and bone (2 patients, 6%).PR or CR was obtained in 10 (8 PR; 2 CR) of 33patients, establishing a response rate of greater than20%, which has previously been observed in suchpatients with very few compounds (ametycin, el-

Vinorelbine in Breast Cancer 31

Table II. Characteristics of patients in phase II studies involvingweekly administration of vinorelbine as a single agent for first ­or second-line treatment

Iiptinium acetate) [Marty et al. 1989b). In thosepatients who had received prior intensive therapy ,neutropenia was more frequent (21 patients ; 10 to37%of courses), although it was noncumulative andreversible in 7 to 15 days. Neutropenic fever oc­curred in 3 patients and led to a reduction in dos­age of 66 to 76%. Thrombocytopenia was not sig­nificant , except for I patient with bone marrowprogression. A mild (grade I to 2) mucositis wasobserved in 2 patients (6.9%) between the fourthand sixth course. Alopecia was observed in less than30% of evaluable patients, usually after the sixthcourse. Eight patients experienced grade I consti­pation (25%) and 2 had grade 2 to 3 constipation(6.9%). Three patients (10%) reported mild paraes­thesias after the eighth course and 20% had de­creased reflexes. In those patients, the median dur­at ion of response was 21 weeks and the median

1st-line 1st-line(Kerbrat et (Bruno etal. 1992) al. 1992)

No. of patients entered 157No. of evaluable 145

patients

5252

2nd-line(Dieras etal. 1989)

3333

time to progression was 34 weeks (range 17 to 45weeks).

3.1.3 Activity in First-Line Single­Agent TreatmentA French multicentre study enrolled 157

patients, of whom 131 could be evaluated (Kerbratet al. 1992). Of the evaluable patients , 54 had Itumour site, 55 had 2 tumour sites and 36 had 3tumour sites. The mean relative dose administeredwas 72.5% of the theoretical dose, a value similaror superior to that achieved in other phase II stud­ies in previously untreated patients ; a similarquantitative and qualitative pattern of side effectswas also noted . A response was achieved in 60patients (10 CR; 50 PR) - a rate of 46% (CI = 37to 54%). The response rate was higher in patientswith soft tissue metastasis (61%). The median dur­ation of response was 32 weeks (range, 4 to 44weeks).

A similar study has been conducted by a multi­centre multinational Latin-American group (Brunoet al. 1992). 52 patients with a median age of 51years were included; 40% had received prior ad­juvant chemotherapy. 38% had I tumour site, 27%had 2 tumour sites and 35% had 3 or more tumoursites. 28 patients (44%) experienced a response(3 CR, 25 PR), with the likelihood of response be­ing unrelated to the tumour site.

Median age (years) 57 51[ranqe] [32-741 [29-721

Prior therapy (% of evaluable patients)Surgery 82 67Radiotherapy 62 46Adjuvant 43 40

chemotherapyPalliative hormone 33 31

therapyFirst line 0 0

chemotherapy

Metastatic sites (% of evaluable patients)Nodes 24 60Liver 23 31Lung 18 22S~n 17 20Breast 9 27Bone 5 22

50[30-681

908448

10

100

333918331875

3.1.4 TolerabilityThe main adverse events reported in phase II

studies involving weekly administration of vino­relbine as a single agent are depicted in table III.The relative dose was slightly lower during second­line treatment (66 to 72% of the theoretical dose)than during first-line treatment (72.5%). However,similar adverse events were encountered in thesestudies . 35 to 45% of patients (12 to 16%of cycles)had grade 3 to 4 leucopenia that was reversible,noncumulative and of short duration, thus com­plicated by few neutropenic fevers « 10%) and notoxic death. Anaemia and thrombocytopenia wererare and moderate in nature . Vinorelbine appearsto be mildly emetogenic and causes significant alo­pecia in 20 to 35% of patients. Few neurological

32 Drugs 44 (Suppl, 4) /992

Table III. Main adverse events in phase II studies involving weekly administration of vinorelbine as a single agent for first- or second­

line treatment

Incidence (%)

grade 0 grade 1 to 2 grade 3 to 4

1st-line 2nd·line 1st-line 2nd- line 1st-line 2nd-line

Neutropenia 3 4 45 59 49 36Thrombocytopenia 95 97 4 3 0 1Anaemia 25 65 70 25 5 10Nausea and vomiting 48 82 51 18 1 0Stomatitis 93 93 4 7 3 0Neurological events 84 71 15 29 0 0Alopecia 64 75 35 21 0 4

adverse events were observed, manifested mainlyas loss of osteotendinous reflexes. Significant con­stipation was noted in 2 to 4%of patients, and somemild and readily reversible dysaesthesias were alsoobserved.

3.2 Vinorelbine-Based Combination Therapy

mucosrtis: 40% of patients, but with significantthrombocytopenia in a single patient and no in­crease in neurotoxicity), leading to dose reductionin 40% of patients (table V). Responses have beenachieved in 33 of 54 patients (61%), although a re­sponse rate lower than 50% cannot be rejected yet.

Abbreviations: NVB = vinorelbine; DOX = doxorubicin; FU =fluorouracil.

Table IV. Characteristics of patients receiving vinorelbine­

containing combination chemotherapy regimens for first-line

treatment of advanced breast cancer

The high level of activity observed with vino­relbine as a single agent in the treatment of ABChas emphasised the need for studies in whichvinorelbine is used in combination with otherchemotherapeutic agents (Marty et al. 1989a).

3.2.1 Vinorelbine-Fluorouracil CombinationThe schedule used in this ongoing study com­

bined fluorouracil (750 mg/m 2/day) administeredas a continuous infusion for 5 days and vinorelbineas a 30 mg/m 2 infusion given on days I and 5 every3 weeks (Dieras et al. 1992). The study was plannedwith a group sequential design (Bellissant et al.1990). The predefined minimum rate of responseconsidered acceptable was 50%, and an analysis isconducted every 9 patients. Thus far, 59 patientshave been entered , of whom the first 54 have beenevaluated (sixth group analysis) [table IV]. Less than25% of patients had soft tissue or nodal progres­sion, while the others had visceral involvement (Imetastatic site: 27%). As expected, adverse eventswere more pronounced with the combinationtherapy (grade 3 to 4 neutropenia: 66% of patients;

NVB-DOX

No. of patients entered 88No. of evaluable patients 88Median age (years) 55

[ranqe] [25-681Prior therapy (% of evaluable patients)

Surgery 80Radiotherapy 37Adjuvant chemotherapy 29

(with anthracyclines) (24)Palliative hormone 36

therapyFirst -line chemotherapy 0

Metastatic sites (% of evaluable patients)1 342 273 or more 39

Performance status (% of evaluable patients)o 501-2 503-4 0

NVB·FU

595453[35-681

838367(57)16

o

353728

156717

Vinorelbine in Breast Cancer 33

Table V. Main adverse events in phase II studies with vinorelbine-containing combination chemotherapy regimens for first-line treat­ment of advanced breast cancer

Incidence (%)

grade 0 grade 1 to 2 grade 3 to 4

NVB-DOX NVB-FU NVB-DOX NVB-FU NVB-DOX NVB-FU

Neutropenia 7 9 18 49 75 42Thrombocytopenia 99 93 1 6 0 1Nausea and vomiting 35 61 53 34 12 6Stomatitis 60 39 28 24 12 34Constipation 69 74 27 17 3 10Alopecia 26 28 29 41 45 31Cardiac toxicity 91 100 3 0 6 0

Abbreviations: NVB = vinorelbine ; DOX = doxorubicin; FU = fluorouracil.

3.2.2 Doxorubicin-Vinorelbine CombinationIn this trial, the planned dose of doxorubicin

was 50 mg/m2 every 21 days, with vinorelbine 25mg/m2 administered on days I and 8 of each cycle(M. Spielmann, personal communication). 88patients with a median age of 55 years were eva­luable for response and toxicity (table IV). 34% ofpatients had I metastatic site, 27% had 2 and 39%had 3 or more. The median relative dose was 83%for vinorelbine and 75% for doxorubicin. CR wasachieved in 20 patients (23%), while PR was at­tained by 45 patients (51%). Thus, the response ratewas 74% (CI: 65 to 83%). Here again, neutropeniawas the main adverse event, with neutropenic fe­ver complicating 17% of cycles. The combinationtherapy was also associated with mucositis (12% ofpatients; grade 3 to 4). Eight cases of cardiac tox­icity were observed (only among the 21 patientswho had received prior anthracycline-containingadjuvant chemotherapy).

3.2.3 Epirubicin-Vinorelbine CombinationAn ongoing phase I-II trial involving adminis­

tration of vinorelbine on days I and 7, and epi­rubicin on day I every 3 weeks was undertaken (S.Giacchetti et aI., personal communication). Fourdose levels were planned:• vinorelbine 25 mg/m? and epirubicin 50 mg/m-;• vinorelbine 25 mg/m2 and epirubicin 60 mg/m-;• vinorelbine 30 mg/m2 and epirubicin 60 mg/rn-;

• vinorelbine 30 mg/m 2 and epirubicin 75 mg/rn-,At least 6 patients were included at each dose level.The third dose level has been completed with amed ian relative dose of 75%. Neutropenia was themain adverse event and was observed in 45% ofpatients. A response was observed in 6 of 8 patients.

20 patients with advanced breast cancer, ofwhom 7 had previously received adjuvant chemo­therapy and 9 had received chemotherapy, havebeen treated with the combination of intravenousboluses of epirubicin 60 mg/m? on day I and vi­norelbine 25 mg/m-' on days I and 8 every 3 weeksin an uncontrolled study (Chadjaa et al. 1992). Of64 cycles evaluable for toxicity, 13 were associatedwith grade III or IV granulocytopenia, 7 were as­sociated with grade III or IV leucopenia, I wasassociated with granulocytopenic fever, 3 were as­sociated with grade II mucositis and 13 wereassociated with grade III alopecia.

In the 15 patients evaluable for response, therewas an overall response rate of 46% (I completeand 6 partial remissions). This response rate sug­gests that the regimen used is as active as mostcombinations of 3 or more drugs .

The recommended dosage regimen, based on theresults to date, is epirubicin 60 mg/m 2 on day Iand vinorelbine 30 mg/m? on days I and 7.

3.2.4 Other Vinorelbine-Conta ining Regim ensA number of vinorelbine-containing combina­

tion regimens can be considered for the treatment

34

of ABC; however, few have been evaluated inclinical studies. We have used 2 such regimens inABC and as second- or third-line treatment in ad­vanced ovarian carcinoma in approximately 60patients for each regimen. In both regimens vi­norelbine was used at a dose of 30 mg/m? on daysI and 7 of each 21-day cycle. Thiotepa was ad­ministered at a dose of 10 to 12 mg/m2 on days Iand 7 for the first regimen , and hexamethylmelam­ine was given at a daily dose of300 mg/rn? on daysI to 7 for the second regimen. Haematological tox­icity was moderate, with 20% of patients experi­encing grade 3 to 4 neutropenia; no other adverseevents were encountered. The antitumour activitycould not be assessed in patients with ABC, sincethese regimens were used as maintenance therapyafter a response had been achieved.

3.2.5 Present Status of Vinorelbine-ContainingCombination RegimensThus far, 2 combination regimens have de­

served adequate study as first-line treatment ofABC: vinorelbine-doxorubicin and vinorelbine­fluorouracil. Both regimens were used in a repre­sentative population of patients, of whom morethan 40% had previously received adjuvantchemotherapy - with anthracyclines in a signifi­cant proportion of patients. Each of the 2 regimensachieved a response rate of more than 50% with20% of patients attaining a CR. As was expected,adverse events were more pronounced with com­bination regimens and appear to depend mainly onthe combined agent. With the addition of doxo­rubicin, the incidence of severe neutropenia in­creased, as did the incidence of drug-induced vom­iting, alopecia and cardiac toxicity. Withfluorouracil , grade 3 to 4 neutropenia was seen in40% of patients, and severe mucositis leading to a30% dose reduction for fluorouracil was observedin 40% of patients. Yet less than 5% of patients hadtheir treatment stopped because of adverse events.

4. Conclusion

Used as a single agent , vinorelbine achieved re­sponse rates greater than 20% in patients who had

Drugs 44 (Suppl. 4) 1992

Table VI. Antitumour activity of the main antineoplastic agentsin advanced breast cancer, used as single-agent therapy eitherin first - or second-l ine treatment (after Marty et a!. 1989b)

Agenta Dose (mg/m2) Response rate (%)

1st-line 2nd·line

Doxorubicin 30-75 40-50 15-25

Epirubicin 50-90 40·50 15-25

Mitoxantrone 10-14 20-35 15-25

Vinorelbine 30/week 40-50 > 20

Cyclophosphamide 400-600 34 NA

Fluorouracil 600 34 NA

Methotrexate 60 34 NA

Altretamine 150/day for 27 2

7 daysMelphalan 2-6/day for 23 NA

5 days

Ametycin 10-12 20-25 21

Elliptinium acetate 80/day for 20-30 15-25

3 daysVincristine 1.4 21 NA

Chlorambucil 2-6/day for 20 NA

5 days

a Only those agents with a reported response rate > 20% infirst -line treatment have been included.

Abbreviation: NA = data not available.

received prior first-line anthracycline-containingchemotherapy for ABC, and greater than 40% inpatients without prior chemotherapy for metastaticprogression. Such a level of activity has never beenreported with vinca alkaloids and is known onlywith anthracyclines (Marty et al. 1989b). Table VIsummarises the data obtained with effective agentsin phase II studies conducted in patients with ABC.Most certainly, a response rate of at least 50% isachieved when vinorelbine is used in combinationwith either fluorouracil or an anthracycline in sim­ilar subsets of patients with metastatic breast can­cer who have not received prior chemotherapy formetastatic progression.

Not only is vinorelbine a new therapeutic toolfor patients who ultimately progress after first-linetherapy (a frequent if not constant situation), butit pro vides new possibilities for first-line treat­ment. The increasing use of anthracyclines in ad­juvant treatment has already limited the use of this

Vinorelbine in Breast Cancer

class when metastatic progression occurs, thuswarranting new effective agents. The response rateachieved so far with the combination of fluorour­acil and vinorelbine shows that alternative possi­bilities are already available. Furthermore, vino­relbine appears to be a drug of choice when amaintenance phase of treatment is considered. Thishas led to the approval of vinorelbine for main­tenance therapy of ABC in France in 1991. Ob­viously, the optimal combinations are far frombeing fully explored and studies in preparation willcompare some of them to the reference treatments.Nevertheless, vinorelbine has already extended therange of available regimens for the treatment ofbreast cancer.

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Correspondence and reprints: Prof. M. Marty, Department ofMedical Oncology, Hopital Saint Louis, 1 Av CI. Vellefaux, F75010Paris, France.