Trials of Vinorelbine and Docetaxel in the Treatment of Advanced Non–Small-Cell Lung Cancer

Trials of Vinorelbine and Docetaxel in the Treatment of Advanced Non–Small-Cell Lung Cancer Vincent A. Miller Abstract Docetaxel was chosen for study in the combination chemotherapy of advanced non–small-cell lung cancer on the basis of its reproducible high single-agent activity, novel mechanism of action, and relative lack of neurotoxicity. Preclinical and clinical data suggested schedule-dependent synergism with vinorelbine. Trials of docetaxel and vinorelbine have explored a variety of schedules. One approach has been to give docetaxel on day 1 of a 3-week cycle with vinorelbine on day 0 or days 1 and 5. Febrile neutropenia and non-neutropenic infections have been dose limiting, and low-dose intensity (8-13 mg/m2/week) of vinorelbine has been achieved. Our phase I study showed that docetaxel 60 mg/m2 and vinorelbine 45 mg/m2 every 2 weeks could be safely given with prophylactic filgrastim. In the ensuing phase II trial, we observed a 51% confirmed response rate in 35 patients (95% confidence interval [CI]: 34-68). With a median follow-up of 12 months, the predicted median and 1-year survivals are 14 months and 60%, respectively. Use of prophylactic filgrastim and the every-2-week schedule of administration allowed for single-agent dose intensity of both drugs to be given. Febrile neutropenia occurred in five patients and 5/384 cycles. Cumulative toxicities of excessive lacrimation, fatigue, and onycholysis were observed. More recently, a weekly schedule of administration for both drugs has been studied. Docetaxel and vinorelbine appear highly active together when given on an every-2-week schedule with prophylactic filgrastim, and the combination may offer one alternative to cisplatin-based therapy. However, confirmatory phase II and III studies are needed. Certain cumulative toxicities (onycholysis, lacrimation) may limit the duration of therapy. Application of this regimen for a shorter period, such as in induction or postoperative settings, may provide optimal benefit while minimizing toxicity. Clinical Lung Cancer, Vol. 1, Suppl. 1, S24-S26, 2000

Key words: Non–small-cell lung cancer, Vinorelbine, Docetaxel, Filgrastim

Introduction

bine 15 mg/m2 when given with docetaxel 75 mg/m2 on day 1 of an every-3-week schedule in previously treated patients with NSCLC. Previously these investigators had shown that vinorelbine 15 mg/m2/day given daily for 3 consecutive days with docetaxel every 3 weeks resulted in intractable myelosuppression. A phase II trial was then undertaken by this group, utilizing docetaxel 60 mg/m2 every 3 weeks with weekly vinorelbine 15 mg/m2.9 At Memorial Sloan-Kettering Cancer Center (MSKCC), a phase I trial also studied two schedules for the vinorelbine and docetaxel combination. The first administered vinorelbine on days 1 through 3 with docetaxel on day 1. Four of four patients developed febrile neutropenia with this schedule despite prophylactic filgrastim therapy. The treatment was subsequently modified such that both drugs were given on day 1 only of an every-2-week cycle. Vinorelbine 45 mg/m2 followed immediately by docetaxel 60 mg/m2 had an acceptable toxicity profile when given with prophylactic filgrastim.8 Febrile neutropenia developed in 4 of 209 cycles. This every-2-week regimen then proceeded to a phase II trial. More recently, a weekly schedule of administration for both drugs was studied.10 The authors administered vinorelbine 20 mg/m2 and docetaxel at an initial dose of 20 mg/m2 weekly. Docetaxel was escalated by 5 mg/m2/week increments in suc-

Both vinorelbine and docetaxel are effective as single agents in non–small-cell lung cancer (NSCLC) with response rates of 25%-30%.1 Several in vitro and in vivo models demonstrated schedule-dependent synergy between these agents.2-4 This may be due to a common mechanism of bcl-2 phosphorylation and inactivation induced by drugs that act on microtubules (ie, taxanes and vinca alkaloids).5 Phase I Trials Based on these preclinical findings, several phase I trials were initiated combining vinorelbine and docetaxel in patients with breast cancer and NSCLC.6-8 Fumoleau et al recommended doses of vinorelbine 20 mg/m2 days 1 and 5 with docetaxel 75 mg/m2 day 1 of an every-3-week cycle for phase II studies. Schiller et al studied two schedules of the combination. Maximum tolerated dose (MTD) was reached with weekly vinorelResearch supported, in part, by Rhône-Poulenc Rorer Submitted: Dec. 10, 1999; Revised: Jan. 25, 2000; Accepted: Jan. 27, 2000 Address for correspondence: Vincent A. Miller, MD, Memorial SloanKettering Cancer Center, 1275 York Ave. New York, NY 10021 Fax: 212-794-4357; e-mail: [email protected]

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April 2000

Table 1

Phase II Trials of Vinorelbine and Docetaxel in NSCLC

Investigator

No. of patients

Vinorelbine (V)

Docetaxel (D)

Filgrastim

Interval

Kourousis11

46

25 mg/m2 day 1

100 mg/m2 day 2

Y

3 weeks

39

mg/m2

Trillet-Lenoir12 Krug13

20

35

Johnston10* Balana14†

21 38

Hotton9

20

45

mg/m2

20

mg/m2

mg/m2

day 1 day 1

days1 and 6 or 1 and 15

15

22

days 1 and 5

mg/m2

75

mg/m2

day 1

N

3 weeks

60

mg/m2

day 1

Y

2 weeks

35

mg/m2

day 1

Y

Weekly

day 1 or 6

N

3 weeks

N

V-weekly D-3 weeks

75

day 1

mg/m2

60

mg/m2

day 1

* Some patients were treated on the phase I portion of the study, which did not utilize filgrastim. † Several schedules were studied to assess for toxicity/efficacy differences.

cessive cohorts of patients, while the vinorelbine dose remained fixed. When the MTD was determined to be docetaxel 25 mg/m2 with vinorelbine 20 mg/m2, accrual was restricted to chemotherapy-naive patients, and a new MTD was then defined using prophylactic filgrastim in a phase II study. Phase II Trials Six phase II trials have evaluated the docetaxel and vinorelbine combination for patients with NSCLC (Table 1). A Greek trial treated 46 patients with vinorelbine 25 mg/m2 on day 1 and docetaxel 100 mg/m2 on day 2 with prophylactic filgrastim.11 Thirty-five patients (76%) had stage IV disease, and nearly all (93%) had a World Health Organization (WHO) performance status of 0-1. Cases of anemia, thrombocytopenia, neuropathy, and fatigue were mild. However, nearly half of the patients required hospitalization for either neutropenic fever or non-neutropenic pulmonary infections, and four toxic deaths occurred on study. An overall response rate of 37% included four complete responses (10%) and eleven partial responses (27%), with a 5-month median duration of response. Median survival was 5 months, and the 1-year survival was 24%. A phase II multicenter French trial studied the regimen of Fumoleau et al in NSCLC.12 Vinorelbine 20 mg/m2 was administered on days 1 and 5 with docetaxel 75 mg/m2 on day 1 after premedication with prednisolone and diosimine (a putative neuroprotective agent). Prophylactic filgrastim was not adTable 2

ministered in this trial. Of the 39 patients accrued, 21% had a WHO performance status of 2, and 85% had stage IV disease. Grade 4 neutropenia (85%), febrile neutropenia (41%), grade 3-4 stomatitis (46%), and infections (38%) were common. Two deaths resulted from febrile neutropenia. Partial responses were documented in nine patients (27%), with a median response duration of 4 months. Survival data were not reported. Thirty-five patients were enrolled in the Memorial SloanKettering phase II trial13 using vinorelbine 45 mg/m2 followed by docetaxel 60 mg/m2 every 2 weeks with prophylactic filgrastim for a minimum of 6 days and until the absolute neutrophil count was ≥ 10,000/mm3. Other supportive therapies included dexamethasone 8 mg p.o. b.i.d. for 5 doses, commencing 24 hours before chemotherapy, and ciprofloxacin 500 mg p.o. b.i.d. on days 3-9. Patient characteristics were: stage IV, 91%; median age, 58 years; women, 51%; and 71% with Karnofsky performance status of 80%-90%. Confirmed major objective responses (partial response or improved) were documented in 18/35 patients (51%, 95% confidence interval [CI]: 34-68) with a median response duration of 6 months. At a median follow-up of 12 months, the predicted median survival is 14 months, and 1-year survival is 60%. Febrile neutropenia occurred in five patients and 5/384 cycles. However, other toxicities developed with prolonged therapy including onycholysis with loss of nails (51%) and bothersome lacrimation (80%). More recently performed trials have now reported prelimi-

Comparison of Dose Intensity (DI) and Clinical Outcomes in Vinorelbine (V) plus Docetaxel (D) Phase II Trials

Investigator

DI-D*

DI-V*

Response rate (95% CI)

Median survival

1-Year survival

Kourousis11

33

8

37% (22-51)

5 months

24%

Trillet-Lenoir12

25

13

27% (12-42)

Not Reported

NR

Johnston10

35

20

40%†

Not Reported

NR

Balana14

25

13

25% (10-42)

Not Reported

NR

Hotton9

20

15

18% (7-39)

9 months

NR

30

23

51% (34-68)

14 months

60%

Krug13 mg/m2/week.

*Doses in †Confidence interval could not be calculated with available data in published reference.

April 2000

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Vinorelbine and Docetaxel for Advanced Non–Small-Cell Lung Cancer Table 3

Comparison of Toxicities in Vinorelbine plus Docetaxel Phase II Trials Kourousis11 Trillet-Lenoir12

Krug13

Neutropenia, grade 4

46%

85%

54%

Conclusions

Febrile neutropenia

24%

41%

23%

Mucositis, grade 3/4

2%

46%

0

Neuropathy, grade 3/4

2%

0

0

Neuropathy, grade 1/2

54%

18%

66%/20%

4

2

1

Docetaxel and vinorelbine are highly active together and may offer one alternative to cisplatin-based therapy for patients with an adequate performance status. As doses are increased, response rates seem to improve, but supportive measures such as prophylactic filgrastim and ciprofloxacin may be necessary. Certain cumulative toxicities (onycholysis, lacrimation) may limit therapy. Application of this regimen for a shorter period, such as in induction or postoperative settings, may provide optimal benefit while minimizing toxicity.

Toxic deaths

nary efficacy results. The trial of Hotton et al9 documented an 18% response rate and a 9-month median survival in 22 patients with NSCLC who had previously received platinumbased therapy. Seven patients experienced neutropenic fever and, without prophylactic filgrastim, vinorelbine dose reductions or omissions were frequent. A Spanish trial reported a 25% response rate in 28 assessable patients treated on different schedules of the combination, and the investigators suggested that administration of docetaxel on day 1 rather than day 6 might be both more efficacious and less toxic.14 The intriguing possibility that the presence of β-tubulin mutations could predict for taxane resistance was also assessed in preliminary fashion and appears promising. Finally, initial results from the weekly study reported a 40% response rate in chemotherapynaive NSCLC patients.10 Febrile neutropenia and infection without neutropenia were the most common dose-limiting toxicities. As shown in Table 2, the MSKCC schedule, or alternatively the weekly approach, was the best approach for docetaxel and vinorelbine dose intensities achieved in single-agent phase II trials of these drugs in NSCLC. A shift in the toxicity profile observed with the scheduling changes in the various trials is highlighted in Table 3. The French trial,12 which did not use prophylactic filgrastim, had higher frequencies of grade 4 neutropenia and neutropenic fevers and significant mucositis than the other two trials. The Greek trial11 had fewer problems with neutropenia but still had a high rate of non-neutropenic infections. The day 1 and 2 schedule was predicted preclinically to have more toxicity.14 With filgrastim and ciprofloxacin, the MSKCC trial had somewhat fewer infectious complications. However, other problems

S26

such as onycholysis and eye irritation with lacrimation became more prominent. These complications were cumulative, developing after many cycles of therapy and occasionally requiring months to resolve.

April 2000

References 1. Miller VA, Ng K, Grant SC, et al. New chemotherapeutic agents in NSCLC. In: Roth JA, Cox JD, Hong WK, eds. Lung Cancer. Malden, MA: Blackwell Science, Inc. 1998; 217-234. 2. Hino H, Kobayashi K, Hayashihara K, et al. In vitro combination effect of docetaxel (RP56976) with vinca alkaloids on cancer cell lines. Proc Am Assoc Cancer Res 1995; 36: 299 (Abstract #1780). 3. Aoe K, Ueoka H, Kiura K, et al. Effect of docetaxel with cisplatin or vinorelbine on lung cancer cell lines. Anticancer Res 1999; 19:291-299. 4. Bissery MC, Vrignaud P, Bayssas M, et al. Preclinical in vivo activity of docetaxel-containing combinations. Proc Am Soc Clin Oncol 1995; 14:489a (Abstract #1599). 5. Haldar S, Basu A, Croce CM. Bcl2 is the guardian of microtubule integrity. Cancer Res 1997; 57:229-233. 6. Fumoleau P, Fety R, Delecroix V, et al. Docetaxel combined with vinorelbine: phase I results and new study designs. Oncology (Huntingt) 1997; 11(6 Suppl 6):29-31. 7. Schiller JH, Larson M, Larson M, et al. Phase I trial of docetaxel and vinorelbine in patients with advanced non-small cell lung cancer previously treated with platinumbased chemotherapy. Proc Am Soc Clin Oncol 1997; 16:481a (Abstract #1733). 8. Miller VA. Docetaxel (Taxotere) and vinorelbine in the treatment of advanced nonsmall cell lung cancer: preliminary results of a phase I/II trial. Semin Oncol 1997; 24:S14-15–S14-17. 9. Hotton KM, Kim K, Larson ML, et al. Phase I/II trial of docetaxel and vinorelbine in patients with non-small cell lung cancer (NSCLC) previously treated with platinumbased chemotherapy. Proc Am Soc Clin Oncol 1999; 18:509a (Abstract #1963). 10. Johnston E, Crawford J, Garst A, et al. Phase I trial of weekly docetaxel (D) and vinorelbine (V) in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1999; 18:476a (Abstract #1838). 11. Kourousis C, Androulakis N, Kakolyris S, et al. First-line treatment of advanced non small cell lung carcinoma with docetaxel and vinorelbine. Cancer 1998; 83:2083-2090. 12. Trillet-Lenoir V, Monnier A, Douillard JY, et al. Interim results of a phase II study of docetaxel (Taxotere) and vinorelbine in chemotherapy naive patients with advanced non small cell lung carcinoma (NSCLC). Annals of Oncology 1996; 7(Suppl):95. 13. Krug LM, Kris M, Grant SC, et al. Phase II trial of dose dense docetaxel plus vinorelbine with prophylactic filgrastim (G-CSF) in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1999; 18:460a (Abstract #1775). 14. Balana C, Barnadas A, Martin C, et al. A phase II study of sequence-dependent docetaxel (D)/vinorelbine (V) DNA damage-induced apoptosis in patients with non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1999; 18:463a (Abstract #1786).