A phase III studyr compared fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and assessed safety and quality of life in patients with disseminated cutaneous melanoma.
Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Non-progressive patients received a maintenance treatment consisting of fotemustine 100 mg/m2 every 3 weeks or DTIC 250 mg/m2/d for 5 days every 4 weeks.
Two hundred and twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n = 229; 15.2% v 6.8%; P = .043) and in full analysis set (n = 221) (15.5% v 7.2%; P = .053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P = .059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P = .067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms.
ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favour of fotemustine in terms of overall survival and time to BM was evidenced.r
Efficacy
Kaplan-Meier of Overall Survival:r
© Journal of Clinical Oncology 2004
Toxicity
Myelosuppression was the most common adverse event in both treatment arms. Grade 3 and 4 haematological toxicities are shown below.
Toxicityr |
Fotemustine
(n=112) |
Dacarbazine (DTIC)
(n=112) |
Grade 3 (%) |
Grade 4 (%) |
Grade 3 (%) |
Grade 4 (%) |
Leucocytes |
23 |
4 |
2 |
2 |
Neutrophils* |
25 |
26 |
2 |
4 |
Platelets |
22 |
21 |
0 |
6 |
Haemoglobin |
4 |
0 |
3 |
2 |
AST |
2 |
0 |
2 |
0 |
ALT |
2 |
0 |
4 |
0 |
Alkaline phosphatase |
2 |
0 |
3 |
0 |
GGT |
10 |
1 |
10 |
1 |
Bilirubin |
4 |
0 |
0 |
0 |
* Assessable patients: 111 in fotemustine and 108 in dacarbazine
Adapted from Avril et al © JCO 2004
The most frequent nonhaematological adverse events related to fotemustine therapy were nausea (20%), vomiting (13%), asthenia (4.5%) and reaction at injection site (4.5%). The most frequent nonhaematological adverse events related to DTIC were nausea (17%), vomiting (8%), fever (4%) and headache (4%). Grade 3 and 4 adverse events are shown below.
Toxicityr |
Fotemustine
(n=112) |
Dacarbazine (DTIC)
(n=112) |
Vomiting |
1 |
2 |
Febrile neutropenia |
2 |
0 |
Nausea |
0 |
1 |
Asthenia |
0 |
1 |
Somnolence |
1 |
0 |
Fever |
0 |
1 |
Hepatotoxicity |
0 |
1 |
Infection |
0 |
1 |
Adapted from Avril et al © JCO 2004