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Bevacizumab Plus Fotemustine As First-Line Treatment in Metastatic Melanoma Patients: Clinical Activity and Modulation of Angiogenesis and Lymphangiogenesis Factors

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Bevacizumab Plus Fotemustine As First-Line Treatment in Metastatic Melanoma Patients: Clinical Activity and Modulation of Angiogenesis and Lymphangiogenesis Factors Published OnlineFirst October 28, 2010; DOI: 10.1158/1078-0432.CCR-10-2363 Clinical Cancer Cancer Therapy: Clinical Research Bevacizumab plus Fotemustine as First-line Treatment in Metastatic Melanoma Patients: Clinical Activity and Modulation of Angiogenesis and Lymphangiogenesis Factors Michele Del Vecchio1, Roberta Mortarini2, Stefania Canova1, Lorenza Di Guardo1, Nicola Pimpinelli3, Mario R. Sertoli4, Davide Bedognetti4, Paola Queirolo5, Paola Morosini6, Tania Perrone7, Emilio Bajetta1, and Andrea Anichini2 Abstract Purpose: To assess the clinical and biological activity of the association of bevacizumab and fotemustine as first-line treatment in advanced melanoma patients. Experimental Design: Previously untreated, metastatic melanoma patients (n ¼ 20) received bevaci- zumab (at 15 mg/kg every 3 weeks) and fotemustine (100 mg/m2 by intravenous administration on days 1, 8, and 15, repeated after 4 weeks) in a multicenter, single-arm, open-label, phase II study. Primary endpoint was the best overall response rate; other endpoints were toxicity, time to progression (TTP), and overall survival (OS). Serum cytokines, angiogenesis, and lymphangiogenesis factors were monitored by multiplex arrays and by in vitro angiogenesis assays. Effects of fotemustine on melanoma cells, in vitro, on vascular endothelial growth factor (VEGF)-C release and apoptosis were assessed by ELISA and flow cytometry, respectively. Results: One complete response, 2 partial responses (PR), and 10 patients with stable disease were observed. TTP and OS were 8.3 and 20.5 months, respectively. Fourteen patients experienced adverse events of toxicity grade 3–4. Serum VEGF-A levels in evaluated patients (n ¼ 15) and overall serum proangiogenic activity were significantly inhibited. A significant reduction in VEGF-C levels was found in several post-versus pretherapy serum samples. In vitro, fotemustine inhibited VEGF-C release by melanoma cells without inducing significant cell death. Serum levels of interleukin (IL)-10 and IL-12p70 showed the highest levels in sera of PR patients, compared with patients with stable or progressive disease whereas IL- 23 showed the opposite pattern. Conclusions: The combination of bevacizumab plus fotemustine has clinical activity in advanced melanoma and promotes systemic modulation of angiogenesis and lymphangiogenesis factors. Clin Cancer Res; 16(23); 5862–72. Ó2010 AACR. Authors' Affiliations: 1Unit of Medical Oncology 2, Department of Medical Oncology, 2Human Tumors Immunobiology Unit, Department of Experi- Treatmentofadvancedmelanomaremainsunsatisfac- mental Oncology and Molecular Medicine, Fondazione IRCCS Istituto tory, because no therapy has demonstrated to affect over- 3 Nazionale dei Tumori, Milan; Department of Dermatological Sciences all survival (OS), with the exception of a recent and Department of Human Pathology and Oncology, University of Flor- ence, Florence; 4Department of Oncology, Biology, and Genetics, Uni- immunotherapy study based on administration of the versity of Genova; 5Department of Medical Oncology A, Istituto Nazionale anti-CTLA-4 monoclonal antibody (mAb) ipilimumab 6 per la Ricerca sul Cancro, Genova; Medical Affairs, Roche S.p.A., Monza; with/without a gp100 vaccine (1). Moreover, there is and 7Scientific Direction, Italfarmaco, Cinisello Balsamo, Italy no evidence that polychemotherapy is better than mono- Note: Supplementary data for this article are available at Cancer therapy, and no regimen can be considered of choice in Research Online (http://cancerres.aacrjournals.org/). metastatic disease. Nowadays, the CVD combination Current address for S. Canova: Unit of Medical Oncology, S. Gerardo (cisplatin, vinblastine or vindesine, and dacarbazine) is Hospital, 20052 Monza, Italy. widely used (2), as it can yield high response rates with Current address for E. Bajetta: Institute of Oncology, Policlinico di Monza, 20052 Monza, Italy. manageable toxicity. However, all phase III trials have M. Del Vecchio and R. Mortarini contributed equally to this work. failed to show an effective advantage of the combined therapy over the single approaches (immunotherapy or Corresponding Author: Andrea Anichini, Department of Experi- mental Oncology and Molecular Medicine, Fondazione IRCCS Istituto chemotherapy; ref. 3, 4), with the exception of a phase III Nazionale dei Tumori, 20133 Milan, Italy. Phone: 39-0223902817; Fax trial by Eton et al. (2). In such study, comparing CVD 39-0223903237; E-mail: [email protected] or Emilio Bajetta, Institute of Oncology, Policlinico di Monza, 20052 Monza, Italy. versus CVD plus interferon (IFN)-a and interleukin (IL)- Phone: 39-0392810661; Fax: 39-0392810331; E-mail: emilio.bajetta@ 2, in 190 melanoma patients, the response rate was 48% policlinicodimonza.it. for the combination versus 25% for CVD (P ¼ 0.001), doi: 10.1158/1078-0432.CCR-10-2363 time to progression (TTP) was 4.9 versus 2.4 months (P ¼ Ó2010 American Association for Cancer Research. 0.008), and the median survival was 11.9 versus 9.2 5862 Clin Cancer Res; 16(23) December 1, 2010 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst October 28, 2010; DOI: 10.1158/1078-0432.CCR-10-2363 Biochemotherapy for Melanoma Translational Relevance On the basis of these clinical data, we carried out a phase II study to investigate the clinical and biological There is an urgent need for improved therapies in activity of the bevacizumab–fotemustine combination in advanced cutaneous melanoma. So far only ipilimumab untreated metastatic melanoma patients. On the basis of has shown significant impact on overall survival, recent evidence (14, 15) of the relevance of serum biomar- although durable complete responses have been kers (detected by multiplex assays) as prognostic factors of observed in some patients treated with high-dose inter- response to therapy with biological agents such as IFN-a2b leukin 2. However, in randomized trials, biochemother- or IL-2, we designed multiplex ELISA arrays to detect 16 apy regimens have been shown to improve response different angiogenesis, lymphangiogenesis, and immuno- rates in advanced disease, thus suggesting that this is a modulatory factors. The results of the study indicated that promising approach that could be further developed by the combination of bevacizumab plus fotemustine has new combinations of cytotoxic drugs and biological clinical activity and modulates both angiogenesis and agents. In this study, we show that the combination lymphangiogenesis factors. of the antiangiogenesis monoclonal antibody beva- cizumab with the nitrosourea fotemustine has clinical Materials and Methods activity as first-line treatment in metastatic disease. Moreover, this biochemotherapy regimen significantly Patients reduced systemic levels not only of vascular endothelial Eligible patients were at least 18 years of age, with growth factor (VEGF)-A, but also of VEGF-C, suggesting histologically or cytologically confirmed measurable that this therapeutic approach may contribute to the diagnosis of metastatic, inoperable nonchoroidal mela- inhibition of both angiogenesis and lymphangiogen- noma; an Eastern Cooperative Oncology Group (ECOG) esis, 2 relevant processes in melanoma development performance status (PS) of 0 to 1, no previous treatment and progression. of metastatic disease (exception for a vaccination with a wash-out period of at least 4 weeks), normal hematologic, hepatic, and renal functions; absence of brain metastases; and life expectancy of at least 3 months. Exclusion criteria months (P ¼ 0.006). Among the new chemotherapeutic were history of bleeding, diathesis, or coagulopathy, treatments of advanced melanoma, fotemustine is a pro- clinically significant cardiovascular disease, arterial mising drug, and there is a growing interest for bevaci- thromboembolism less than 6 months before the first zumab, a recombinant humanized mAb that binds to and study treatment, uncontrolled hypertension, and a his- inhibits the biological activity of human vascular tory of other malignancy within the past 5 years (except endothelial growth factor (VEGF)-A (see ref. 5 for review). curatively treated nonmelanoma skin cancer or carci- Bevacizumab is clinically active in different solid tumors noma in situ of the cervix). The trial was approved by (6–8): in colorectal cancer the addition of bevacizumab the Institutional Review Board or ethics committee of to irinotecan/fluorouracil/leucovorin has been shown to each participating center and was conducted in accor- improve survival of metastatic patients (9). Bevacizumab- dance with the principles of the Declaration of Helsinki based approaches in advanced melanoma were reported and with the Good Clinical Practice. All patients provided in a randomized phase II trial comparing bevacizumab written, informed consent. versus bevacizumab plus low-dose IFN-a2b (10). In that study,8of32patients(5inthebevacizumabarmand3in Study design and treatment the bevacizumab plus IFN-a2b arm) showed prolonged This was a multicenter, single-arm, open-label, phase II stabilization of disease (10). Additional evidence has study. The primary endpoint was the best tumor response been reported more recently, in a phase II biochemother- at any time during therapy. Secondary objectives were apy study based on paclitaxel, carboplatin, and bevaci- toxicity assessment, duration of response, TTP, and OS. zumab (11). The authors reported that 17% of the Eligible patients
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