Cancer Treatment Today

Avastin for melanoma has been studied with paclitaxel alone, Abraxane and paclitaxel/carboplatin.

Avastin is investigative because reliable evidence does not show a high probability of improved outcomes or that beneficial effects outweight any harmful effects.

As a single agent, Avastin has been found to produce responses and disease stabilization in patients with metastatic melanoma. A study from Spain has also found the combination of Taxol and Avastin to have clinical benefit in over half of the patients with metastatic melanoma.

Abraxane and Avastin is under study in a phase II trial at Northern California Melanoma Center. an open-label, single arm multicenter Phase II study to evaluate the safety and efficacy of the combination of Abraxane and Avastin as first-line therapy for patients with unresectable metastatic malignant melanoma. The patient sample will be approximately 50 individuals, males and females 18 years of age or older with measurable metastatic melanoma. It is expected to be completed in 2011.

The group in Rochester, Minnesota, conducted a two-stage phase II study of the triple chemotherapy regimen in 53 patients with unresectable stage IV melanoma. Carboplatin was given on day 1 of a 28-day cycle. Paclitaxel was given on days 1, 8 and 15. Bevacizumab was given on days 1 and 15. Treatment was continued until patients achieved remission or experienced intolerable toxicity. They reported that 45% of patients with metastatic melanoma that has failed first-line chemotherapy appear to benefit from the combination of Taxol and Paraplatin. The rationale for adding Avastin rests on the anti-angiogenic properties of this agent. This was a trial which included 53 patients who had unresectable Stage IV melanoma and had not received prior therapy. All received treatment with Paraplatin, Taxol, and Avastin. The partial response rate was 17%, and 57% had stable disease for at least eight weeks. Median progression-free survival was six months, and median overall survival was 12 months.

The O’Day study randomized 214 subjects to receive or not receive bevacizumab with chemotherapy of melanoma. Patient who had had prior targetted therapy were not excluded from the trial. The O’Day study of Taxol/carboplatin/Avastin was thought to show a significant difference but a last-minute review of the clinical data changed the outcome and researchers who presented it said the Phase II study in fact failed to meet its primary goal of proving that Avastin extended the time melanoma patients lived without their disease progressing[ID:nLL728528]. It also failed to show a statistically significant increase in overall survival.The study found the median overall survival in the Avastin arm was 12.3 months, against 9.2 months in the control arm, but there was a 19 percent likelihood that this result happened by chance.

Despite the disappointment, principal investigator Steven O’Day of the Angeles Clinic and Research Institute in California said the data collected on Avastin were “very encouraging and warrant continued investigation”.

Bevacizumab (Avastin) failed to improve survival in advanced melanoma when added to carboplatin and paclitaxel. in a recent randomized, multicenter clinical trial, adding the targeted agent to chemotherapy improved progression-free survival by 22% compared with chemotherapy alone, but the benefit did not achieve statistical significance. A preliminary analysis revealed a significant benefit in overall survival in the bevacizumab arm, but the advantage did not hold up in a final review of the data.

Temodar with Avastin is in a phase II clinical trial: Temozolomide and Bevacizumab in Treating Patients With Stage IV Melanoma That Cannot Be Removed By Surgery, NCT00568048. This phase II trial is studying how well giving temozolomide together with bevacizumab works in treating patients with stage IV melanoma that cannot be removed by surgery. A 2010 ASCO abstract says: “The primary endpoint was met (DSR12 ≥ 18 patients) showing promising activity in this high-risk population with PFS 4.2 months. Response and OS were significantly higher in BRAF wild type patients. TEM/BEV has a low toxicity profile. A confirmatory phase III trial is required.

More recent data is more promising. A study presented at ASCO 2010, was a randomized phase II trial in chemotherapy naïve patients (pts) with unresectable stage IV MM treated with either Temodar (200 mg/m² on days 1-5) and Avastin(BEV) (10mg/kg IV days 1 and 15 ) every 28 days (arm A); or CBDCA (AUC 6; day 1), nab-P (100mg/m2 days 1, 8 and 15), and BEV (10mg/kg on days 1 and 15) every 28 days (arm B). Carboplatin and Abraxane. The primary objective of this study was to independently assess progression-free survival at 6 months (PFS6) in each arm. Both treatment arms exhibited tolerable toxicities with a suggestion of clinical benefit. over expected outcomes for chemotherapy alone. The regimen in Arm B is being considered for phase III clinical testing.

Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma. Cancer. 2009;115:119-127.

Jaissle GB, Ulmer A, Henke-Fahle S, et al. Suppression of melanoma-associated neoangiogenesis by bevacizumb. Archives of Dermatology. 2008;144:525-527.

Varker KA, Biber JE, Kefauver C, et al. A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon affa-2b in metastatic malignant melanoma. Annals of Surgical Oncology. 2007;14:2367-2376.

Jaissle GB, Ulmer A, Henke-Fahle S, et al. Suppression of melanoma-associated neoangiogenesis by bevacizumb. Archives of Dermatology. 2008;144:525-527.

Gonzalez-Cao M, Viteri S, Diaz-Lagares A, et al. Preliminary results of the combination of bevacizumab and weekly paclitaxel in advanced melanoma. Oncology. 2008;74:12-16.

O’Day SJ, Sosman JA, Peterson AC, et al. BEAM: A randomized phase II study evaluating the activity of Bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated Advanced Melanoma. European Journal of Cancer Supplements, vol. 7, no. 3, September 2009, page 13.

Perez DG, Suman VJ, Fitch TR, et al: Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: A North Central Cancer Treatment Group study, N047A. Cancer 115:119-127, 2009.

R. Dummer, O. Michielin, B. Seifert, A. F. Ochsenbein, R. Cathomas, M. R. Schlaeppi, M. Simcock, S. Gillessen, S. M. Goldinger, R. von Moos, Swiss Group for Clinical Cancer Research (SAKK); University Hospital, Zurich, Switzerland; CHUV, Lausanne, Switzerland; Universität Basel, Basel, Switzerland; Inselspital Bern, Bern, Switzerland; Kantonsspital Graubünden, Chur, Switzerland; Kantonsspital St. Gallen, St. Gallen, Switzerland; SAKK Coordinating Center, Bern, Switzerland; Department of Medical Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Universität Zürich, Zürich, Switzerland; Medical Oncology, Kantonsspital Graubünden, Chur, Switzerland
First-line temozolomide (TEM) combined with bevacizumab (BEV) in metastatic melanoma (MM): A multicenter phase II trial (SAKK 50/07). J Clin Oncol 28:15s, 2010 (suppl; abstr 8521)