VEGF Inhibitor Axitinib Shows Promise in BRAF Wild-Type Metastatic Melanoma

Treatment improves overall survival.

A phase 2 trial of treatment with the VEGF inhibitor axitinib after earlier treatment with paclitaxel/carboplatin shows an improvement in overall survival (OS) compared with a historical cohort of patients with advanced melanoma. Improvements in overall survival are rarer in oncology than improvements in progression-free survival (PFS), and an OS benefit in a small phase 2 trial is rarer still.

Active treatment was administered to patients with advanced melanoma who did not have mutations of the BRAF gene that would otherwise have qualified them for treatment with dabrafenib or trametinib.

Patients enrolled in the trial had normal organ function and good performance status (as indicated by a score of 0 or 1 on the ECOG scale). Patients received oral treatment with axitinib 5 mg twice daily on each of the first 14 days of 21-day treatment cycles, consisting of infusions of carboplatin and paclitaxel. Patients received up to 6 cycles of therapy. Dosage reductions were initiated if patients experienced severe neutropenia, febrile neutropenia, or thrombocytopenia, among other potential severe side effects.

Adverse events of grade 3 included hypertension, neutropenia, and anemia. Encouragingly, no adverse events of grade 4 severity were reported.

A total of 8 partial responses were reported in the 36 patients receiving treatment who were evaluable at the end of the study. Median PFS was 8.7 months, and median overall survival duration was 14.0 months.

Without axitinib, PFS in similar patients treated with carboplatin/paclitaxel therapy alone was 4.2 months, and overall survival was 8.6 months.

Researchers commented on the robustness of the findings, stating, “[these results are] particularly remarkable as large randomized trials targeting VEGF in combination with chemotherapy have failed to demonstrate significant improvements in tumor response, PFS, or OS in patients treated with VEGF inhibitors”

Results are even more surprising in this trial considering that axitinib alone in patients with metastatic melanoma resulted in median PFS rates of only 3.9 months. Considering this past result, the combination of paclitaxel/carboplatin with axitinib appears to have highly synergistic effects.

In fact, the exceptional results of this trial indicate that axitinib may be even more effective than immunotherapies in similar populations. For instance, with ipilimumab alone, median PFS in patients with advanced melanoma was less than 3 months.

The combination may also be superior to bevacizumab, which has demonstrated a median PFS of 5.6 months in similar patients; lenvatinib with oral temozolomide, which has demonstrated a median PFS of 5.4 months in a comparable group; and vemurafenib and dabrafenib, which have resulted in median PFS rates of 5.3 months and 5.1 months, respectively.

Axitinib may be different from other VEGF inhibitors due to its exceptional potency. In addition, axitinib has outperformed other medications in other cancers, such as sorafenib in renal cell carcinoma. Even so, these findings must be treated with guarded enthusiasm, considering the small size of this phase 2 trial.

Reference

• Algazi AP, Cha E, Ortiz-Urda SM, et al. The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial. Br J Cancer. 2015;112(8):1326-1331.
• Kim KB, Sosman JA, Fruehauf JP, 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. J Clin Oncol. 2012;30(1):34-41.