A published data meta-analysis of 18 randomized trials (15 of which had survival information) comparing chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) demonstrates no impact on OS.[Level of evidence:1iiA]
Signal transduction inhibitors
Sorafenib. The multikinase inhibitor sorafenib (Nexavar) has activity against both the vascular endothelial growth factor signaling and the Raf/MEK/ERK pathway at the level of Raf kinase. However, two large, multicenter, placebo-controlled, randomized trials of carboplatin and taxol plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[28,29]
BRAF inhibitors. Thirty-two patients with metastatic melanoma characterized by the BRAF V600E mutation were entered into the phase II component of a phase I and II trial and received PLX4032, an orally available inhibitor of mutated BRAF, at the recommended phase II dose of 960 mg twice daily. The number of prior treatments ranged from zero to more than three regimens. Twenty-four patients had a partial response and two had a complete response (i.e., an 81% response rate), with responses lasting from 2 months to 18 months and with four responses ongoing. The most common side effects included the following:
- Nausea. (Refer to the PDQ summary on Nausea and Vomiting for more information.)
- Fatigue. (Refer to the PDQ summary on Fatigue for more information.)
- Cutaneous squamous cell carcinoma.
- Pruritus. (Refer to the PDQ summary on Pruritus for more information.)
- Palmar-plantar dysesthesias.
There were no grade 4 adverse events.[Level of evidence: 3iiiDiv] A randomized phase III trial of DTIC versus PLX4032 (NCT01006980) is ongoing with patients who have unresectable stage III and stage IV melanoma but who have not received prior therapy for advanced disease. The primary endpoint is OS, and accrual is expected to be completed shortly.
A number of phase II trials of signal transduction inhibitors that have potential for the treatment of melanoma are ongoing, including single-agent trials or combination trials of MEK, AKT, and PI3 kinase inhibitors. (Information about ongoing clinical trials is available from the NCI Web site.)
Kit inhibitors. A number of phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-kit mutation. (Information about ongoing clinical trials is available from the NCI Web site.)
Treatment Options Under Clinical Evaluation for Patients With Stage IV and Recurrent Melanoma
Treatment options under clinical evaluation for patients with stage IV and recurrent melanoma include the following:
- Patients who have mutations and are receiving antiangiogenesis agents should be considered appropriate candidates for clinical trials evaluating immunotherapy and signal transduction inhibitors. Although it is expected that novel therapies will be approved over the next year, the vast majority of patients are not cured, and clinical trials remain a compelling option for treatment, especially those trials that provide combinations of therapies.
- Palliative radiation therapy for bone, spinal cord, or brain metastases.
- Complete surgical resection of all known disease (SWOG-9430 [NCT00002860]).
- Hyperthermic isolated limb perfusion for in-transit and/or satellite extremity recurrences. Isolated limb infusion is being studied as a minimally invasive regional chemotherapy technique for extremity recurrences.[32,33]