Randomized Phase II Trial of Sorafenib with Temsirolimus or Tipifarnib in Untreated Metastatic Melanoma (SWOG S0438)
Mené sur 63 patients atteints d'un mélanome métastatique, cet essai randomisé de phase II évalue l'activité antitumorale de deux combinaisons de thérapies ciblées, sorafenib et temsirolimus d'un côté, sorafenib et tipifarnib de l'autre
Purpose Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase (MAPK) and PI3 kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate two molecularly-targeted drug combinations in patients with untreated metastatic melanoma. Patients and Methods This randomized Phase II study enrolled patients between May 2008 and November 2009 with non-ocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A: oral sorafenib 200 mg b.i.d. plus intravenous temsirolimus 25 mg weekly; Arm B: oral sorafenib 400 mg q.a.m., 200 mg q.p.m. daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate (ORR), and toxicity for the two regimens. Results On Arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to Arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS 7 months, with 1 patient achieving PR. Conclusion The combinations of molecularly-targeted agents tested did not demonstrate sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates.