Randomized phase II trial of sorafenib (SO) with temsirolimus (TEM) or tipifarnib (TIPI) in metastatic melanoma: Southwest Oncology Group Trial S0438.

8502 Background: BRAF and N-RAS mutations occur in 50% and 15%-20% of melanomas, respectively, while lack of functional PTEN enhances PI3 kinase/AKT/mTOR pathway signaling. Combinations that presumably inhibit parallel or sequential steps may overcome resistance to single agents. This randomized phase II trial tested 2 such combinations—SO plus TEM or TIPI—as first-line therapy of advanced melanoma. Methods: To assess the objective response (OR) rate and progression-free survival (PFS), patients (pts) with previously untreated non-ocular metastatic melanoma were randomized to (arm A) SO 200 mg po bid plus TEM 25 mg iv weekly, or (arm B) SO 400 mg po qam and 200 mg po qpm continuously plus TIPI 100 mg po days 1-21 q28 days in 2-stage accrual. After the first 30 pts in each arm, ≥ 3 responses or ≥ 9 patients progression-free at > 4 months were required to proceed to stage 2, adding 25 pts. Dose adjustments (1 or both drugs) were based on reported agent-specific toxicities. Results: In stage 1, 48 pts enrolled on arm A, 45 evaluable for PFS and 44 for response. In Arm A, stage I partial response (PR) = 2 pts, 4-mo PFS = 11 pts, Arm A then accrued to stage 2, total 67 pts; the final results will be reported. In stage I, 42 pts enrolled on Arm B, 41 evaluable for PFS and response with 1 PR and 4-mo PFS = 8 pts. Arm B was then closed. Toxicity was predominantly diarrhea, rash, hyperlipidemia and fatigue. Serious toxicity: fatal interstitial pneumonitis, gastrointestinal bleed, hypokalemia, left ventricular dysfunction and pulmonary dysfunction (1 pt each in arm A), and grade 4 hyperlipidemia (1 pt in arm B). Conclusions: These combinations appear to show insufficient activity, possibly due to poor pathway inhibition at tolerated doses. It was later reported that SO is inactive against BRAF and modestly inhibits several other cellular kinases. Molecularly targeted combinations that block parallel signaling pathways, including MAP kinase and others, may still hold promise in melanoma. Successful combination Rx will depend on drugs with improved therapeutic index in pts selected by tumor genotype. No significant financial relationships to disclose.