Randomized phase II trial of sorafenib with temsirolimus or tipifarnib in
untreated metastatic melanoma (S0438).
Author(s): Margolin KA, Moon J, Flaherty LE, Lao CD, Akerley WL 3rd, Othus M, Sosman JA,
Kirkwood JM, Sondak VK.
Affiliation(s): University of Washington, SWOG Statistical Center, Seattle, WA98109., USA.
kmargoli@seattlecca.org
Publication date & source: 2012, Clin Cancer Res. , 18(4):1129-37
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 and phosphoinositide 3-kinase/AKT/mTOR
pathways are activated in most cutaneous melanomas. The purpose of this trial was
to prospectively evaluate 2 molecularly targeted drug combinations in patients
with untreated metastatic melanoma.
EXPERIMENTAL DESIGN: This randomized phase II study enrolled patients between May
2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy,
and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice
daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400
mg every morning, 200 mg every night 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, and toxicity for the 2
regimens.
RESULTS: On arm A (63 evaluable patients), the median PFS was 2.1 months and
median overall survival (OS) was 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 was 7 months,
with 1 patient achieving PR.
CONCLUSIONS: The combinations of molecularly targeted agents tested did not show
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.
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