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Demetri, G.D. et al.

George D. Demetri, Christopher R. Garrett, Patrick Schöffski, Manisha H. Shah, Jaap Verweij, Serge Leyvraz, Herbert I. Hurwitz, Antonio Lopez Pousa, Axel Le Cesne, David Goldstein, Luis Paz-Ares, Jean-Yves Blay, Grant A. McArthur, Qiang Casey Xu, Xin Huang, Charles S. Harmon, Vanessa Tassell, Darrel P. Cohen, Paolo G. Casali, Christopher R. Garrett, Patrick Schöffski, Manisha H. Shah, Jaap Verweij, Serge Leyvraz, Herbert I. Hurwitz, Antonio Lopez Pousa, Axel Le Cesne, David Goldstein, Luis Paz-Ares, Jean-Yves Blay, Grant A. McArthur, Qiang Casey Xu, Xin Huang, Charles S. Harmon, Vanessa Tassell, Darrel P. Cohen, Paolo G. Casali,

Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure.

PURPOSE: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. EXPERIMENTAL DESIGN: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. RESULTS: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. CONCLUSIONS: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.[1]

References

Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Demetri, G.D., Garrett, C.R., Schöffski, P., Shah, M.H., Verweij, J., Leyvraz, S., Hurwitz, H.I., Pousa, A.L., Le Cesne, A., Goldstein, D., Paz-Ares, L., Blay, J.Y., McArthur, G.A., Xu, Q.C., Huang, X., Harmon, C.S., Tassell, V., Cohen, D.P., Casali, P.G. Clin. Cancer Res. (2012) [Pubmed]

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