Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma

Autor: Robynne G. Ashe, Carla L. Warneke, Lance C. Pagliaro, Paul G. Corn, Marcella M. Johnson, John J. Wright, Pheroze Tamboli, Eric Jonasch, Ana Aparicio, Nizar M. Tannir, Chaan Ng
Rok vydání: 2009
Předmět:
Zdroj: Cancer.
ISSN: 1097-0142
0008-543X
DOI: 10.1002/cncr.24685
Popis: Renal cell carcinoma (RCC) affects >40 000 patients per year in the United States and is responsible for approximately 13,000 deaths.1 Once it becomes metastatic, RCC is difficult to treat, and the median survival is between 1 year and 2 years.2,3 Several treatment modalities have been used to treat metastatic RCC, including immunotherapy,4,5 chemotherapy,6,7 and targeted therapies.3,8,9 Several targeted agents have received approval from the US Food and Drug Administration (FDA) for use in patients with advanced RCC, including sorafenib, sunitinib, and temsirolimus. Although each of these drugs is active as a single agent, few patients achieve a complete response (CR), virtually all patients experience disease progression, and long-term survival is rare. These observations have led to the hypothesis that combining agents with different mechanisms of action may lead to improved clinical outcomes. We explored this concept by combining sorafenib with low-dose IFN in a randomized phase 2 trial. Sorafenib is an orally bioavailable small molecule inhibitor of wild-type and mutant (the V599E point mutation, which is a substitution of the amino acid valine for glutamic acid at codon 599 in the v-raf murine sarcoma viral oncogene homolog B1 [BRAF]) B-Raf and c-Raf kinase isoforms and of receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor 2 (VEGFR-2), VEGFR-3, platelet-derived growth factor receptor β, fms-related tyrosine kinase 3, and the cytokine receptor c-KIT. IFN is an immunomodulatory cytokine that is produced by leukocytes and other immunomodulatory cells, and it possesses direct cellular antiproliferative effects and stimulates major histocompatibility complex Class I expression.10 The rationale for combining an antiangiogenic agent with IFN is based on 2 principal observations: 1) Lower doses of IFN have an antiangiogenic effect, which inhibits growth levels of VEGF and basic fibroblast growth factor10,11; and 2) this effect also may antagonize the recognized up-regulation of VEGF by receptor tyrosine kinases.12 It is noteworthy that IFN blocks VEGF through decreased transcription,12 a mechanism that is different from targeted therapies (blockade of receptor activation); thus, cross-resistance would not be predicted by combining the 2. We chose a dose of 0.5 MU IFN twice daily because of its potential antiangiogenic activity and because our recently reported randomized study revealed no difference in efficacy outcomes between this dose and 5 MU IFN daily in patients with previously untreated, metastatic RCC despite producing fewer side effects and higher quality-of-life measures.13 There is a growing interest in using molecular biomarkers in earlier phase trials to help choose the most promising investigational agents worthy of further study. We chose to focus on tissue-based markers of phoshatidylinositol-3 kinase (PI3K) pathway activation. The PI3K pathway is involved directly or indirectly in maintenance of cellular viability,14,15 protein synthesis,16 and cell cycle regulation.17 Emerging data suggest that the up-regulation of PI3K pathway components is associated with a poor outcome in patients with RCC.18,19 Downstream protein kinase B (AKT) effector molecules are associated with hypoxia-inducible factor (HIF) regulation,20 providing a direct mechanistic link to angiogenesis. Differential expression of HIF-1 α (HIF1α) and HIF2α) appears to generate distinct phenotypes, and the up-regulation of c-Myc has been observed in HIF2α-predominant tumors.21 In addition, HIF1α expression depends on raptor, a component of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) complex, and rictor, a component of mTORC2; whereas HIF2α depends only on mTORC2, which feeds back and phosphorylates serine 473 (S473) on AKT.22 Taken together, we hypothesize that S473 activation of AKT is a biomarker of a resistance phenotype either through c–Myc-dependent pathway activation or through the up-regulation of alternate HIF2α-dependent angiogenic pathways. To detect efficacy signals reliably, randomized trials are required. Randomized phase 2 studies, although they are not powered to detect survival differences, can aid in objectively selecting regimens with a potential differential impact on patient outcome. Herein, we present data from the first randomized phase 2 study comparing sorafenib versus sorafenib plus low-dose interferon (IFN), and we report on predictive tissue biomarkers.
Databáze: OpenAIRE
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