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

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