Anna Berkenblit

355 Background: Tivozanib hydrochloride (T) was superior to sorafenib (S) in progression-free survival (medians of 11.9 vs. 9.1 months, respectively; 12.7 vs. 9.1 months, respectively, for metastatic treatment-naïve pts) in the phase III TIVO-1 study in pts with mRCC. T showed a differentiated safety profile with lower rates of dose interruptions/reductions v S (18/12 vs. 35/43, respectively; p

354 Background: Tivozanib hydrochloride (T) is a potent, selective, tyrosine kinase inhibitor of all 3 VEGF receptors with a long half-life. T has shown tolerability and has extended progression-free survival (PFS) compared with sorafenib (S; median 11.9 months vs. 9.1 months; p =0.042) in a phase III trial (TIVO-1) as initial targeted therapy for pts with mRCC. We report results of PFS subgroup analyses from TIVO-1. Methods: Pts with clear-cell mRCC, prior nephrectomy, and ≤1 prior treatment for mRCC were randomized to T (n=260) or S (n=257). Cox proportional hazards model was used to evaluate PFS. Results: Significant improvement in PFS by T vs. S was observed for the following prespecified subgroups: white, Eastern Cooperative Oncology Group (ECOG) performance status 0, ≥1 year since diagnosis, no prior treatment, ≥2 metastatic sites, North America/Western Europe, baseline systolic blood pressure (SBP) ≤140 mm Hg, and baseline diastolic BP (DBP) ≤90 mm Hg. Exploratory subgroup analysis showed a similar significant improvement by T vs. S in Memorial Sloan-Kettering Cancer Center (MSKCC) favorable prognostic group, and pts who developed hypertension on study had significantly longer PFS than pts with normal BP. The improvement in PFS by T vs S was more marked for the subgroups that developed hypertension (selected subgroups shown in the table). Conclusions: PFS subgroup analyses showed a consistent advantage with T vs. S for mRCC. Clinical trial information: NCT01030783. [Table: see text]

364 Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life and has shown superior efficacy, measured as progression-free survival (PFS), as first-line, targeted therapy vs. sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (J Clin Oncol2012;30[suppl]:Abstract 4501). Patients who progressed (PD) on sorafenib could receive tivozanib in an open-label, prospective multicenter extension study of TIVO-1. We report preliminary efficacy and safety data for patients who had PD on sorafenib and subsequently received tivozanib in this extension study. Methods: Patients with PD on sorafenib, per RECIST version 1.0, were eligible to receive tivozanib dosed at 1.5 mg/day PO for 3 weeks followed by a 1-week rest, in repeated 4-week cycles, until PD or unacceptable toxicity. Patients were to have been no more than 4 weeks from last dose of sorafenib until initiation of tivozanib, and have an ECOG performance status of ≤2. Dose adjustments were performed as previously reported. Objectives included assessing objective response rate (ORR), duration of response, PFS for tivozanib following PD on sorafenib, and overall survival. Results: As of January 20, 2012, 127 patients (72.4% male) were evaluable for response. Median age was 59.0 years (range: 23–85 years). ORR was 7.9% (95% CI 3.8–14.0%; partial response [PR]=7.9%; stable disease [SD]=65.4%; PD=18.9%), and 71.3% of patients showed tumor shrinkage. Median duration of PR was 11.1 months (95% CI ≥7.5 months). Median duration of SD was 12.7 months (95% CI ≥7.4 months). Median PFS was 5.6 months (95% CI 5.4–9.1 months). Median OS was not yet reached. Most commonly reported treatment-emergent adverse events (all grades/Grade ≥3) were hypertension (22.4%/10.2%), asthenia (11.0%/3.1%), fatigue (11.0%/3.9%), palmar-plantar erythrodysesthesia (11.0%/1.6%), and diarrhea (10.2%/1.6%). Conclusions: Tivozanib has anti-tumor activity after PD on sorafenib. The adverse-event profile of tivozanib after sorafenib is similar to that observed in TIVO-1. Clinical trial information: NCT01076010.

361 Background: TIVO-1, a randomized Phase III trial in first-line targeted therapy for patients (pts) with ccRCC, demonstrated significant improvement in progression-free survival (PFS) in pts receiving tivozanib hydrochloride (T) vs. sorafenib (S) (11.9 vs. 9.1 months [12.7 vs. 9.1 in treatment-naïve pts]). To further characterize molecular ccRCC subtypes and assess relationships between subtypes and vascular endothelial growth factor tyrosine kinase inhibitor activity, we characterized available molecularly annotated datasets from TIVO-1. Methods: Tumor subtypes were established using hierarchical clustering and evaluated in two microarray ccRCC datasets using gene set enrichment analysis with 51 signatures representing a set of molecular phenotypes. A 9-gene signature comprising genes associated with hypoxia-inducible factor (HIF) transcription was quantified by RT-PCR on all available (69/517) formalin-fixed, paraffin-embedded material from patients using a predefined classifier score and cutoff. Results: Hierachical clustering generated 3 distinct tumor classes. Molecular clusters defining HIF gene expression (low), endothelial cell content (low), extracellular matrix (low), proliferation (high) epithelial cell phenotype (high), and metabolism (high) were differentially expressed in cluster 3 tumors, which represented approximately 15% of the populations. Based on predefined analysis, the hypoxia signature was significantly associated with better PFS on T using a previously established classifier (Table). The hypoxia signature was not significantly associated with PFS on S. There was no significant correlation to single largest diameter for either agent. Conclusions: A novel molecular subtype of ccRCC is characterized by a distinct molecular profile and can be classified by a low hypoxia signature. This hypoxia gene signature may help identify T responders. This signature is seen in subsets of other solid tumors supporting the broad exploration of this candidate T response biomarker. Clinical trial information: NCT01030783. [Table: see text]

The central role played by the class I_A phosphatidylinositol-3-kinase (PI3K) signaling node in human cancer is highlighted in the multiple mechanisms by which these signals become dysregulated. Many studies suggest that constitutive PI3K activation in human cancer contributes to drug resistance, including targeted agents and standard cytotoxic therapy. The combination of activation mechanisms and the multiple downstream cascades that emanate from the PI3K node contributes to the difficulty in measuring PI3K activation as a biomarker. Although many agents suppress the pathway in models, the challenge remains to translate this biology into a patient selection strategy (i.e., identify patients with “PI3K activated” tumors) and subsequently link this biomarker definition to drug responses in patients. The various genetic and epigenetic lesions resulting in pathway activation necessitate combined approaches using genetic, genomic, and protein biomarkers to accurately characterize “PI3K activated” tumors. Such a combined approach to pathway status can be assessed using a statistical stratification of patients in a randomized trial into “pathway on” and “pathway off” subsets to compare the treatment effect in each arm. Instead of considering individual biomarkers for their predictive ability, this strategy proposes the use of a collection of biomarkers to identify a specific “pathway on” patient population predicted to have clinical benefit from a pathway inhibitor. Here, we review the current understanding of the mechanisms of PI3K activation in breast cancer and discuss a pathway-based approach using PI3K as a predictive biomarker in clinical development, which is currently in use in a global phase 3 setting.