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Background Enhanced phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key adaptive changes accounting for epidermal growth factor receptor (EGFR) inhibitor-resistant growth in head and neck squamous cell carcinoma (HNSCC). We designed a phase II clinical trial of EGFR tyrosine kinase inhibitor (TKI), erlotinib, in association with the mTOR inhibitor, everolimus, based on the hypothesis that the downstream effects of Akt through inhibition of mTOR may enhance the effectiveness of the EGFR-TKI in patients with recurrent/metastatic HNSCC. Patients and methods Patients with histologically or cytologically confirmed platinum-resistant HNSCC received everolimus 5 mg and erlotinib 150 mg daily orally until disease progression, intolerable toxicity, investigator or patient decision. Cytokines and angiogenic factors profile, limited mutation analysis and p16 immunohistochemistry status were included in the biomarker analysis. Results Of the 35 assessable patients, 3 (8%) achieved partial response at 4 weeks, 1 confirmed at 12 weeks; overall response rate at 12 weeks was 2.8%. Twenty-seven (77%) patients achieved disease stabilization at 4 weeks, 11 (31%) confirmed at 12 weeks. Twelve-week progression-free survival (PFS) was 49%, median PFS 11.9 weeks and median overall survival (OS) 10.25 months. High neutrophil gelatinase lipocalin (P = 0.01) and vascular endothelial growth factor (VEGF) (P = 0.04) plasma levels were significantly associated with worse OS. Conclusions The combination of erlotinib and everolimus did not show significant benefit in unselected patients with platinum-resistant metastatic HNSCC despite a manageable toxicity profile. Markers of tumor invasion and hypoxia identify a group of patients with particularly poor prognosis. Clinical trial number NCT00942734.

Background: We investigated cytokines and angiogenic factors (CAFs) in patients with metastatic renal cell carcinoma (mRCC) treated in a randomized phase II clinical trial of sorafenib versus sorafenib+ interferon-a (IFN-a) that yielded no differences in progression-free survival (PFS). We aimed to link the CAF profile to PFS and select candidate predictive and prognostic markers for further study. Methods: The concentrations of 52 plasma CAFs were measured pretreatment (n = 69), day 28, and day 56 using multiplex bead arrays and enzyme-linked immunosorbent assay. We investigated the association between baseline levels of CAFs with PFS and posttreatment changes. Results: Unsupervised CAF clustering analysis revealed two distinct mRCC patient groups with elevated proangiogenic or proinflammatory mediators. A six-marker baseline CAF signature [osteopontin, vascular endothelial growth factor (VEGF), carbonic anhydrase 9, collagen IV, VEGF receptor-2, and tumor necrosis factor-related apoptosis-inducing ligand] correlated with PFS benefit (hazard ratio 0.20 versus 2.25, signature negative versus positive, respectively; P = 0.0002). While changes in angiogenic factors were frequently attenuated by the sorafenib+ IFN combination, most key immunomodulatory mediators increased. Conclusions: Using CAF profiling, we identified two mRCC patient groups, a candidate plasma signature for predicting PFS benefit, and distinct marker changes occurring with each treatment. This platform may provide valuable insights into renal cell carcinoma biology and the molecular consequences of targeted therapies.

Background In a Phase II RCC study of pazopanib (VEG102616) a response rate of 34.7% and disease control rate (CR + PR +SD) of 80% were observed (Hutson, JCO 2009. Previously, we reported that elevated levels of E-Selectin, lower levels of IL-6 and HGF were correlated with longer PFS and decrease in tumor shrinkage. Higher levels of IL-6 and IL-8 correlated with greater tumor burden (Tran ASCO 2010). IL-8, OPN, HGF and TIMP1 correlated with PFS and IL-6, IL-8 and OPN were prognostic markers (Yuan GU ASCO 2011, Tran ESMO 2011). In this study, we measured CAF levels at baseline, week 4 and week 12 after inititation of pazopanib therapy and evaluated for dynamic changes in CAF as potential marker for tumor response and clinical benefits Methods Six candidate CAFs (TIMP1, IL-6, IL-8, HGF, E-Selectin, and OPN) were measured in 173 patients (pts) whose plasma samples were collected during the treatment at week 4, and week 12 by using Searchlight Protein Array (Aushon). CAF levels at each time point and changes of CAF levels from baseline at week 4 and week 12 were correlated with maximum tumor shrinkage (MTS) by linear regression; PFS by Cox regression; baseline tumor burden using baseline sum of longest tumor diameter and best response by Spearman. Results Decreases in OPN levels from baseline at week 4 (p = 0.030) and week 12 (p = 0.006) show significant correlations with MTS. At week 4, changes in E-Selectin from baseline was trending (p = 0.053) in correlation with MTS. With PFS, changes in IL-6 level from baseline at week 12 has near significant correlation with PFS (p = 0.05). E-Selectin has an inverse baseline to week 4 significant correlation with best response status week 4 (p = 0.0245) but not at week 12. Conclusion Decreasing levels of osteopontin from baseline at week 4 and 12 correlated with improved tumor shrinkage; while increase in IL-6 portends shorter PFS and E-Selectin was inversely correlated with best response status. Additional investigation is needed to evaluate the dynamic changes of CAFs as an approach to monitor patients while on pazopanib therapy as marker of tumor response. Disclosure Y. Liu: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No A. Martin: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No K.L. Baker-Neblett: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No. L.N. Pandite: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No. J.V. Heymach: Stock ownership: No Membership on an advisory board or board of directors: Yes; GSK Corporate-sponsored research: Yes; GSK for biomarker analysis. Other substantive relationships: No. All other authors have declared no conflicts of interest.

Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor EVE may be an efficacious and well-tolerated treatment option. The open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour assessments were every 12 weeks. Primary objective was treatment effect on progression-free survival (PFS) per central review based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III success was 5.1%. Results of central and local PFS analysis were consistent. Objective response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months (95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis (63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) in IFN + BEV arm. Conclusions In RECORD-2, PFS and tolerability were similar for first-line EVE + BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. Disclosure A. Ravaud: Alain Ravaud is a member of global, European, and/or French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, Bayer-Schering, and Dendreon, and has received institutional grant support from Pfizer, Novartis, and Roche. O. Anak: Ozlem Anak is an employee of Novartis Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria from Novartis and Roche and served on an advisory board for Roche. All other authors have declared no conflicts of interest.

Background In mRCC, prognosis is still solely determined based on clinical criteria. Although multiple candidate biomarkers exist, none has yet been incorporated into practice. We identified CAFs associated with PFS in mRCC pts with ECOG PS £1 treated in a randomized, placebo-controlled, phase III clinical trial of pazopanib (Sternberg, JCO 2010, Tran, ASCO 2010 #4522). In this study, we evaluated the prognostic significance of these CAFs relative to established clinical parameters. Methods Seven candidate CAFs (IL-6, IL-8, VEGF, HGF, TIMP1, osteopontin [OPN], E-Selectin) in plasma obtained pretreatment, and 5 clinical variables indicative of poor prognosis (time from diagnosis to treatment upper [U]LN [Heng, JCO 2009]) were correlated with PFS (n = 343; n = 225 pazopanib/n = 118 placebo) using uni- and multivariable Cox proportional hazard models. Correlations with ECOG PS, Motzer's (MSKCC) and Heng's risk criteria were also assessed. CAFs were measured using SearchLight (Aushon). Results Median PFS for all pts was 29.9 weeks (95% CI 24.6–32.1), 39.6 weeks (95% CI 32.1-48.1) for those treated with pazopanib and 13.4 weeks (95% CI 12.1–19.1) for placebo. IL-6, IL-8, and OPN were prognostic [Table]. Considering treatment group, 2 clinical variables (hemoglobin ULN [HR 1.95, p = 0.0151]) were predictors of short PFS in multivariate analysis. Adjusting for those 2, only OPN and IL-6 in the placebo arm (OPN high 7.9 v low 24 weeks, p = 0.034; IL-6 high 7.9 v low 24.1 weeks, p = 0.03), and OPN alone in the pazopanib arm (high 31.3 v low 56.4 weeks, p = 0.0007), remained prognostic. Although the 3 clinical classifications were associated with PFS, none was as strong a prognostic marker as the CAFs [Table]. Conclusion In mRCC pts with good PS, circulating OPN and IL-6 are prognostic for PFS independent of established clinical criteria. CAF PFS (wks) P Clinical PFS (wks) P IL-6 Low 24·0 ECOG 0 18·4 0·144 High 9·9 1 13·0 OPN Low 24·0 MSKCC Good 24·0 0·011 High 8·4 Interm/Poor 12·1 IL-8 Low 23·9 0·002 Heng Good 24·3 0·139 High 8·4 Interm/Poor 12·6 Disclosure Y. Liu: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No . L.N. Pandite: Stock ownership: Yes; GSK Membership on an advisory board or board of directors: No Corporate-sponsored research: No Other substantive relationships: No. J.V. Heymach: Stock ownership: No Membership on an advisory board or board of directors: Yes; GSK Corporate-sponsored research: Yes; GSK for biomarker analysis Other substantive relationships: No. All other authors have declared no conflicts of interest.