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Background Clinical effectiveness and safety data of pazopanib in patients with advanced or mRCC in real-world setting from Asia Pacific, North Africa, and Middle East countries are lacking. Methods PARACHUTE is a phase IV, prospective, non-interventional, observational study. Primary endpoint was the proportion of patients remaining progression free at 12 months. Secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI). Results Overall, 190 patients with a median age of 61 years (range: 22.0-96.0) were included. Most patients were Asian (70%), clear-cell type RCC was the most common (81%), with a favourable (9%), intermediate (47%), poor (10%), and unknown (34%) MSKCC risk score. At the end of the observational period, 78 patients completed the observational period and 112 discontinued the study; 60% of patients had the starting dose at 800 mg. Median RDI was 82%, with 52% of patients receiving < 85%. Of the 145 evaluable patients, 56 (39%) remained progression free at 12 months, and the median PFS was 10 months (95% CI: 8.48-11.83). 19% of patients (21/109) were long-term responders (on pazopanib for >= 18 months). The best response per RECIST 1.1 was CR/PR in 24%, stable disease in 44%, and PD in 31%. Most frequent (> 10%) TEAEs related to pazopanib included diarrhoea (30%), palmar-plantar erythrodysesthesia syndrome (15%), and hypertension (14%). Conclusions Results of the PARACHUTE study support the use of pazopanib in patients with advanced or mRCC who are naive to VEGF-TKI therapy. The safety profile is consistent with that previously reported by pivotal and real-world evidence studies., Novartis Pharmaceuticals Corporation, The PARACHUTE study was sponsored by Novartis Pharmaceuticals Corporation; pazopanib is an asset of Novartis AG as of 1 March 2015.

Background This study was conducted to collect clinical safety, tolerability, and efficacy data with the use of everolimus (EVE) combined with exemestane (EXE) in patients with advanced breast cancer (ABC). Methods The EVEREXES trial initiated in 2012, provided early access to the first dual blockade treatment with EVE + EXE in patients with HR+, HER2 - ABC in Asia and other emerging growth countries. Postmenopausal women with HR+, HER2 - ABC who had documented recurrence or progression, following a nonsteroidal aromatase inhibitor therapy, were treated with EVE (10 mg/day) + EXE (25 mg/day) orally. Results A total of 235 patients received >= 1 dose of study medication. At the end of the study, all patients ceased the treatment. Disease progression (66.0%) was the primary reason of discontinuation. The most common AEs (>= 20%) were stomatitis, decreased appetite, hyperglycemia, rash, aspartate aminotransferase increased, anemia, alanine aminotransferase increased, cough, and fatigue. No new safety concerns were identified in the current study. Median progression-free survival (PFS) in the Asian subset was similar to that of the overall population (9.3 months in both groups). Confirmed overall response rate (ORR) was achieved for 19.6% of the patients. Efficacy of EVE + EXE across subgroups (prior CT, line of treatment, and presence of visceral metastases) was maintained. Conclusion The safety and efficacy results from EVEREXES trial are consistent to data previously reported in BOLERO-2. These results support that EVE + EXE could be a viable treatment option for the postmenopausal women with HR+, HER2 - ABC in Asian region., Novartis Pharma AG, Base, Switzerland; NovartisNovartis, The EVEREXES trial was funded by Novartis Pharma AG, Base, Switzerland. Funding for medical editorial support was also provided by Novartis.

IF 7.191 (2017); International audience; BACKGROUND:Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.PATIENTS AND METHODS:A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI

Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase (ALK) positive (ALK+) non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced ALK+ or ROS proto-oncogene 1 positive (ROS1+) tumours. Patients received oral ceritinib (750 mg·day−1 as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had ALK+ NSCLC and 13 had ROS1+ NSCLC. The median age of ALK+ patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 and 50.0% had brain metastases. Of the 149 efficacy evaluable ALK+ NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0% versus 42.4%) and those receiving prior crizotinib for >5 months (51.6% versus 36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day−1) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with ALK+ NSCLC., Ceritinib (750 mg per day) showed similar efficacy as in clinical trials in crizotinib-pretreated ALK+ NSCLC patients http://ow.ly/8oXe30h27D0

Background Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. It gained approval based on the results of the RECORD-1 (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 1) trial, which included patients with metastatic renal cell carcinoma (mRCC) whose disease progressed after receiving vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Bevacizumab is a monoclonal antibody targeting angiogenesis that is approved in patients with mRCC. The sequence of everolimus second-line therapy after failure of bevacizumab ± interferon (IFN) first-line therapy has not yet been studied. Methods AVAstin® followed by afiniTOR® (AVATOR) was a noninterventional retrospective multicenter European observational study of 42 unselected patients with mRCC who were previously or currently treated with everolimus after failure of bevacizumab ± IFN. The primary end point was everolimus progression-free survival (PFS). Secondary end points were related to the overall survival (OS) of patients receiving the drug sequence and everolimus treatment and safety. Results Exploring the duration of second-line everolimus treatment, 63.8% of patients received at least 3 months of everolimus and 28.8% received at least 8 months of treatment. At the time of data analysis, 15 patients (36%) were still receiving everolimus, 40% had stopped because of progressive disease, and 24% had discontinued treatment for other reasons. Patients receiving everolimus after bevacizumab experienced a median PFS of 17 months (95% confidence interval [CI], 5 [not reached]). Median OS was not reached with everolimus second-line therapy. At 32 months after the start of first-line therapy, 53.3% of patients were still alive. All grades of common adverse events (AEs) were consistent with the known safety profile of everolimus. Conclusion The AVATOR-studied sequence displayed a longer than expected median PFS. Further prospective exploratory studies need to be performed to confirm these encouraging results in a larger cohort of patients.

To determine whether 2D or 3D Choi and modified Choi (mChoi) criteria could assess the efficacy of everolimus against metastatic renal cell carcinoma (mRCC). RECIST-1.1, Choi, and mChoi criteria were applied retrospectively to analyse baseline and 2-month contrast-enhanced computed tomography (CECT) images in 48 patients with mRCC enrolled in the everolimus arm of the French randomized double-blind multicentre phase III trial comparing everolimus versus placebo (RECORD-1). The primary endpoint was centrally reviewed progression-free survival (PFS) calculated from the initial RECORD-1 analysis. Mean attenuation was determined for 2D target lesion regions of interest drawn on CECT sections whose largest diameters had been measured, and for the 3D whole target lesion. The median PFS was 5.5 months. The median PFS for everolimus responders defined using 3D mChoi criteria was significantly longer than for non-responders (7.6 versus 5.4 months, respectively), corresponding to a hazard ratio for progression of 0.45 (95 % CI: 0.22–0.92), with respective 1-year survival rates of 31 % and 9 %. No other 2D or 3D imaging criteria at 2 months identified patients who would benefit from everolimus. At 2 months, only 3D mChoi criteria were able to identify mRCC patients with a PFS benefit from everolimus. • Choi criteria could not identify everolimus-treated patients with significantly prolonged PFS. • mCHOI enabled identification of everolimus-treated mRCC patients with a PFS benefit. • 3D attenuation measurement criteria appeared to perform better than single-slice measurement.

ABSTRACT Optimal development of targeted drug combinations is one of the future challenges to be addressed. Computerization and mathematical models able to describe biological phenomena and to simulate the effects of changes in experimental conditions may help find solutions to this issue. We propose the concept of ‘multiparameter trials’, where biological, radiological and clinical data required for modeling purpose are collected and illustrated by the ongoing academic EVESOR trial. The objective of the model-based work would be the determination of the optimized doses and dosing schedules of everolimus and sorafenib, offering the maximization of the predicted modeled benefit/toxicity ratio in patients with solid tumors. It may embody the ‘proof of concept’ of model-based drug development of anticancer agent combinations.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.

International audience; BACKGROUND:Real-world data of everolimus after vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy in metastatic renal cell carcinoma (mRCC) are limited.PATIENTS AND METHODS:The retrospective, noninterventional SECTOR (SECond line with afiniTOR) study (N = 165) assessed outcomes of second-line everolimus after initial VEGFR-TKI (TKI-everolimus, n = 144) and of third-line VEGFR-TKI after everolimus (TKI-everolimus-TKI, n = 59) in patients with mRCC. The primary end point was duration of everolimus therapy for both populations.RESULTS:Median duration was 4.0 months (range, 0.0-33.0 months) for second-line everolimus and 18.0 months (range, 2-78 months) for sequential VEGFR-TKI and everolimus. Median overall survival (OS) for this sequence was 36.0 months (95% confidence interval [CI], 27.0-56.0 months) and was longer for patients who received a first-line TKI for ≥ 9 months (not reached) than for < 9 months (28.0 months; P < .001). During second-line everolimus treatment, commonly reported adverse events (all grades) were fatigue (n = 66, 40.7%), anemia (n = 58, 35.8%), and stomatitis (n = 41, 25.3%). Median duration from initiation of first-line TKI to the end of the third-line TKI was 24.0 months (95% CI, 19.0-29.0 months). Median OS for this sequence was 41.0 months (95% CI, 25.0-57.0 months) and was significantly longer for patients who received the first-line TKI for ≥ 9 months (37.5 months) than for < 9 months (19.0 months; P < .0001).CONCLUSION:These results reflect clinical use of sequential TKI-everolimus and TKI-everolimus-TKI and provide additional evidence that everolimus could be an option in second-line therapy in mRCC. Results of the CheckMate-025 (Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma) and METEOR (Metastatic RCC Phase 3 Study Evaluating Cabozantinib versus Everolimus) studies might change the treatment landscape.

Background PARACHUTE, a phase IV, prospective, observational study of treatment patterns and outcomes planned to describe the clinical effectiveness and safety of pazopanib in patients (pts) with advanced or mRCC who are naive to VEGF-TKI therapy in the real-life setting from Asia Pacific, North Africa, and the Middle East countries where data from the registration trials are lacking. Methods Eligible pts were ≥18 years with advanced or mRCC and clinical decision to initiate pazopanib treatment or had already started new treatment with pazopanib within 15 days prior to study entry and naive to any prior anti-VEGF therapy. Primary endpoint was the proportion of patients remaining progression free at 12 months (mo). The secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI). Results Between Jun 2017 and Dec 2018, 200 pts were enrolled from 15 countries in Asia, North Africa and Middle East. A total of 101 pts with a median age of 62 y (range, 32.0-95.0) were included in this interim analysis. Majority of the pts were Asian (63%) followed by Caucasian (36%). Clear cell was the main (82%) histologic type. At data cut-off (May 2, 2019) of 12 mo observation period, 29 pts completed the observational period and 72 discontinued the study. Only 57% of pts had the starting dose at 800mg. Median RDI was 79% with 52% pts received under 10%) TRAEs include diarrhoea (27%), palmar-plantar erythrodysaesthesia syndrome (12%) and hypertension (15%). Conclusions The interim results of the PARACHUTE study support the use of pazopanib in pts with advanced or mRCC who are naive to VEGF-TKI therapy. Safety profile is consistent with the previously reported pivotal and realworld evidence studies. The efficacy data are still immature due to limited number of pts and the short follow-up duration. Editorial acknowledgement Anuradha Bandaru, Novartis Healthcare Pvt Ltd (Hyderabad, India). Legal entity responsible for the study Novartis. Funding Has not received any funding. Disclosure R. Kanesvaran: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Novartis, MSD, BMS, Ipsen, Eisai, J&J, Astellas, Amgen, Mundipharma, Sanofi, Roche, AZ. P. Danchaivijitr: Advisory / Consultancy: MSD and Pfizer. B. Karabulut: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono, Bayer, Pfizer, Novartis, MSD, BMS, J&J, Astellas, Amgen, Sanofi, Roche. Y.F. Wong: Advisory / Consultancy: Merck and Roche. K. Slimane: Full / Part-time employment: Novartis. M. Erman: Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Novartis, BMS, Astellas, Roche, AstraZeneca, Boehringer Ingelheim, Nobel, Gen Pharma, MSD, Pierre Fabre, Amgen, Takeda, Mustafa Nevzat Pharma, Teva.

Background: Acquired resistance to endocrine treatments (ET) occurs in more than 70% of cases of luminal breast cancer (LBC). We used patient derived xenografts (PDX) models of LBC to study molecular changes associated with acquired resistance to different ET modalities. Methods: A PDX model of LBC, established from an early stage BRCA2-mutated breast cancer, was treated with different ET (tamoxifen, fulvestrant, oophorectomy and letrozole) during several months. Tumors escaping to therapies were re-engrafted and maintained under therapy. ET-resistant and parental hormono-responders tumors were analyzed with immunohistochemistry (IHC), RT-PCR and Affymetrix Gene Expression Arrays. Hormono-resistant tumors were additionally studied for their in vivo response to ET, mTOR and PARP inhibitors. Results: From the initially ET sensitive HBCx22 xenograft model (Cottu, BCRT 2012) two resistant models were obtained respectively to tamoxifen (HBCx22-TamR) and to estrogen deprivation (HBCx22-OvaR). Unsupervised clustering of gene expression showed a clear cut separation between parental, TamR and OvaR tumors. Genes differentially expressed in TamR and OvaR tumors compared to parental HBCx22 were only partially overlapping. Up-Regulated genes in both TamR and OvaR tumors (n = 302) were involved in response to wounding, nucleotide metabolism, immune system, adhesion and cell growth. Biological Processes (BP) specifically deregulated in OvaR tumors (n = 380) included embryonic development, antigen presentation, amino acid and lipid metabolism. The top BP specifically regulated in TamR tumors (n = 1059) were response to estrogen and steroid hormones, TGF-b signaling, hypoxia, regulation of cell proliferation, with several strongly up-regulated genes of the histone clusters 1 and 3. Ingenuity Transcription Factor Analysis predicted activation of NFKB, SP1, AP-1 and JUN, and inhibition of ESR1. RT-PCR and IHC analyses confirmed the down regulation of ER controlled genes in the TamR tumors. Expression of ER co-regulators determined by RT-PCR showed that GREB1 was strongly reduced in TamR, while PBX1, GATA3 and FOXA1 were inhibited in OvaR. IHC analysis showed a loss of PTEN expression in HBCx22, with high levels of p-AKT and p-RPS6 in both parental and TamR and OvaR tumors. In vivo ET showed that the TamR xenograft was resistant to all modalities of ET, while OvaR was resistant to estrogen deprivation while retaining some sensitivity to tamoxifen and fulvestrant. Treatment with the mTOR inhibitor RAD001 arrested tumor growth but did not show any additive effect when combined to ET in TamR or OvaR tumors. Conversely, the combination of RAD001 with Olaparib was highly synergistic and induced complete tumor response in 70% of mice. Conclusions: According to the therapeutic selection, tumors derived from a PDX model of ER+ breast cancer show specific resistance patterns and gene expression profiles including disruption in the ER transcriptional program. The analysis of additional resistant tumors established from a second ER+ PDX will be presented at the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-07.

The objective of the study was to describe the occurrence of stomatitis and noninfectious lung disease in patients with metastatic renal cell carcinoma (mRCC) treated with second-line everolimus in a real-world setting. This multicenter, prospective, observational study was conducted in France by physicians with experience of treatment of patients with mRCC. Patients aged ≥18 years who received everolimus after first-line antivascular endothelial growth factor (VEGF) therapy were included in the study. The primary safety assessments were occurrence of stomatitis (in terms of severity, event dates, and therapeutic management) and noninfectious pneumonitis (in terms of detection methodology, severity, event dates, and therapeutic management). Between September 2010 and August 2012, 284 patients were enrolled at 77 centers, of whom, 274 received everolimus therapy. Most patients had mRCC of clear cell histology (88%), and most of them (84%) received first-line sunitinib. In total, 40% of patients experienced treatment-related stomatitis, and 15% of patients experienced noninfectious lung disease. Most of them had a single episode. The incidence of grade 3 stomatitis and noninfectious lung disease were 8 and 3%, respectively. Mean time to the first episode was 27 days for stomatitis and 72 days for noninfectious lung disease from treatment initiation. Stomatitis and noninfectious lung disease resulted in treatment discontinuations in 2 and 7% of patients, respectively. The primary first-episode treatment was mouthwash (86%) for stomatitis and corticosteroids (65%) for noninfectious lung disease. This study confirms that stomatitis and noninfectious lung disease are commonly associated with everolimus use. Both adverse events were rarely severe and were managed easily and efficiently.

Schwannoma is the most common benign tumor of peripheral nerve. Only 7% of schwannomas arise from the median nerve, and its localization in the motor branch is extremely rare. A 57-year old right-handed female presented with a carpal tunnel syndrome symptoms associated to a little painful thenar swelling in the left hand with no motor or sensory deficit. An electromyogram confirmed the clinical diagnosis of carpal tunnel syndrome. Ultrasonography (US), performed to study the thenar swelling, revealed an infracentimetric avascular well-limited intramuscular mass. Surgical resection of the mass was performed satisfactorily with preservation of nerve fascicles. Histopathology concluded to a benign schwannoma of the motor branch of the median nerve. In the literature reviewed by us, this is the third case of motor branch of the median nerve schwannoma.

Some salient features of physical properties of Tripropyleneglycol diacrylate (TPGDA) and the low molecular weight nematic liquid crystal E7 are discussed. A variety of experimental techniques giving complementary information of monomer and Electron Beam (EB) cured systems are employed to illustrate the effect of curing. A detailed thermophysical analysis is made first to assess the conditions of miscibility, determine the order-disorder transition and the glass transition temperature. DSC spectra yield the energy change at the transitions from which important parameters are readily extracted such as solubility limits and amount of liquid crystal dissolved in the polymer. Polarized Optical Microscopy enables us to follow phase transitions and morphology changes in different regions of the phase diagram. Consistent data are obtained from mechanical measurements in particular with regards to the variation of the glass transition temperature with liquid crystal concentration and the related plasticizing effect.

This study aimed to explore patient and nurse satisfaction, compliance with best practice, technical feasibility and safety of home infusion of the bisphosphonate zoledronic acid (ZOL).This was a prospective 1-year survey of home ZOL therapy (4 mg Zometa, 15-min i.v., every 3-4 weeks) in patients with bone metastases secondary to a solid malignancy. A physician questionnaire, nurse satisfaction/feasibility questionnaire and patient satisfaction questionnaire were administered at several time-points.Physician participation rate was 56.5% (87/154). Physicians enrolled 818 patients visited by 381 predominantly community nurses. Of the 788 case report forms received, 763 met inclusion criteria. Patient characteristics were as follows: median age, 68 years (30-95); M/F, 40/60; ECOG-PS 0 or 1, 78.6%; and primary tumour site, breast (55.2%), prostate (28.4%), lung (7.2%) or other (9.4%). Nurse satisfaction rates were high: organisation of home ZOL therapy, 90.9%; ease of infusion, 96.7%; patient-nurse relationship, 97.5%; and relationship with hospital staff, 73%. Patient satisfaction was also very high (95.3%). The main reasons were quality of the nurse-patient relationship (57.6%), less travel/waiting (68.8%), home environment (52.9%) and less disruption to daily routine (36.6%). ZOL therapy was well tolerated, the discontinuation rate due to adverse events (including deaths whether related to diseases progression or not) was 33.6%. The incidence of osteonecrosis of the jaw was 0.6% and of fractures, 0.2%. Practitioner compliance with best practice was 76.7-83.7% for recommended and/or tolerated dosage, 73% for dental hygiene checks at inclusion and 48-56% thereafter, 66% for pre-infusion hydration, and often undocumented for calcium/vitamin D supplementation.Home ZOL therapy was well tolerated. Both patient and nurse satisfaction were very high. However, better compliance with best practice should be encouraged.

To evaluate first-generation rapamycin analogs (everolimus, temsirolimus, and rapamycin) and second-generation drugs inhibiting mTOR kinase (AZD-8055), PI3K (BKM-120) or both (BEZ-235 and GDC-0980) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) cells characterized for acquired resistance to sorafenib or sunitinib. Anti-proliferative (MTT assay) and cell signaling (Western blot) effects of rapamycin analogs (1–20 μM) and second-generation drugs (0.03–20.0 μM) were assessed in human HCC SK-HEP1, RCC 786-0, and sorafenib- (SK-Sora) or sunitinib-resistant (786-Suni) cells. In SK-HEP1 cells displaying high PTEN and Bcl2 expression, rapamycin analogs had poor anti-proliferative effects. However, SK-Sora cells were more sensitive to rapamycin analogs (≥1 μM) than SK-HEP1 cells. In 786-0 cells, lacking PTEN and Bcl2 expression, ≥1 μM rapamycin analogs blocked mTORC1 signaling, transiently activated Akt, and inhibited cell proliferation. Protracted sunitinib exposure in 786-Suni cells yielded an increase in p27 expression and a decreased sensitivity to rapamycin analogs, although mTORC1 function could be inhibited with rapamycin analogs. Second-generation drugs induced more potent growth inhibition than rapamycin analogs at concentrations >0.03 μM in parental cells, SK-Sora, and 786-Suni cells. Growth inhibitory concentrations of these new drugs also blocked mTORC1 downstream targets. Rapamycin analogs inhibited mTORC1 downstream targets and yielded anti-proliferative effects in HCC and RCC cells. Second-generation drugs also appeared to be potent inhibitors of mTORC1 signaling; however, they appeared to be far more potent in inhibiting cellular proliferation in parental HCC and RCC cells and in cells developing resistance to sorafenib or sunitinib.

Aim: RECORD I results indicate that stomatitis and non-infectious lung disease were the most frequent AEs leading to dose reduction or treatment discontinuation with everolimus (eve). AFINITE study was designed to prospectively collect data related to these two AEs and their management in real life practice. Methods: Between 09/10 and 08/12, 284 mRCC pts from 77 French centres, received eve as 2nd line were recorded. Primary endpoint was to describe the occurrence of stomatitis and non-infectious lung disease. Main secondary endpoints were: best tumoral response, self-reported tolerance of eve, extent of exposure to eve and the main reasons for dose reduction or discontinuation. Amongst 284 pts, 274 were analysed. Median age was 66 yrs, male 72%, clear cell histology 88%, sunitinib as first TKI 83%. Main comorbidities were: hypertension 51%, diabetes 16%, and hypercholesterolemia 2&%. At eve initiation, MSKCC classification was good 50%, intermediate 40% or poor 10%. Results: 43% pts had at least 1episode of stomatitis during eve treatment 17% Grade 1, 17% Grade 2 and 8% Grade 3. Main treatment was mouthwash 82%, analgesics 26% or anti-fungal agent 11%. 17% of pts had at least 1 episode of non-infectious lung disease during eve treatment, 4% were Grade 1, 11% Grade 2 and 2.5% Grade 3. Main treatment was corticosteroids 65%. The most others frequent all grades AEs were asthenia 24%, anaemia 16 %, diarrhoea 11%, hypertriglyceridemia 7%, decreased appetite 7%, hypercholesterolemia and hyperglycaemia 5% each. Eve discontinuation related to stomatitis and non-infectious lung disease was respectively 2% and 7%. Dose modification related to stomatitis and non-infectious lung disease was respectively 6% and 4 %. One pt showed a CR to eve, 13% a PR and 43% had stable disease. Overall, the median duration of treatment was 3.2 months and 66% of pts finished the study without interruption. Conclusions: This study conducted in real life confirms that stomatitis and non-infectious lung disease occur commonly with EVE use. These AEs were rarely severe and were relatively easily and efficiently managed. Disclosure: F. Joly Lobbedez: Ad board Novartis Pfizer et GSK; J. Eymard: Ad Board: Novartis Sanofi Janssen Astellas L. Albiges Sauvin: Ad.Board/Honoraria: Novartis, Pfizer, Sanofi, Amgen Research Grant: novartis, Pfizer T. Nguyen: Novartis advisory board; A. Guillot: Advisory board: Pfizer Novartis Janssen Astellas; F. Rolland: Novartis advisory board, Novartis personnal fees; D. Spaeth: Novartis Grant; P. Colin: Novartis ad borad T. Lebret: Ad Board: Novartis GSK Roche Bayer; K. Slimane: Novartis full time employee; N. Kelkouli: full time employee; A. Ravaud: Ad board: Novartis Pfizer GSK BMS. All other authors have declared no conflicts of interest.

Aim: The best doses and dosing schedules of everolimus (EVE) and sorafenib (SOR) which enable maximization of benefit/toxicity ratio may be searched using mathematical modeling of data derived from an adequately designed multi-parameter phase 1 trial. Methods: This academic study is composed of 4 arms (A; B; C & D) with different dosing schedules and doses of EVE and SOR. Multiparameter assessments include: pharmacokinetics (PK); pharmacodynamics (PD) with control of signaling pathway inhibition (ERK, AKT, S6K) in 2 tumor biopsies & repetitive PBMC assays; kinetics of circulating tumor DNA kinetics & VEGF angiogenesis markers; tumor angiogenesis changes using repeated DCE-ultrasounds; and radiological/clinical effects. The optimal doses and dosing schedules of EVE and SOR will be searched using simulations and then tested. The protocol was approved by ethic committee in 2012. Results: 8 patients with different metastatic tumor types (CRC: 3; pancreas: 2; breast: 1; HCC: 1; endom: 1) have been enrolled in 2 arms out of 4 (A: EVE 5mg qd 2 weeks and then SOR 200 mg bid + EVE; or B: SOR 200 mg bid 2 weeks and then SOR + EVE 5 mg qd). 4 patients were assessable for response: 2 SD (for more than 4 months) and 2 PD. Most of side effects were grade 1-2. Grade 3 toxicities were transaminase elevation, hypokalemia and fatigue. A SUSAR was observed: confirmed blood grade 3 hemolytic anemia in a patient on SOR alone (arm B). Longitudinal measurements of ERK, AKT & pAKT signals in PBMCs; VEGF & VEGFR2 in serum and DCE-US angiogenesis suggest that the anti-angiogenic effect induced by run-in EVE (41% reduction) would be reversed by combination to SOR (431% increase). Addition of EVE to run-in SOR would increase the anti-angiogenic effects. However the lack of effect on AKT and ERK pathways induced by EVE (150% increase) might be reversed by the combination to SOR (21% decrease). Conclusions: The on-going EVESOR trial suggests there may be strong PD interactions between everolimus and sorafenib regarding inhibition of AKT & ERK signaling pathways and anti-angiogenic effects, with large impact by the respective drug dosing schedules. The intermittent arms C and D will bring more data on these PD interactions. EVESOR trial aims at optimizing the doses and dosing schedules of the 2 drugs. Disclosure: All authors have declared no conflicts of interest.

Sjögren's syndrome is characterized by an increased risk of developing non-Hodgkin's lymphoma. The lymphoma is most frequently extra-nodal, preferentially affecting the salivary gland: low-grade MALT lymphoma. Conversely, underlying Sjögren's syndrome has been recently identified by some authors in patients with non-Hodgkin's lymphoma. In the present report, we present three cases of Sjögren's syndrome disclosed by low-grade salivary gland MALT lymphoma. The patients were all women aged 33, 38 and 52 years. Extension work-up revealed nodal and bone marrow involvement in one case and no evidence of disseminated disease in the two others. Using the European criteria, all of our patients had certain Sjögren's syndrome. Labial salivary gland biopsy and immunopathological studies in newly diagnosed low-grade MALT lymphoma would be helpful in identifying the real frequency of this association.

6036 Background: ThePI3K/mTOR pathway is activated in >50% of HNSCC with preclinical synergism between everolimus and carboplatin/paclitaxel. Methods: Patients (pts) with untreated locally advanced HNSCC with ECOG PS2) followed by chemoradiotherapy. Endpoints were safety (CTCv3.0), antitumor activity (RECIST1.1), pharmacodynamic biomarkers on tumor biopsy. Results: A total of 50 pts with stage IV HNSCC (41 males, 9 females, median age 61) were enrolled. Among 7 patients included in the phase I, no dose-limiting toxicity was reported and the recommended dose (RD) of everolimus was 50 mg/w. Safety evaluation in 46 pts treated at RD for 325 cy and a mean number cy/pt of 7.1 (95%CI: 6.3-7.8) showed grade (Gr) 1-2 adverse events consisting of asthenia (50%), nausea/vomiting (28%), alopecia (26%), mucositis (24%), and constipation (20%). Hematological toxicities (Gr1-2/3-4) were neutropenia (35%/39%), anemia (61%/17%), and thrombocytopenia (54%/13%). Everolimus-related Gr3 toxicities were rashes (1pt), pruritus (1pt), dyspnea (1pt), hyperglycemia (2pts), and Gr1-2 hypercholesterolemia (23pts). There was no toxic death. Among 38 pts evaluable for antitumor activity, one pt experienced a complete response (2.6%), 29 pts a partial response (76.3%), and 8 pts a stable disease (21%) for an overall response rate of 79% (no progression reported). Interestingly, 20 major responses (>50% reduction tumor volume) were observed in large necrotic primary tumors/N3 involvement. Efficacy was not correlated to KRAS/BRAF/PI3KCA/EGFR mutations. Significant decreases of Ki67/p-S6K activities were observed in post CAPRA biopsies compared to baseline. Conclusions: Weekly everolimus with carboplatin/paclitaxel as induction regimen was well tolerated with 11% grade 3 and no grade 4/5 toxicity. Translational data showed direct effects of everolimus in tumors. CAPRA yields high rate of objective responses in patients with locally advanced HNSCC. Clinical trial information: NCT01333085.

Background. Activation of the PI3K pathway is associated with resistance to endocrine treatments (ET) in luminal breast cancer (LBC). Everolimus, an mTOR inhibitor, has been approved in combination with exemestane in endocrine resistant breast tumors. However, no definite signature of ET resistance or predictive factors of sensitivity to everolimus (EVE) treatment have been evidenced so far. In order to further decipher these molecular patterns, we used patient derived LBC xenografts (LBC-PDX) treated with various ET and EVE based combinations. Methods. 3 LBC-PDX (named HBCx-3, HBCx-21 and HBCx-34) were treated with ET during several months to establish hormono-resistant (HR) xenografts. Both parental and HR models were treated by tamoxifen, estrogen deprivation, fulvestrant, EVE alone, and EVE combined with all three ET modalities. Tissue Micro Arrays from control and treated tumor samples were generated for IHC analyses. RT-PCR analyses were conducted on genes related to proliferation, ER, PI3K, IGF-1R and angiogenesis pathways. Results. In primary PDX, ET showed a poor level of sensitivity for HBCx-3 and a high and sustained efficacy of ER targeting and/or ER deprivation for HBCx-21 and HBCx-34 tumors. In vivo resistance to ET was confirmed in all HR variants with tumor growth rates faster than parental xenografts. ER expression was conserved in HR tumors, but expression of the ER-responsive genes PS2, PR and MYB was strongly decreased, indicating impaired ER transcriptional activity. Acquired resistance to tamoxifen and ovariectomy was also associated to a strong decrease of IGF-1R signaling in HBCx-21, and was related to higher P-AKT expression, although P-pS6 was highly expressed in both sensitive and resistant tumors. Furthermore, in vivo experiments showed that EVE alone was highly efficient in all models independently of P-AKT expression/PTEN loss. EVE combined with fulvestrant yielded the most complete and durable tumor growth inhibition. In HBCx-3, proliferation and pS6 levels were markedly decreased only by the EVE-fulvestrant combination. In HBCx-21 and HBCx-34 HR models, EVE-based treatments decreased proliferation, expression of angiogenesis markers, as well as P-pS6 expression with no variation in (P-)AKT nor (P-)mTOR levels. A high IGF-1R protein expression was found only in the HBCx-34 TAM-R tumor, which was strongly decreased in the fulvestrant-treated tumors. Conclusions. LBC-PDX with confirmed HR status have been established and may serve as models to study alternate therapies. Of note, in the HBCx-21 and -34 models, activation of the PI3K pathway is poorly correlated with baseline sensitivity to ET, suggesting other pathways of resistance. EVE alone is highly efficient in all settings, and combination with fulvestrant is promising at the in vivo and molecular levels. Proteomic, genomic and gene expression studies are ongoing. Citation Format: Paul H. Cottu, Thomas Bagarre, Jean-Jacques Fontaine, Franck Assayag, Sophie Richon, Sophie Chateau-Joubert, Aurélie Thuleau, Patricia de Cremoux, Khemaies Slimane, Didier Decaudin, Anne Vincent-Salomon, Ivan Bièche, Elisabetta Marangoni. Endocrine resistant luminal breast cancer xenografts are powerful models for the analysis of sensitivity to endocrine and everolimus treatments . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 85. doi:10.1158/1538-7445.AM2013-85

Background: Current management of advanced HNSCC is limited to surgery, radiotherapy, and chemotherapy. The frequent activation of the PI3K/AKT/mTOR signaling pathway in HNSCC has suggested that inhibition of PI3K/mTOR may have potential therapeutic activity. Preliminary results of the phase I/II CAPRA clinical trial combining the mTOR inhibitor everolimus with paclitaxel and carboplatin have shown promising antitumor activity. Experimental evidences have suggested that mTOR inhibition using rapalogues may be hampered by a negative feedback resulting in PI3K activation. The aim of our study was to evaluate the antiproliferative effects of novel PI3K/mTOR inhibitors in comparison to everolimus in a panel of three HNSCC cell lines. Materials and Methods: HNSCC cell lines (SQ20B, HEP2, and SCC61) were treated with mTORC1 specific inhibitor everolimus, the dual PI3K/mTOR inhibitor BEZ235, and the specific PI3K inhibitor BKM120. Antiproliferative effects were assessed using MTT assay. Protein expression and phoshorylation were assessed by western blot. Results: HNSCC cancer cells were characterized for predictive factors of mTOR inhibitors. SQ20B and SCC61 cells displayed an epithelial phenotype whereas HEP2 cells displayed mesenchymal characteristics. SQ20B and SCC61 cells also had a constitutively activated AKT pathway in contrast to HEP2 cells. Others potentials predictive factors of mTOR inhibitors (Bcl2, Cyclin D1, p27, c-Myc) were differentially expressed in HEP2, SCC61, and SQ20B cells. In all cell lines, everolimus displayed IC50 over 6 μM. Novel mTOR inhibitors were 2-30 times more potent with IC50 ranging from 0.2 to 0.8 μM for BEZ235 and from 2.1 to 2.4 μM for BKM120. Everolimus and BEZ235 were less potent in HEP2 compared to SQ20B and SCC61 cells. In SQ20B and SCC61 cell lines everolimus displayed low IC25 (0.02μM) close to BEZ235 (0.1μM) and lower than BKM120 (1.4μM). All inhibitors displayed potent inhibition of S6 phosphorylation in all cells. Everolimus and the novel mTOR inhibitors inhibited the constitutive AKT activation observed in SQ20B and SCC61. In contrast, everolimus but not the novel mTOR inhibitors, significantly increased AKT activation in HEP2 cells. In combinations with carboplatin or paclitaxel, everolimus and BEZ235 displayed synergistic antiproliferative effects in HEP2 and additive effects in SQ20B, whereas BKM120 displayed mostly additive effects in both cell lines. Conclusion: Novel generation of PI3K/mTOR inhibitors displayed more potent antiproliferative effects than everolimus in HNSCC cell lines. Everolimus and BEZ235 were more active in epithelial cells with constitutionally activated AKT pathway whereas BKM120 potently inhibited cell proliferation in all HNSCC models. Several combinations with chemotherapies were shown to be synergistic and may be regarded as an attractive strategy in HNSCC patients. Citation Format: Aurelie Hesbert, Marie Serova, Armand de Gramont, Khemaies Slimane, Eric Raymond, Sandrine Faivre. Effects of novel PI3K/mTOR inhibitors BKM120 and BEZ235 in comparison to everolimus in Head & Neck Squamous cell carcinomas (HNSCC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4411. doi:10.1158/1538-7445.AM2013-4411

Background: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are approved for advanced renal cell carcinoma (RCC), as first-line and second-line therapy, respectively. No data have been reported on programmed sequential strategies combining alternative use of sunitinib and everolimus prior to progression. Such strategy is expected to delay the emergence of first-line acquired resistance and improve tumor control. The aim of our study was to assess the effects of three sequences administration of sunitinib and everolimus. Methods: Nude mice (n=5/group) were engrafted with human RCC cells (CAKI-1) then randomized to vehicle, everolimus, sunitinib, sunitinib alternated with everolimus every week (S1), every two weeks (S2), and every three weeks (S3). Median time to tumor progression (mTTP) was determined in each group. Angiogenesis and necrosis were evaluated using CD31 and HE staining. Inhibition of mTOR pathway was evaluated using phospho-S6 (pS6) and e-cadherin/vimentin expressions were analyzed by immunofluorescence staining. Results: The S1, S2 and S3 regimens increased mTTP by 30 to 80% relative to sunitinib or everolimus alone. The vascular surface areas (vessels size and number) in tumors were reduced in all treated groups relative to control, especially S1 and S2. All three sequential therapies induced larger necrosis areas in tumors as compared to control. In each group, tumor response seemed associated with a decrease in pS6 expression and changes in epithelial-mesenchymal phenotype with a decrease in vimentin and an increase in e-cadherin expression Conclusion: Sunitinib and everolimus programmed sequential regimens prior to progression yielded longer mTTP than sunitinib and everolimus monotherapies. The sequential combinations of these two agents in a RCC mouse clinical trial, increased antiangiogenic effects, leading potentially to tumor necrosis, especially with the S1 and S2 regimens. mTTP for each group and effects of sequential treatments in tumors angiogenesis and necrosis Treatment groups mTTP (in days) Vascular Surface Area per field (% vs control) Number of vessels per field % of necrosis surface per field Control 24 100 22 23 Sunitinib 36 30 5 47 Everolimus 50 28 7 27 S1 64 15 5 37 S2 59 20 4 51 S3 59 42 5 37 Citation Format: Célia Dos Santos, Annemilaï Tijeras-Raballand, Maria Serova, Chantal Dreyer, Khemaies Slimane, Armand de Gramont, Sandrine Faivre, Eric Raymond. Sunitinib alternated with everolimus in renal cell carcinoma: a sequential combination strategy for antitumor efficacy in mice clinical trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 321. doi:10.1158/1538-7445.AM2013-321

Background. Most ER+ tumors will eventually escape endocrine treatments. PI3K/mTOR pathway targeting has improved clinical results in endocrine treatments resistant (ETR) patients, however with unsustained responses. Our laboratory has developed several models of ETR luminal breast cancer (LBC) patient derived xenografts (PDX) suitable for biological studies (Cottu et al, AACR 2012 & IMPAKT 2012). The aims of the present study were 1) to analyze the biological factors associated with acquired ETR in relevant models of LBC; 2) to determine the therapeutic interest of combining everolimus with different ET models resistant to different endocrine treatments (ET). Methods. Implementation of LBC models has been reported (Cottu et al, BCRT 2012). ETR models were derived by selecting tumors growing under continuous ET, subsequently re-engrafted and rechallenged with endocrine therapies (tamoxifen, letrozole, fulvestrant), and with everolimus alone and combined with ETs. When possible, initial sensitive tumors were simultaneously treated with the same protocols. At progression, or after at least 120 days of continuous therapies, tumor tissue was retrieved. Tissue microarrays (TMA) were performed to analyze the biological modifications associated to ET and mTOR targeting. Triplicate immunohistochemistry of P-AKT/AKT, P-mTOR/mTOR and P-S6 were performed in addition to standard markers. Transcriptomic and RTPCR analyses are also being conducted. Results. Three models resistant to tamoxifen and 2 models resistant to surgical ovariectomy used a surrogate to estrogen deprivation, were developed from 3 initial PDX, and were maintained as independent hormone-resistant variants. All these models retained a luminal phenotype, based on IHC and transcriptomic analyses and had a wt PI3KCA. ETR models had an expression profile very similar to the initial PDX, suggesting that minor changes may be associated with the acquisition of an ETR phenotype. Three of these models have been tested. One tamoxifen resistant model confirmed a resistance specific to tamoxifen only and a high level of sensitivity to a fulvestrant everolimus combination. A second PDX yielded 2 other models resistant to tamoxifen and ovariectomy. These 2 models developed a resistance to all ET modalities. Therapeutic testing with combinations of everolimus and ETs were highly efficient, but everolimus alone was as efficient in these 2 models with complete and durable responses. Activation of the PI3K pathway was demonstrated in all cases by IHC analyses (expression of pAKT and pS6), and complementary ongoing RTPCR analyses. Everolimus based effects were associated with tumor fibrosis, a strong inhibition of Ki67 and pS6, but not always pAKT. The expression of ER was not modified by treatments, except in the fulvestrant-treated mice where it was strongly inhibited. Conclusion. We have developed and validated a platform of ETR models derived from our LBC original PDX. These models retained a luminal phenotype although highly resistant to ET. Activation of the PI3K pathway has been confirmed in ETR models, and everolimus alone, or combined with ET confirms high and durable efficacy. Updated mechanistic analyses performed at different time points will be presented at the meeting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-14.

Objective To explore patient and nurse satisfaction, compliance with practice guidelines, technical feasibility, and safety of home infusion of the bisphosphonate ZOL. Methods This was a prospective longitudinal 1-year survey of home ZOL therapy in patients with bone metastases secondary to a solid malignancy. Randomly selected physicians prescribed home ZOL therapy (4 mg Zometa®, 15-min IV infusion, every 3-4 weeks). Three questionnaires were administered at 3 time points: physician questionnaire, nurse satisfaction and feasibility questionnaire, and patient satisfaction questionnaire. The main end-points were patient and nurse satisfaction with home ZOL therapy. Results Of the 154 physicians who agreed to participate, 87 (56.5%) enrolled 818 patients for whom 788 case report forms were received of which 763 met inclusion criteria. Overall, 343 nurses (97.5% community) took part. Patient characteristics were: median age 68 yrs (30-95); male-female ratio 40/60; primary cancer: breast 55.2%, prostate 28.4%, lung 7.2%, other 9.4%; ECOG-PS 0 or 1: 78.6%. Overall, 90.9% of nurses were either highly satisfied or satisfied with how home ZOL therapy was run; 96.7% found the infusion either very easy or easy to perform; 97.5% felt that home therapy promoted a good relationship with patients, and 73% were either highly satisfied or satisfied with their hospital contacts. Among patients, 95.3% were either very satisfied or satisfied with home ZOL therapy. Causes for satisfaction were quality of the nurse-patient relationship (57.6%) in addition to expected reasons (e.g. less time travelling/waiting (68.8%), less disruption to daily routine (36.6%)). ZOL therapy was well tolerated (discontinuation due to adverse events 6.1%; osteonecrosis of the jaw 0.6%, fractures 0.2%). Practitioner compliance with recommendations was 73% for dental hygiene checks at inclusion and 48-56% thereafter, 66% for pre-infusion patient hydration, and often undocumented for calcium/vitamin D supplementation. Conclusions There was a very high level of both patient and nurse satisfaction with home ZOL therapy. However, improved compliance with practice guidelines should be encouraged. Disclosure T. Lebret: Consulting fees : Amgen, Novartis Advisory board : Amgen, Novartis Honorarium study Novartis, J. Mouysset: Honorarium study Novartis, A. Lortholary: Honorarium study Novartis, C. El Kouri: Honorarium study Novartis, L. Bastit: Honorarium study Novartis M. Ktiouet: Novartis Employee K. Slimane: Novartis Employee, X. Muracciole: Advisory board Novartis Consulting fees Novartis, S. Guerif: Consulting fees Novartis.

Background PI3K/mTOR is a survival pathway that was shown activated in 57-81% of patients (pts) with head & neck squamous cell carcinoma (HNSCC) and might drive resistance to cytotoxics. Methods We have previously shown synergistic cell-cycle dependent effects between rapamycin/everolimus and carboplatin, or paclitaxel in HNSCC cells (Aissat 2008). Based on this preclinical translational rationale, a two-step phase I/II trial was designed using 9 consecutive weekly (w) cycles of oral everolimus combined with carboplatin (AUC2) and paclitaxel (60mg/m2) followed by chemoradiotherapy in pts with untreated locally advanced HNSCC. Results A total of 27 pts with stage IV HNSCC (median age 58, range 46-84; ECOG 0-2) have been enrolled in this phase I/II study (42 pts scheduled for the phase II). Among the 7 pts enrolled in the everolimus dose escalation phase I step, 6 pts were evaluable for safety (3pts at 30 mg/w and 3pts at 50 mg/w). No dose-limiting toxicity (defined during the first 4 weeks of treatment) was reported. Transient asymptomatic grade 3 neutropenia (3 pts), anemia (3 pts), and thrombocytopenia (1 pt) were observed. The most frequently reported adverse events were mild to moderate asthenia, skin toxicity, and alopecia. The recommended dose of everolimus for the phase II step was 50 mg/w. So far, among pts treated in the phase I/II, 11/13 objective responses (1CR, 10 PR, 2SD) were observed in evaluable pts. Interestingly, several major responses (ranging -60 to -80% by RECIST) were observed in large necrotic primary tumors and lymph nodes of >6cm diameters. Preliminary genetic analysis of tumors showed neither KRAS, BRAF, PI3KCA, nor EGFR mutations in tumors responding to this combination. Conclusions Weekly 50 mg everolimus combined with carboplatin and paclitaxel was well tolerated with no DLT, allowing repeated cycles. Major clinical responses in pts with bulky, locally advanced and necrotic diseases deserve further evaluation of this combination in pts with HNSCC. Updated results will be presented at meeting. Disclosure S. Faivre: Novartis, honorarium, compensated E. Raymond: Novartis, honorarium, compensated K. Slimane: Novartis, employment, compensated 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 Treatment options for patients with papillary renal cell carcinoma (RCC) are limited. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in clear cell metastatic RCC; mTOR signaling is also dysregulated in papillary RCC. The ongoing RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe; ClinicalTrials.gov, NCT00688753) trial is evaluating everolimus monotherapy in treatment-naive patients with advanced papillary RCC. Here, we present the results of a preliminary analysis. Patients and methods RAPTOR is an open-label, single-arm, multicentre phase II trial. Adult patients with advanced type I or type II papillary RCC and ECOG performance status of 0 or 1 were enrolled. Prior systemic therapy for RCC was not permitted. Patients received oral everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary end point is proportion of patients progression free at 6 months. Results At data cut-off (April 11, 2012), 71 of 92 (77%) enrolled patients were eligible for analysis according to central pathology review (confirmed papillary renal cancer); 16 of the 92 patients were still on treatment. Most patients were men (73%) and most were Conclusions Results of this interim analysis have demonstrated that everolimus provides clinical benefit to patients with advanced papillary RCC. These results support the further evaluation of everolimus as a first-line treatment option for patients with advanced papillary RCC. Disclosure B. Escudier: Bernard Escudier has served as a consultant to and received honoraria from Bayer, Pfizer, Roche, Novartis, GlaxoSmithKline, and Aveo. S. Bracarda: Sergio Bracarda has served as an advisory board member to Pfizer, GlaxoSmithKline, Novartis, and Bayer, and has received honoraria from Pfizer and Novartis. K. Slimane: Khemaies Slimane is an employee of Novartis Pharma S.A.S. C. May: Christoph May is an employee of Novartis Pharma GmbH. C. Porta: Camillo Porta served as consultant/speaker for Novartis, Pfizer, GSK, Hoffman La Roche, Bayer-Schering, Aveo Pharmaceuticals, Astellas, Boehringer Ingellheim, and Recordati and received research grants from Novartis and Bayer-Schering. V. Grunwald: Viktor Grunwald served as consultant to Roche, Bayer, Novartis, Pfizer, GlaxoSmithKline, and Aveo/Astellas, received honoraria from GlaxoSmithKline, Novartis, and Pfizer, and received research funding from Pfizer and GlaxoSmithKline. All other authors have declared no conflicts of interest.

10067 Background: Classic Kaposi’s sarcoma (CKS) is an angioproliferation associated with human herpes virus 8 (HHV8), which sometimes requires systemic treatment. Rapamycin and everolimus are mTOR...

TPS234 Background: Papillary renal cell carcinoma (RCC) is genetically and morphologically distinct from other RCCs, and accounts for up to 10% of RCC diagnoses. All RCC histologies are generally resistant to chemotherapy. Newer targeted treatment approaches have demonstrated clinical benefit in patients with clear cell RCC, but options for the treatment of papillary RCC remain limited. Everolimus, an oral mTOR inhibitor, has demonstrated efficacy in the pivotal RECORD-1 study in patients with mRCC with a “clear cell component” histology that progressed on vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy, and everolimus is now indicated for use in this patient population. Because mTOR is also aberrantly activated in papillary RCC, mTOR inhibition presents a novel means for targeted therapy in papillary RCC. The ongoing RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe) trial is evaluating the efficacy and safety of everolimus monotherapy in treatment-naive patients ...

Distal latero-circumflex arteries (DLCA) and posterior descending artery (PDA) are anatomically too far and cannot be revascularized with internal mammary artery (IMA) by a conventional procedure. The reimplantation of the right IMA into the left IMA in situ increases (2 times) the length of right IMA graft available. Fifty-five patients underwent this technique. Their preoperative status was: 22 males, 3 females; mean age: 57 years, 38% myocardial infarction (MI). Coronary angiography showed: stenosis of the left main coronary artery: 3; stenosis of 3 vessels: 15; 2 vessels: 10; 2.3 anastomoses by patient were performed with Y right and left IMA procedure: 24 LDA, 8 diagonals, 25 DLCA and 1 PDA anastomosis. No deaths were observed in this short series. Morbidity was: 1 MI, 2 sternal sepsis, 1 bilateral phrenic paralysis (all were cured without sequelae). To date (March 90) 15 patients have been followed for 3 to 12 months, 12 are angina-free, 3 are significantly improved, 11 have a negative exercise test. Thallium test is normal in the revascularized area in 14 patients. Seven angiographies have been performed (6 months to 1 year) and all Y right IMA are patent.

Distal latero-circumflex arteries (DLCA) and posterior descending artery (PDA) are anatomically too far and cannot be revascularized with internal mammary artery (IMA) by a conventional procedure. The reimplantation of the right IMA into the left IMA in situ increases (2 times) the length of right IMA graft available. Fifty-five patients underwent this technique. Their preoperative status was: 22 males, 3 females; mean age: 57 years, 38% myocardial infarction (MI). Coronary angiography showed: stenosis of the left main coronary artery: 3; stenosis of 3 vessels: 15; 2 vessels: 10; 2.3 anastomoses by patient were performed with Y right and left IMA procedure: 24 LDA, 8 diagonals, 25 DLCA and 1 PDA anastomosis. No deaths were observed in this short series. Morbidity was: 1 MI, 2 sternal sepsis, 1 bilateral phrenic paralysis (all were cured without sequelae). To date (March 90) 15 patients have been followed for 3 to 12 months, 12 are angina-free, 3 are significantly improved, 11 have a negative exercise test. Thallium test is normal in the revascularized area in 14 patients. Seven angiographies have been performed (6 months to 1 year) and all Y right IMA are patent.