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`Ex. 1123-0001
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`Vol. 47, Supplement 2
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`September 2011
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`ISSN 0959-8049
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`European Journal of Cancer
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`Late Breaking and Best of
`2011 European Multidisciplinary Cancer Congress
`and Award Abstracts
`
`'
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`Amsterdam - Boston - London - New York - Oxford - Pan's a Philadelphia - San Diego 0 St Louis
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`0959-8049 (201 109) 47 :2 ; 1-3
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`Ex. 1123-0002
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`European Journal of Cancer
`'
`including EJC Supplements
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`Ex. 1123-0003
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`
`Presidential Sessions
`
`worldwide cost of cancer due to premature death and disability (not
`including direct medical costs) was estimated to be US$895 billion. This
`is not simply due to an increase in absolute numbers, but also the rate of
`increase of expenditure on cancer. What are the drivers and solutions to
`the so-called cancer—cost curve in developed countries? How are we going
`to afford to deliver high quality and equitable care? Here, expert opinion
`from health-care professionals, policy makers, and cancer survivors has
`been gathered to address the barriers and solutions to delivering affordable
`cancer care. Although many of the drivers and themes are specific to a
`particular field - eg, the huge development costs for cancer medicines -
`there is strong concordance running through each contribution. Several
`drivers of cost. such as over-use, rapid expansion, and shortening life
`cycles of cancer technologies (such as medicines and imaging modalities),
`and the lack of suitable clinical research and integrated health economic
`studies, have converged with more defensive medical practice, a less
`informed and overly bureaucratic regulatory system, a lack of evidence-
`based sociopolitical debate, and a declining degree of fairness for all
`patients with cancer. Urgent solutions range from re—engineering of the
`macroeconomic basis of cancer costs (eg, value-based approaches to bend
`the cost curve and allow cost—saving technologies), greater education of
`policy makers, doctors, payers, and the general public, and an informed
`and transparent regulatory system. A radical shift
`in cancer policy is
`also required. Political
`toleration of unfairness in access to affordable
`cancer treatment is unacceptable. Equity in cancer care is a fundamental
`principle for all developed countries and access to effective health care
`is a human right. The cancer profession and industry should also take
`responsibility and not accept a substandard evidence base and an ethos
`of very small benefit at whatever cost; rather, we need delivery of fair prices
`and real value from new technologies. Delivering affordability also means
`educating the public that value-based care is not poor care; dramatically
`re-engineering care pathways to make them more cost effective; and
`introducing radical controls on the off-label use of cancer technologies.
`
`Presidential Session lll
`Monday 26 September 2011, 12:15-14:25
`LATE BREAKING ABSTRACT
`9LBA
`Everolimus in Combination with Exemestane for Postmenopausal
`Women with Advanced Breast Cancer Who Are Refractory to
`Letrozole or Anastrozole: Results of the BOLERO-2 Phase III Trial
`
`J. Baselga', M. Camponez, T. Sahmoud3, M. Piccart‘, H. Burris5,
`H. Rugos, S. Noguchi7, M. Gnants, P. Mukhcpadhyay9, G. Hortobagyi'°.
`’Massachusetts General Hospital, Department of Oncology, Boston, USA;
`2 Centre Regional Rene Gauducheau, Department of Medical Oncology,
`Nantes Saint Herblain, France; 3Ncvartis Pharmaceuticals Corporation,
`Global Oncology Development, Florham Park NJ, USA; ‘Jules Bordet
`Institute, Department of Medicine, Brussels, Belgium; 5Sarah Cannon
`Research Institute, Drug Development Program, Nashville, USA;
`5University of California San Francisco, Department of Medicine
`(HematologylOncology), San Francisco, USA; 7Osaka University,
`Department of Breast and Endocrine Surgery, Osaka, Japan; “Medical
`University of Vienna, Department of Surgery Comprehensive Cancer
`Center, Vienna, Austria; 9Novarlis Pharmaceuticals Corporation, Oncology
`BDM, Florham Park NJ, USA; “University of Texas MD Anderson Cancer
`Center, Department of Breast Medical Oncology Houston, USA
`
`rapamycin (mTOR) pathway
`Background: The mammalian target of
`is constitutively activated in homrone herapy-resistant advanced breast
`cancer (ABC).
`In phase ll
`trials everolimus (EVE) showed promising
`efficacy both as monotherapy and in combination with endocrine therapy
`in patients with estrogen receptor positive (ER+) ABC. This double-blind,
`placebo—controlled phase III study (clinicaltrialsgov: NCT00863655; Trial
`Sponsor: Novartis Pharmaceuticals) evaluated EVE + exemestane (EXE)
`in patients with ER+ ABC refractory to letrozole or anastrozole.
`to
`Patients
`and Methods: Eligible patients were randomized (2:1)
`EVE (10 mgld) or matching placebo, with both arms receiving EXE
`(25 mgld); treatment continued until progression or unacceptable toxicity.
`The primary endpoint was progression—free survival (PFS) assessed by
`the investigators. Secondary endpoints included survival, response rate,
`and safety. A preplanned interim analysis was performed and reviewed
`by the independent data monitoring committee (IDMC) after observing
`359 PFS events.
`Results: 724 patients were randomized from 24 countries (485: EVE+EXE;
`239: EXE). Baseline characteristics were well balanced; median age was
`62 years; 56% had visceral involvement and 84% were sensitive to prior
`hormone therapy. Prior therapy included letrozole or anastrozole (100%),
`tamoxifen (48%), fulvestrant (16%) and chemotherapy (68%). At the interim
`analysis, the IDMC disclosed that the trial met its primary endpoint (PFS),
`as assessed by local investigators (HR: 0.43 [95% CI: 0.35-0.54}, median
`6.9 vs 2.8 months; p = 1.4><10"‘5), and that results were consistent across
`
`6 P
`
`residential Session II
`Sunday 25 September 2011, 12:20-14:40
`LATE BREAKING ABSTRACT
`7LBA
`A Multicentre Randomised Trial of lbandronate Compared to single
`Dose Radiotherapy for Localised Metastatic Bone Pain in Prostate
`Cancer (RIB)
`P. Hoskin', s. Sundarz, K. Reczko3, s. Forsytha, N, Mithal‘, B. Sizer5,
`L. Toys, M. Stratford7, M. Jitla|3. ’Mount Vernon Hospital, Centre for
`Cancer Treatment, Northwood, United Kingdom; 2Nottingham University
`Hospitals NHS Trust, Department of Oncology, Nottingham, United
`Kingdom; 3University College London, Cancer Research UK & UCL
`Cancer Trials Centre, London, United Kingdom; ‘Kent & Canterbury
`Hospital, Oncology Clinical Trials, Canterbury, United Kingdom; 5Essex
`County Hospital, Department of Oncology, Colchester, United Kingdom;
`5Royal Devon and Exeter Hospital, Exeter Oncology Centre, Exeter,
`United Kingdom; 7University of Oxford, Gray Institute for Radiation
`Oncology & Biology, Oxford, United Kingdom
`
`Background: Single dose radiotherapy (RT) is standard treatment for
`patients with localised metastatic bone pain. We compare lbandronate (IB).
`a bisphosphonale drug, with RT for treating metastatic bone pain in prostate
`cancer patients.
`Material and Methods: 470 patients were randomised to receive either a
`single dose of 6 Gy local RT or a single 6mg intravenous infusion of IB.
`Patients reported their primary site of pain at baseline. then 4, 8. 12, 26 and
`52 weeks after treatment. After reassessment at 4 weeks, non-responders
`crossed over to the alternative therapy, receiving their second treatment no
`later than week 8. The primary endpoint was pain relief at 4 and 12 weeks.
`compared to baseline. Pain relief was measured using a combination of
`analgesic use and pain score, based on two methods: (1) WHO pain ladder
`and (ii) analgesic use defined in morphine equivalents (Mercadante 1993),
`where a positive difference from baseline indicates worsening pain relief.
`The trial was powered (90%) to detect a difference in WHO response rate
`from 70% (RT) to 85% (IB).
`Results: The median follow-up was 11.6 months. Baseline characteristics
`(age, site of pain, prior treatment, performance status) were well-balanced.
`The WHO response rate at 4 weeks was 53% (RT) vs 49% (IB), p =0.49;
`and at 12 weeks 49% vs 56%, p=0.24. Using the Mercadante score, the
`mean difference from baseline to 4 weeks was -3.2 units (RT) vs +1.2 (IB),
`p= 0.11; and to 12 weeks -0.2 vs -1.7, p =0.73. However, the proportion
`of patients with a high score difference at 4 weeks (>+5.86 units) was
`10% (RT) vs 20% (IB), p= 0.004. At 6 months the mean differences were
`+3.99 (RT) vs +1.95 (IB) p=0.66. There was no difference at 12 months.
`The proportion crossing over treatments was 31% (IB) and 24% (RT),
`p = 0.10. The median survivals (months) were 11.8 (only RT), 114 (only IB),
`12.7 (RT then IB), 16.8 (IB then RT).
`Conclusions: When treating uncomplicated localised metastatic bone pain
`from prostate cancer this large trial generally shows no material difference
`between a single infusion of ibandronate and a single dose of RT. There
`appeared to be more patients in the IB group with worse Mercadante
`scores at 4 weeks (compared to baseline), consistent with more IB patients
`needing re-treatment after 4 weeks. importantly, there was no long—term
`difference in pain relief between IB and RT at 6 or 12 months. Single
`doses of bisphosphonates could have an important role in the treatment of
`metastatic bone pain.
`
`Presidential Session III
`Monday 26 September 2011, 12:15-14:25
`LATE BREAKING ABSTRACT
`8LBA
`Delivering Affordable Cancer Care in High-income Countries:
`a Lancet Oncology Commission
`R. Sullivan‘, J. Peppercorn’, K. Sikora3, J. Zalcberg‘, N. Meropol5.
`E. Amirs, D. Khayat7, P. Boyle“,
`I. Tannocks, T. Fojo9. ‘King's College
`London - Kings Health Partners Integrated Cancer Centre, London,
`United Kingdom; 2 Duke Cancer institute, Duke University Medicial
`Centre, Durham, USA; 3CancerPartnersUK, Head Office, London, United
`Kingdom; ‘Peter MacCallum Cancer Centre, University of Melbourne,
`Melbourne, Australia; 5University Hospitals Seidman Cancer Center
`Case Comprehensive Cancer Center, Case Western Reserve University,
`Cleveland, USA; 5Division of Medical Oncology and Hematology, Princess
`Margaret Hospital and University of Toronto, Toronto, Canada; 7Hépital
`Pitié-Salpétriére, Division of Oncology, Paris, France; 8/nternational
`Prevention Research Institute, Head Office, Lyon, France; “Medical
`Oncology Branch Center for Cancer Research, National Cancer lnstutute,
`Bethesda, USA
`
`The burden of cancer is growing, and the disease is becoming a major
`unsustainable economic burden for all developed countries.
`In 2008, the
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`Ex. 1123-0004
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`Presidential Sessions
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`the various subgroups. PFS analysis based on central assessment was
`also significant (HR: 0.36 [95% CI: 0.27-0.47], median 10.6 vs 4.1 months;
`p=3.3><10"15). Both analyses crossed the pre-specified thresholds for
`significance. Response rates were 9.5% and 0.4% on EVE+EXE and
`EXE arms,
`respectively; p<0.0001. Most common grade 3/4 adverse
`events were stomatitis (8% vs 1%), anemia (5% vs <1”/7). dyspnea
`(4% vs 1%), hyperglycemia (4% vs <1%), fatigue (3% vs 1%), and
`pneumonitis (3% vs 0%) for the EVE+EXE and EXE groups, respectively.
`Conclusion: EVE, when added to an aromatase inhibitor, significantly
`improves PFS and response rate and has a manageable safety profile.
`EVE in combination with an aromatase inhibitor is a new therapeutic option
`for women with previously treated ABC.
`
`Presidential Session III
`Monday 26 September 2011, 12:15-14:25
`LATE BREAKING ABSTRACT
`10LBA
`The EORTC 10041lB|G 03-04 MINDACT (Microarray in Node Negative
`and 1 to 3 Positive Lymph Node Disease May Avoid ChemoTherapy)
`Trial: Patients’ Baseline Characteristics and Logistics Aspects After
`a Successful Accrual
`
`M. Piccartl, J. Bogaertsz, F. Cardoso3, G. Werutsky“, S. Delaloges,
`L. Van ’t veers, I. Rubio7, C. Moulina, K. Engeleng, G. Viale1°,
`A.M. Thompson”, R. Passalacqua”, U. Nitz”, P. Vuylsteke”,
`J.Y. Pierga15, E. Rutgersff. ’JuIes Bordet Institute, Medicine, Brussels,
`Belgium; ZEORTC, Statistics, Brussels, Belgium; 3ChampaIimaud Cancer
`Center, Breast Cancer Unit & Breast Cancer Research, Lisbon, Portugal;
`‘EORTC, Clinical Research Physicians Unit, Brussels, Belgium; 5lnstitut
`Gustave Roussy Breast Cancer, Paris, France; “Netherlands Cancer
`Institute, Pathology, Amsterdam, The Netherlands; 7Hospital Universitario
`Vall d’Hebron, Centro de Cancer de Mama, Barcelona, Spain;
`“EORTC, Fellowship Programme, Brussels, Belgium,’ QEORTC, Project
`Management, Brussels, Belgium; “European Institute of Oncology/,
`Pathology Milan, Italy; ”NinewelIs Hospital, Surgery and Molecular
`Oncology, Dundee, United Kingdom; ’2Azienda istituti Ospitaliari di
`Cremona, Medical Oncology, Cremona, Italy; 13 West German Study
`Group, Niederrhein Breast Centre, Monchengladbach, Germany;
`"Clinique Sainte Elisabeth, service d'OncoIogie, Namur, Belgium;
`15 Curie Institute, Medical Oncology Paris, France; “Netherlands Cancer
`Institute, Surgery, Amsterdam, The Netherlands
`
`Background: Personalized medicine and genomic risk profiling have
`been increasingly demanded for cancer management. The MINDACT trial
`investigates the added clinical value of the 70—gene profile (Mammaprintm)
`to standard clinicopathological criteria for the accurate selection of breast
`cancer (BC) pts for adjuvant chemotherapy (CT).
`Material and Methods: All pts had their risk assessed by the 70-
`gene test [genomic (G) risk: high vs low] and by a modified version of
`Adjuvant! Online 8.0 [clinical (C) risk: high vs low]. G and C-high risk
`pts were proposed adjuvant CT. Discordant pts (G-lowIC-high or G-high/
`C—low) were randomised between the two risk assessments to decide
`on adjuvant CT. Pts assigned to CT were offered a 2"‘ randomisation
`between an anthracycline-based regimen and the combination doceIaxel—
`capecitabine. G-low and C-low risk pts were not assigned to CT. HR positive
`pts were offered an endocrine therapy randomisation (7 years of letrozole
`vs 2 years of tamoxifen followed by 5 years of letrozole) and ovarian function
`suppression if premenopausal.
`
`N (%)
`G-high
`
`1827 (28)
`
`C-
`high
`C-low
`
`G—low
`
`1436 (22)
`CT: 718; no CT: 718
`2586 (40)
`
`Total
`
`3263 (50)’
`
`3264 (so)*
`
`4022 (52)
`
`6527
`
`678 (10)
`CT: 340; no CT: 338
`2505 (38)
`Total
`*The 50-50 split is coincidental
`Results: The trial was closed to screening in July 2011. Since March 2007,
`11,300 pts were registered, 7,491 had the G test done, and 6,527 (58%)
`were enrolled in 104 sites in 9 countries. The proportion of registered!
`enrolled pts increased over time (46% in the 15‘ year to 63% in the
`last year). Monthly accrual increased from about 25 in the first year to
`over 200 pts in the last year. Current pts’ baseline characteristics at
`enrolment are: 33% of pts <50 years of age, 80% were node negative,
`71% had LN status verified by sentinel node biopsy, 83% had breast
`conservation surgery, 72% had tumors <2cm, 88% were HR positive
`(ER or PR+ or both), 11% HER2 positive, and 9% triple negative. Pts’
`
`risk allocations at enrolment are described in the table. As per status at
`enrollment the attribution to chemotherapy would be 11.6% lower using the
`70—gene profile.
`Conclusions: MINDACT is the largest European randomised prospective
`trial evaluating the clinical value of a gene expression profile for risk
`assessment and adjuvant CT prescription for BC. Accrual has been
`successfully completed and the tria|’s complex logistics. including real-time
`collection of frozen tumor tissue, were proven feasible in a multinational,
`multicentric setting.
`
`Presidential Session IV
`Tuesday 27 September 2011, 09:00-11:00
`LATE BREAKING ABSTRACT
`11LBA
`Identification of Novel Somatic Mutations in SF3B1, a Gene Encoding
`a Core Component of RNA Splicing Machinery, in Myelodysplasia
`with Ring Sideroblasts and Other Common Cancers
`
`E. Papaemmanuill, L. Malcovatiz, M. Cazzola3, E. Hellstrom-Lindberg4,
`D. Bowen5, J.B. Bou|twood°, A.R. Green7, P.A. Futreal‘, M.R. Stratton‘,
`P.J. Campbelli. ’Wellcome Trust Genome Center, Cancer Genome
`Project, Cambridge, United Kingdom; 2 Department of Hematology
`Oncology, Fondazione IRCCS Policlinico San Matteo & University of
`Pavia, Pavia, Italy; 3Department of Hematology Oncology Fondazione
`IRCCS Policlinico San Matteo & University of Pavia, Pavia, Italy;
`‘Department of Hematology, Karolinska instute, Stockholm, Sweden;
`5Department of Hematology, St James Institute of Oncology, Leeds,
`United Kingdom; 5Nuflield Department of Clinical Laboratory Sciences,
`University of Oxford, Oxford, United Kingdom; 7Addenbrooke’s Hospital,
`Department of Hematology Cambridge, United Kingdom
`
`(MDS) are a diverse group of chronic
`Myelodysplastic syndromes
`hematological malignancies, which, with the ageing population, have
`become the most prevalent myeloid cancer. Patients with MDS present with
`peripheral blood cytopenia, bone marrow dysplasia and an increased risk
`of transformation to acute myeloid leukemia (AML). The more recent WHO
`classification—based prognostic scoring system (WPSS) classifies MDS
`patients into five risk groups showing different survivals and probabilities
`of leukemic evolution. However, MDS patients demonstrate a high degree
`of morphological heterogeneity and variable clinical course irrespective of
`WHO subtype.
`this heterogeneity may be attributable to distinct
`We reasoned that
`molecular lesions that contribute to MDS morphology and clinical outcome.
`We used massively parallel sequencing technology to identify somatically
`acquired point mutations across all protein-coding exons in the genome of
`9 MDS patients.
`We report
`the identification of novel somatically acquired mutations
`in patients with MDS.
`In 6/9 patients, we identified recurrent somatic
`mutations in a gene that encodes a core component of the RNA splicing
`machinery, SF3B1. To characterize the pevalence of SF3B1 mutations, we
`undertook targeted resequencing of the gene in 2,087 samples from MDS
`patients, primary cancers and core cancer cell lines. Somatic mutations of
`SF3B1 were found in 150/533 (26.1%) patients with MDS. 16/83 (19.3%)
`patients with MDS/MPN, and 2/38 (5.3%) patients with AML. The gene
`was also mutated in 1-5% of diverse other common tumor types including
`breast cancer, multiple myeloma and renal cancer. In patients with myeloid
`neoplasms, there were close relationships between mutant SF3B1 and
`presence of ring sideroblasts (P<0.001), and in multivariable analysis,
`SF3B1 mutations were independently associated with better overall survival
`(HR=0.18, P=0.028) and lower risk of leukemic evolution (HR=O.32,
`P = 0.048),
`The close association between SF3B1 mutation and ring sideroblasts
`across MDS is consistent with a causal relationship. and makes this the
`first gene to be strongly associated with a specific morphological feature
`in MDS. This molecular lesion has relevant clinical significance, as it
`is
`independently associated with a favorable clinical outcome.|n conclusion,
`mutations in SF3B1 implicate abnormalities of mRNA splicing, a pathway
`not previously known as a target for mutation, in the pathogenesis of MDS
`and cancer in general.
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`Ex. 1123-0005
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`nucleotide exchange. Further mechanistic studies revealed that through
`steric hindrance the compounds block the formation of the Ras—SOS
`complex, a key intermediate of the exchange reaction. At the cellular level,
`our compounds inhibit the formation of active RasGTP and prevent Ras
`signaling to downstream effectors. To define the potential clinic utility of
`these compounds. we performed biological characterization of Ras-driven
`tumors and identified a subset of Ras mutant tumors that depend on
`nucleotide exchange factors for the activation of Ras, suggesting a specific
`profile for the use of exchange inhibitors.
`Conclusions: We conclude that
`the compounds act as competitive
`inhibitors of nucleotide exchange to prevent the activation of Ras. The
`discovery of a binding pocket on Ras with functional significance represents
`a breakthrough finding that will offer a new direction for therapeutic
`intervention of the Ras oncoprotein. Our findings provide new opportunities
`to target the “undruggable" Ras oncoprotein.
`
`Breast Cancer - Advanced Disease
`Sunday 25 September 2011, O9:O0~11:35
`LATE BREAKING ABSTRACT
`16LBA
`Reversal of Tamoxifen Resistance (Hormone Resistance) by Addition
`of Sirolimus (mTOR Inhibitor) in Metastatic Breast cancer
`
`G.S. _B,hattacha_ry3@. J. Biswasz, J.K. Singh3. M. Singh“, K. Govindbabu5,
`A.A. Ranadee, H. Ma|hotra7, RM. Parikhl’, T. Shahids, s. Basug.
`’Orchid Nursing HomeIAMRl, Medical Oncology & Clinical Hematology
`Kolkata, India; 2CNCI, Director, Kolkata, India; 3Mahavir Cancer
`Sansthan, Director, Patna, India; ‘Mahavir Cancer Sansthan, Medical
`Oncology, Patna, India; 5ICON-ARO, Medical Oncology Bangalore,
`India; 5ICON-ARO, Medical Oncology, Pune, India; 7ICON-ARO, Medical
`Oncology, Jaipur, India; 8ICON-AR0, Medical Oncology, Mumbai, India;
`QAMRI, Radiation oncology Kolkata, India
`
`b.
`
`Introduction: The estrogen receptor was first proven therapeutic target
`identified in breast cancer cells.
`Because it is present in 50-75% of breast cancer and has direct correlation
`with cancer phenotype ER modulation has been in main stay of treating
`this disease in this phenotype in last 40 years. A key protein in the
`pathway tumorogenesis is AKT kinase which antagonises the hormone
`therapy like Tamoxifen because of cross-tak. In fact Tamoxifen resistance
`are associated with high levels of activity of AKT.
`mTOR (mammalian Target Of Rapamycin) inhibitors block the downstream
`pathway of AKT and addition of this to Tamoxifen may overcome resistance
`to Tamoxifen.
`Materials and methods: The study was done in two phases
`a.
`In metastatic breast cancer patients who were ER/PgR positive and
`HER-2 negative and could not afford Al
`inhibitors were randomised
`to Tamoxifen (20 mg once a day) or Tamoxifen with Sirolimus (2 mg
`per day).
`In patients who had failed Al and/or Tamoxifen were randomised to the
`above combination also.
`Each phase had 200 patients that is total 400 patients.
`All patients had ER/PgR, HER—2Ineu. Kl-67 done.
`The primary end point was Response Rate and Time to Progression.
`Secondary end points were Safety, Toxicity and Preliminary Pharmacoeco-
`nomic Analysis.
`Results: The results of the phase I study showed response rate of
`36% vs 68% (average ER status 4 to 8, median = 6) and time to
`progression - 9 months vs 16 months.
`The phase II study showed response rates of 4% vs 40% and time to
`progression - 3 months vs 11 months.
`The study was done for the period 2004-2010, single center with 3 referral
`centers. The combination was effective and safe.
`The Sirolimus used was of certified and generic version. Tamoxifen was of
`certified and generic version.
`Conclusion: Pharmaooeconomic analysis shows it to be cost effective
`combination with a good toxicity profile.
`
`Proffercd Papers Sessions
`
`Conclusions: BIBF 1120 in combination with mFOLFOX6, for first«|ine
`mCRC has a similar magnitude of efficacy and safetyltolerability profile
`but lower incidence of SAE in comparison to BE\/. Detailed analysis of
`SAEs is ongoing.
`Funded by Boehringer lngelheimg ClinicaITrials.gov NCT00904839.
`BIBF 1120 arm
`BEV arm
`(n=85)
`(n=41)
`
`88
`32
`15
`
`95 .
`24
`12
`10
`12
`
`Pts with AE Grade :23 by MedDRA preferred
`terms 25%, %
`Neutropenia
`Diarrhoea
`Neurotoxicity
`Paraesthesia
`Astnenia
`Decreased appetite
`Thrombocytopenia
`Peripheral neuropathy
`Abdominal pain
`Polyneuropathy
`Serious AEs (SAE), %
`AEs leading to discontinuation of, "la
`El|BF1120 or BEV
`FOLFOX
`Pts receiving all planned mFOLFOX6 cycles in
`first 6 months, %
`5-FU
`Oxaliplatin
`Total mFOLFOX6 cycles. median
`5-FU
`Oxaliplatin
`Median treatment exposure, days
`5-FU
`Oxaliplatin
`
`Proffered Papers Sessions
`Basic Sciencel Translational Research
`Monday 26 September 2011, 14:45-17:10
`LATE BREAKING ABSTRACT
`15LBA
`Drugging the Undruggable: Small-molecule Inhibition of Ras
`Oncoprotein
`
`G. Fang‘, T. Maured’, L. Garrentonl, N. Skelton3, B. Faubera, S. Malek‘,
`A. Giannetti“, P. Jackson‘, J. Rudolpha, W. Wangz. ’Genentech Inc.,
`Cell Regulationloncology, South San Francisco CA, USA; 2Genentech
`Inc., Structural Biology, South San Francisco CA, USA; 3Genentech
`Inc., Discovery Chemistry South San Francisco CA, USA; “Genentech
`Inc., Biochemical Pharmacology, South San Francisco CA, USA
`
`Background: Ras is a nucIeotide—dependent switch that converts from an
`inactive GDP-bound state to an active GTP-bound state when activated by
`guanine nucleotide exchange factors, such as SOS. Active RasGTP then
`binds to and activates downstream signaling effectors. Ras is the most
`frequently mutated oncogene and hyperactive mutant Ras constitutively
`signals to effectors to promote cell survival, proliferation and metastasis.
`Thus, Ras oncoprotein has been considered by the cancer community to
`be one of the most important oncology drug targets. Despite the enormous
`interest and extensive exploratory efforts in industry and academia, small
`molecules that bind to Ras in a well-defined manner and exert inhibitory
`effects have not been uncovered to date. We describe in this abstract the
`identification and characterization of small—molecu|e inhibitors of the Ras
`oncoprotein.
`Materials and Methods: To explore a new means of directly targeting
`Ras, we used a fragment-based lead discovery approach via an NMR-
`based screen. Hits from the fragment screen were characterized for their
`interactions with Ras by NMR and X-ray crystallography and for their effects
`on Ras activation and signaling in reconstituted biochemical assays in vitro
`and in cellular assays in vivo.
`Results: From the fragment-based screen, we identified a group of
`small molecules that each bind to a common site adjacent to the switch
`|Il|
`regions in the Ras protein. X-ray crystallography studies of three
`compound-Ras complexes indicate that the binding site