Sustained Clinical Efficacy Research Articles

PTPS-14THE NEED FOR MULTI-TARGETED THERAPY IN PEDIATRIC BRAIN TUMORS WITH BRAF MUTATION

Emerging evidence confirms dysregulation of BRAF gene inducing oncogenesis of pediatric brain tumors. To-date few reports show short-lived efficacy using BRAF inhibitors in these tumors. This indicates the need to target diverse pathways to have sustained clinical efficacy. We present two cases where a combination of vemurafenib (BRAF inhibitor) with everolimus (mTOR inhibitor) as a part of an IRB approved protocol was used. A 10-year-boy diagnosed with a left parietal pleomorphic xanthoastrocytoma (PXA) demonstrated tumor progression despite radiotherapy and three surgical interventions over two years. The tumor showed BRAF mutation for which he received a combinatorial therapeutic approach using the above two drugs given orally every day on a 28 day cycle. He experienced a partial response after two cycles and continued response after 13 cycles. This therapy has been well-tolerated with only minor (Grade I) skin rash. The child remains clinically stable with a Lansky score of 100. The second case is a 13-year-old female diagnosed at 1 year of age with a right-sided optic pathway glioma. The biopsy was consistent with pilocytic astrocytoma. The tumor progressed through multiple chemotherapeutic regimens, including carboplatin, vincristine, vinblastine, celexocib. Molecular analysis performed at our institution demonstrated the tumor to harbor a BRAF mutation for which she is currently receiving the above therapeutic regimen. She is tolerating the therapy well, with mild mouth sores. Her tumor after four cycles shows ongoing response and stable vision. It is now known that these tumors can induce escape mechanisms conferring therapeutic resistance and short-lived efficacy, undermining single drug BRAF targeted approach. This is the first ongoing study targeting these pathways (RAF/MAPK/ERK) and PI3K/mTOR pathway in pediatric brain tumors with BRAF mutation. Larger prospective larger studies are warranted to overcome therapeutic limitations through optimal combination therapy targeting multiple signaling pathways.

Apremilast for the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the joints that occurs in patients with psoriasis. The spectrum of PsA includes arthritis, dactylitis, enthesitis, axial involvement, and skin lesions. Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and leflunomide, and biologic DMARDs such as tumor necrosis factor (TNF) antagonists and ustekinumab, have been used to treat PsA. Apremilast is a novel therapy that inhibits phosphodiesterase 4, increases intracellular cAMP levels, and modulates expression of inflammatory mediators in favor of anti-inflammatory activity. It decreases the pro-inflammatory cytokines TNF-α, IFN-γ, IL-17, and IL-23 and increases the anti-inflammatory cytokine IL-10 under certain conditions. One phase II and four phase III clinical trials as well as long-term extension studies showed significant and sustained clinical efficacy and an adequate safety profile for apremilast in patients with active psoriatic arthritis.

Time course of clinical and neuroradiological effects of delayed-release dimethyl fumarate in multiple sclerosis.

Background and purposeDelayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF), demonstrated efficacy and safety in relapsing−remitting multiple sclerosis in the 2-year, randomized, placebo-controlled, phase 3 DEFINE and CONFIRM trials. A post hoc analysis of integrated data from DEFINE and CONFIRM was conducted to determine the temporal profile of the clinical and neuroradiological effects of DMF.MethodsEligible patients were randomized to receive placebo, DMF 240 mg twice (BID) or three times (TID) daily or glatiramer acetate (GA; reference comparator; CONFIRM only) for up to 96 weeks. Patients in the GA group were excluded from this analysis.ResultsA total of 2301 patients were randomized and received treatment with placebo (n = 771) or DMF BID (n = 769) or TID (n = 761). DMF significantly reduced the annualized relapse rate beginning in weeks 0–12 (BID, P = 0.0159; TID, P = 0.0314); the proportion of patients relapsed beginning at week 10 (BID, P = 0.0427) and week 12 (TID, P = 0.0451); and the proportion of patients with 12-week confirmed disability progression beginning at week 62 (BID, P = 0.0454) and week 72 (TID, P = 0.0399), compared with placebo. These effects were sustained throughout the 2-year study period. DMF significantly reduced the odds of having a higher number of gadolinium-enhancing lesions by 88% (BID) and 75% (TID) and the mean number of new or enlarging T2 lesions by 72% (BID) and 67% (TID), from the first post-baseline magnetic resonance imaging assessment at 24 weeks (all P < 0.0001 versus placebo).ConclusionsIn phase 3 clinical trials, DMF demonstrated rapid and sustained clinical and neuroradiological efficacy in relapsing−remitting multiple sclerosis.

Prolonged efficacy of the 300IR 5-grass pollen tablet up to 2years after treatment cessation, as measured by a recommended daily combined score.

BackgroundThe 300IR (index of reactivity) 5-grass pollen tablet has favorable short-term and sustained clinical efficacy in patients with grass pollen-induced allergic rhinoconjunctivitis (ARC). Here, we report maintenance of efficacy and safety over 2 years following treatment discontinuation.MethodsRandomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 3 trial in patients aged 18–50 years with ARC. During study years 1–3, patients received a daily sublingual tablet containing either 300IR 5-grass pollen extract or placebo, according to a discontinuous pre- and coseasonal protocol. Study years 4 and 5 were treatment-free. In response to health authorities’ recommendations, the daily combined score (DCS) was assessed in a post-hoc analysis as the efficacy endpoint. Components of the DCS were daily rhinoconjunctivitis total symptom score (DRTSS) and daily rescue medication score (DRMS).Results633 patients with ARC were randomized to placebo (n = 219) or 300IR 5-grass pollen tablet, beginning 4 months (4 M, n = 207) or 2 months (2 M, n = 207) prior to the estimated start of the grass pollen season and continuing until season’s end. During the first post-treatment year, a statistically significant difference versus placebo in least squares (LS) mean DCS was noted in patients previously receiving active treatment (300IR (2 M) point estimate: −0.16, 95% confidence interval (CI95%): [−0.26, −0.06], p = 0.0019; −31.1%; 300IR (4 M) point estimate: −0.13, CI95%: [−0.23, −0.03], p = 0.0103, −25.3%). During the second post-treatment year, patients in the 300IR (4 M) group, but not the 300IR (2 M) group, showed a statistically significant difference in LS mean DCS versus placebo (point estimate: −0.11, CI95%: [−0.21; 0.00], p = 0.0478, −28.1%). This significant efficacy seen during the post-treatment years in patients previously treated with 5-grass pollen tablet compared favorably with that during the 3 prior years of active treatment. A statistically significant difference versus placebo was also noted in secondary efficacy measures in both post-treatment years (except for DRTSS in year 5). In the absence of any active treatment, the safety profile was similar in the active groups versus placebo group during either post-treatment year.ConclusionsIn adults with grass pollen-associated ARC, 5-grass pollen tablet therapy beginning 4 months before the pollen season and continuing to season’s end demonstrated efficacy across all variables during active treatment, and this effect was prolonged for up to 2 years post-treatment.Trial registrationClinicalTrials.gov identifier: NCT00418379.

Subcutaneous immunoglobulin in CIDP and MMN: a short-term nationwide study

This multi-center Italian prospective observational study reports the 4 months follow-up data of 87 patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) shifted from intravenous to subcutaneous immunoglobulin treatment. A therapeutic shift from intravenous to subcutaneous immunoglobulin was performed in 87 patients (66 CIDP; 21 MMN) affected by immune-mediated peripheral neuropathies with evidence of a sustained clinical response to intravenous immunoglobulin. Patients were evaluated by means of the Overall Neuropathy Limitation Scale, Medical Research Council Scale and Life Quality Index questionnaire, both at the time of therapeutic shift and after 4 months of subcutaneous immunoglobulin treatment. A sustained clinical efficacy was observed after the switch to subcutaneous immunoglobulin: the Overall Neuropathy Limitation Scale score improved in the group of 66 CIDP patients (P = 0.018), with only one subject reporting a worsening of 1 point, and remained stable in the group of 21 MMN patients (P = 0.841), with one subject reporting a worsening of two points. An improvement in the patient's perception of therapeutic setting was reported in both groups. This large multi-center study confirms the short-term clinical equivalence of subcutaneous versus intravenous immunoglobulin and a possible improvement in the patient's perception of therapeutic setting with the subcutaneous administration. However, further studies are required to extend the results to a longer observational period.

A169: Cumulative Long‐Term Safety, Efficacy and Patient‐Reported Outcomes in Children With Juvenile Idiopathic Arthritis Treated With Intravenous Abatacept: Up to 7 Years of Treatment

Background/Purpose: The long-term efficacy and safety of intravenous abatacept in patients (pts) with juvenile idiopathic arthritis (JIA) have been reported previously from the Phase III AWAKEN trial ([1, 2]). Here, we report efficacy, safety and pt-reported outcomes from the open-label, long-term extension (LTE) of AWAKEN, with up to 7 years of follow-up. Methods: Pts entered the LTE if they were JIA ACR 30 non-responders (NR) at the end of the 4-month lead-in period (abatacept only), or if they received abatacept or placebo (pbo) in the 6-month double-blind (DB) period. The Child Health Questionnaire was used to evaluate health-related quality of life (HRQoL); physical (PhS) and psychosocial (PsS) summary and pain scores were analyzed. Pain was assessed by parent global assessment using a 100 mm visual analog scale. Efficacy and HRQoL evaluations are reported up to Day 1765 (~ Year 5.5). Safety is presented for the cumulative period (lead-in, DB and LTE), for all pts who received abatacept during the LTE. Results: Of the 153 pts entering the LTE (58 from DB abatacept group, 59 from DB pbo group, 36 NR), 69 completed the trial (29 abatacept, 27 pbo, 13 NR). For pts treated in the LTE, mean (range) exposure to abatacept was 53.6 (5.6–85.6) months. During the LTE, incidence rates of AEs and serious AEs per 100 pt-years were 209.1 and 5.6. Thirty pts (19.6%) had serious AEs; most were unrelated and were musculoskeletal (8.5%) or infectious events (6.5%). No malignancy was reported. There was one death (accidental; unrelated). At Day 169, JIA ACR 50 and 70 response rates were 79.3% and 55.2% in the abatacept group, and 52.5% and 30.5% in the pbo group; 31.0% and 10.2% of pts in the abatacept and pbo groups, respectively, had inactive disease. By Day 1765, JIA ACR 50 and 70 response rates were 93.9% and 78.8% in the abatacept group, and 80.0% and 63.3% in the pbo group; 51.5% and 33.3% had inactive disease. In the NR group, 69.2% and 53.8% of pts achieved JIA ACR 50 and 70 responses at Day 1765, and 30.8% had inactive disease. In pts who entered the LTE, mean baseline PhS scores were below the range for healthy children (abatacept 30.2, pbo 31.0, NR 29.5). At Day 169, 38.3% of pts had reached a PhS score >50 ((1). By the end of the LTE, 43.5% of pts had reached a PhS score >50. At baseline, mean PsS scores for those who entered the LTE were slightly lower than the mean for healthy children (abatacept 43.5, pbo 44.2, NR 47.0). At Day 169, 54.9% of pts had a PsS score >50 (1). By Day 1765, 58.1% of pts had reached a PsS score >50. At baseline, the mean pain score was 42.9. By Day 169, 13.9% of pts were considered pain free (pain score = 0); this was maintained over the LTE (1). Table 1. NR(%) n=36 DB abatacept (%) n=58 DB pbo (%) n=59 Total (%) n=153 Day 169 (start of LTE) PhS >50 20.0 46.2 41.2 38.3 PsS >50 50.0 57.7 54.9 54.9 Pain free 0 20.4 15.7 13.9 Day 1765 (end of LTE) PhS >50 33.3 55.6 34.8 43.5 PsS >50 58.3 55.6 60.9 58.1 Pain free 0 17.9 16.0 13.1 Conclusion: Long-term treatment with abatacept for up to 7 years was associated with consistent safety, and sustained clinical efficacy and quality-of-life benefits in patients with JIA who remained on therapy.

Sustained efficacy and safety of a 300IR daily dose of a sublingual solution of birch pollen allergen extract in adults with allergic rhinoconjunctivitis: results of a double‐blind, placebo‐controlled study

BackgroundAllergic rhinoconjunctivitis (ARC) due to birch pollen is a growing health concern in Europe. Here, we report the efficacy and safety of 300IR birch pollen sublingual solution administered discontinuously for 2 consecutive years to patients with birch-associated allergic rhinoconjunctivitis.MethodsBirch pollen-allergic adults were randomized in this double blind study to 300IR birch pollen sublingual solution or placebo, daily, starting 4 months before and continuing through the pollen season for two pollen seasons. Randomization was stratified according to the presence or absence of oral allergy syndrome (OAS). The primary efficacy endpoint was the Average Adjusted Symptom Score (AAdSS) over the second pollen season and was analyzed by ANCOVA. Secondary efficacy endpoints included the AAdSS over the first pollen period. Safety was evaluated by means of adverse event monitoring.Results574 patients (284 in the active group and 290 in the placebo group) were randomized and 496 completed the study. Over the second pollen period, the least square (LS) mean AAdSS was significantly lower in the 300IR group than in the placebo group (LS mean difference −2.04, 95% CI [−2.69, −1.40], (p <0.0001) with a relative reduction of 30.6%. Results were consistent in patients with and without OAS (−33.6% and −28.4%, respectively). A significant reduction in LS mean AAdSS was also observed over the first pollen season. The most frequently reported adverse events were application site reactions: oral pruritus, throat irritation, and mouth edema. There were no reports of anaphylaxis.ConclusionsPre- and co-seasonal treatment with 300IR birch pollen sublingual solution demonstrated sustained clinical efficacy over 2 pollen seasons and was well tolerated in adults with birch pollen-associated allergic rhinoconjunctivitis. Efficacy results were consistent in patients with and without oral allergy syndrome.Trial registrationClinicalTrials.gov: NCT01731249.

Allergen immunotherapy and allergic rhinitis: false beliefs.

BackgroundOver the last 100 years, several persistent misconceptions or ‘false beliefs’ have built up around allergen immunotherapy and its use in allergic rhinitis. This is perhaps because enthusiastic physicians administered complex allergen extracts to a diverse population of patients suffering from heterogeneous atopic conditions. Here, we review evidence that counters seven of these ‘false beliefs.’Discussion1. The symptoms of allergic rhinitis can be more heterogeneous, more severe and more troublesome in everyday life than many physicians believe. Large-scale epidemiological surveys show that the majority of allergic rhinitis patients have at least one symptom severe enough to interfere with sleep quality, productivity and/or well-being. 2. Allergen immunotherapy is not necessarily suitable for all allergic rhinitis patients (notably those with mild symptoms). Recent evidence from double-blind, placebo-controlled, randomized clinical trials suggests that the more severe the disease, the greater the treatment effect. 3. Allergen immunotherapy is often accused of lack of efficacy (relative to pharmacotherapy, for example). However, there are now many meta-analyses, systematic reviews and high-quality clinical trials that find overwhelmingly in favor of the efficacy of allergen immunotherapy (including sublingual formulations) in allergic rhinitis induced by pollen and, increasingly, other allergens. 4. Natural-exposure and challenge-chamber trials have shown that symptom relief may become apparent within months or even weeks of the initiation of allergen immunotherapy. 5. In pollen-induced allergic rhinitis, several years of subcutaneous or sublingual allergen immunotherapy are associated with sustained clinical efficacy after subsequent treatment cessation – confirming the disease-modifying nature of this therapy. 6. Most patients seeking treatment for allergic rhinitis are polysensitized, and allergen immunotherapy has proven efficacy in large, robust clinical trials in these groups. Polysensitization is not a contraindication to allergen immunotherapy. 7. Sublingual allergen immunotherapy is safe for home administration. A recent review calculated that 1 billion doses were administered worldwide between 2000 and 2010 and found that the 11 case reports of anaphylaxis (all non-fatal) corresponded to non-standard practice.SummaryModern, evidence-based medicine has generated more than enough robust evidence to remove misconceptions about allergen immunotherapy and allergic rhinitis.

The JAK inhibitor tofacitinib for active rheumatoid arthritis: results from Phase III trials

Tofacitinib is a Janus kinase inhibitor that modulates the transcription of cytokine genes involved in immune regulation and hematopoiesis. This clinical trial report focuses on ORAL Solo, ORAL Standard, ORAL Step and ORAL Scan Phase III trials of the tofacitinib ORAL program. ORAL Solo shows an early and sustained clinical efficacy with tofacitinib monotherapy in rheumatoid arthritis (RA) patients with inadequate response to biologic or nonbiologic disease-modifying antirheumatic drugs. ORAL Standard demonstrates clinical response to tofacitinib plus methotrexate (MTX) in RA patients who had MTX-inadequate response. ORAL Step indicates rapid clinical response to tofacitinib plus MTX in TNF antagonist-inadequate response RA patients. ORAL Scan demonstrates that tofacitinib inhibits radiographic progression and improves clinical parameters in patients treated with tofacitinib and MTX. Upper respiratory tract infection, headache, diarrhea and nasopharyngitis were common adverse events. Tofacitinib is a new ...

THU0352 Long-Term Safety and Efficacy of Golimumab in the Treatment of Ankylosing Spondylitis: Results Through 5 Years of the Go-Raise Trial

BackgroundGolimumab(GLM) has demonstrated significant and sustained clinical efficacy and an acceptable safety profile through 2yrs of the phase 3, randomized, PBO-controlled, GO-RAISE study in pts with ankylosing spondylitis (AS).ObjectivesTo evaluate...

FRI0220 Sustained clinical efficacy after multiple courses of rituximab in rheumatoid arthritis patients with inadequate response to tumour necrosis factor inhibitors: 2-year data from the repeat (repeated courses in routine clinical practice) study

BackgroundIn the last decade, biologic therapy changed dramatically treatment options for rheumatoid arthritis (RA). However, a significant number of patients failed to maintain the initial response to a TNF blocker....

Clinical efficacy, radiographic and safety findings through 2 years of golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of the randomised, placebo-controlled GO-REVEAL study

ObjectivesTo assess long-term golimumab efficacy/safety in patients with active psoriatic arthritis (PsA).MethodsAdult PsA patients (≥3 swollen, ≥3 tender joints, active psoriasis) were randomly assigned to subcutaneous injections of placebo, golimumab...

A new generation of biodegradable polymer-coated sirolimus-eluting stents for the treatment of coronary artery disease: final 5-year clinical outcomes from the CREATE study

The aim of the present study was to evaluate the five-year safety and efficacy of a biodegradable polymer-coated sirolimus-eluting stent with six months dual antiplatelet therapy in daily practice. Two thousand and seventy-seven daily practice patients, exclusively treated with biodegradable polymer-coated sirolimus-eluting stents (EXCEL; JW Medical Systems, Weihai, China), were prospectively enrolled in the multicentre CREATE study. Clinical follow-up was completed in 1,982 patients (95.4%) at five-year follow-up. The rates of cardiac death, non-fatal myocardial infarction (MI), target lesion revascularisation and overall major adverse cardiac events (MACE) at five-year follow-up were 3.0%, 1.5%, 3.7% and 7.4%, respectively. The rates of definite or probable stent thrombosis (ST) at five years and definite ST from one to five years were 1.1% and 0.3%, respectively. Heart failure (hazard ratio [HR]: 3.324, 95% confidence interval [CI]: 1.729-6.391, p<0.001) and prior MI (HR: 2.664, 95% CI: 1.358-5.227, p=0.004) were independent predictors of ST. Landmark analysis of a propensity score matched patient cohort showed that patients with or without clopidogrel treatment after six months had similar clinical outcomes. The present study demonstrates satisfactory and sustained five-year clinical safety and efficacy profiles as evidenced by the low rates of MACE and ST for the EXCEL, a biodegradable polymer-based sirolimus-eluting stent, when patients were treated with six months dual antiplatelet therapy in daily practice.

Multiple Courses of Rituximab Produce Sustained Clinical and Radiographic Efficacy and Safety in Patients with Rheumatoid Arthritis and an Inadequate Response to 1 or More Tumor Necrosis Factor Inhibitors: 5-Year Data from the REFLEX Study

This 5-year observational posthoc analysis of the REFLEX study and its open-label extension assessed clinical efficacy, radiographic response, and safety of rituximab (RTX) in patients with rheumatoid arthritis (RA) who had an inadequate response to tumor necrosis factor (TNF) inhibitors. Patients in REFLEX were originally randomized to placebo (PBO) + methotrexate (MTX; PBO-randomized) or RTX + MTX (RTX-randomized). PBO-randomized patients were rescued with RTX as appropriate. Patients responding to initial RTX treatment could receive further RTX courses. For clinical efficacy and safety analyses, PBO-randomized patients were re-baselined prior to first RTX treatment and the data were pooled with RTX-randomized patient data. Efficacy outcomes 24 weeks after each course were calculated relative to first RTX pretreatment baseline. Radiographic outcomes were assessed relative to randomization baseline for both PBO-randomized and RTX-randomized groups. A total of 480 patients received ≥ 1 RTX course. At 24 weeks, American College of Rheumatology 20/50/70 responses were 62.0%, 30.8%, and 13.0%, respectively at course 1 (n = 400) and 70.3%, 41.8%, and 22.0% at course 5 (n = 91). European League Against Rheumatism good/moderate responses were 77.2% and 84.4% at courses 1 (n = 390) and 5 (n = 90). Rates of adverse events (AE), serious AE, and infections generally remained stable. Rate of progressive joint damage (PJD; change in mean Total Sharp Score) decreased over time in both PBO-randomized (n = 79) and RTX-randomized (n = 105) groups. Mean change from baseline in PJD over 5 years was greater in PBO-randomized versus RTX-randomized patients (5.51 vs 3.21). RTX re-treatment over 5 years is associated with maintained or improved efficacy, continued inhibition of PJD, and a safety profile consistent with that previously reported. A delay in initiating RTX treatment may result in increased PJD.

An alternative allergen:adjuvant formulation potentiates the immunogenicity and reduces allergenicity of a novel subcutaneous immunotherapy product for treatment of grass‐pollen allergy

Subcutaneous specific immunotherapy (SCIT) has proven sustained clinical efficacy against allergy. The recommended regimen for SCIT is a gradual updosing over a period of weeks. Commonly, in commercial products for SCIT, the specific allergen is formulated with an adjuvant, most often in the form of aluminium hydroxide (AlOH). It has been shown that allergen-specific IgG antibodies are induced as a result of successful SIT. To investigate the possibility of optimizing the formulation of AlOH-based grass-pollen allergy vaccines for SCIT in a way that allows for shorter updosing regimens while maintaining the immunogenicity of the vaccine. Mice were immunized with various concentrations of Phleum pratense (Phl p) allergen extract and AlOH or a fixed dilution of the maintenance doses of one conventional and one alternatively formulated vaccine. The kinetics of Phl p-specific IgG antibody responses in serum and spleen T cell responses were determined. Allergenicity, measured as the ability of the formulations to activate human basophils, was also determined. In addition, human T cell responses and the expression of dendritic cell surface markers after vaccine challenge in vitro were analysed. Specific IgG antibody responses were shown to depend on the AlOH concentration, but not on the allergen concentrations. The immunogenicity of the conventional formulation and the alternative formulation was shown to be similar with regard to the in vivo-induced IgG and T cell responses. In contrast, the allergenicity of the alternative formulation was significantly reduced compared with the conventional formulation. The optimization of the formulation allows for administration of a lower dose of allergen while maintaining the immunogenicity of the product and at the same time reducing allergenicity. This study indicates that the optimization of the allergen and the adjuvant formulation could benefit the safety/efficacy profile and allow for shorter updosing.

Biologic Therapies for Spondyloarthritis: What Is New?

The course of axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS), is strongly influenced by the degree of disease activity over time, which is mainly based on inflammation, and by the impairment of function, which is based on structural damage-mainly, new bone formation-and inflammation. In AS, nonsteroidal anti-inflammatory agents are currently recommended as the first choice of medical therapy, and there is also a clear role for regular exercise and physiotherapy in order to preserve and prevent loss of spinal mobility. For patients who have insufficiently responded to conventional medications, there are now four biologics approved for the treatment of patients with active AS in many countries, all directed against TNFα: infliximab, etanercept, adalimumab, and golimumab; studies with certolizumab are currently ongoing. Several studies with patients classified as nonradiographic axSpA have also shown a good response to TNF blockers; in patients with early disease and high CRP levels, the response rates were even better. Long-term studies with TNF blockers have shown declining retention rates over time but sustained clinical efficacy in the patients who remained on treatment. States of drug-free remission are rarely reached and only for relatively short periods of time. More studies including magnetic resonance imaging (MRI) are needed to further examine the lack of effect of anti-TNF treatment on radiographic progression in the axial skeleton. Whether the effect of an early intervention with biologics will prevent the development of bone growth in patients with nonradiographic axial SpA remains to be seen. Biologics other than TNF blockers are currently not recommended for the treatment of patients with axSpA, because of insufficient evidence of clinically relevant efficacy. The anti-IL-17a antibody secukinumab may be efficacious, on the basis of a proof-of-concept trial. Finally, first data on biosimilars of TNF blockers have recently been presented.

Recurrence rates and patient assessed outcomes of 0.5% 5-fluorouracil in combination with salicylic acid treating actinic keratoses

Actinic keratoses (AK) have been classified as early in situ squamous cell carcinomas and should be treated. To evaluate the clinical benefit of 5-fluorouracil 0.5%/salicylic acid 10.0% (5-FU/SA) versus 3% diclofenac/hyaluronic acid (HA) for the treatment of AK and report patients' assessments of efficacy, tolerability and practicability. Randomised, placebo-controlled, double-blind, parallel-group, multicentre trial. Patients received topical 0.5% 5-FU/SA once daily, its vehicle or diclofenac/HA twice daily for maximum of 12 weeks. Lesion recurrence rates were evaluated at 6 and 12 months after end of treatment (EOT). Patients' assessments were evaluated at 6 weeks, EOT, post-treatment (PT) visit, 6 and 12 months. At 12 months 85.8% of lesions did not recur in the 5-FU/SA group compared to 79.8% (p=0.04419) in the vehicle and 81.0% (p=0.02476) in the diclofenac/HA groups. At PT visit 93.2% patients (n=163/175) in the 5-FU/SA group rated clinical improvement as "very good" or "good" compared to vehicle (66.7%, n=62/93, p<0.0001) and diclofenac/HA (81.6%, n=142/174, p<0.0001). Local side effects (inflammation and burning) were more common with 0.5% FU/SA but in general did not lead to discontinuation of therapy. Overall, patients were satisfied with the therapy. At 12 months, there were no differences in practicability and handling between treatments. Topical 0.5% 5-FU/SA demonstrated superior sustained clinical efficacy versus diclofenac/HA with acceptable tolerability. Patient satisfaction was high.

Sa2038 Early Normalization of C-Reactive Protein (CRP) by Infliximab is a Predictive Factor of Sustained Long-Term Clinical Efficacy in Crohn's Disease

Sa2038 Early Normalization of C-Reactive Protein (CRP) by Infliximab is a Predictive Factor of Sustained Long-Term Clinical Efficacy in Crohn's Disease

Abstract 2733: LJM716: an anti-HER3 antibody that inhibits both HER2 and NRG driven tumor growth by trapping HER3 in the inactive conformation.

Abstract HER3 (ErbB3) is a member of the ErbB family of receptor tyrosine kinases (RTK). Inappropriate HER2/ HER3 dimerization as a result of HER2 or neuregulin (NRG) over-expression in cancer results in HER3 mediated activation of PI3K signaling. Consequently, HER3 is a mediator of oncogenic transformation. Although, ligand blocking HER3 antibodies inhibit growth of neuregulin driven xenograft models they are ineffective in models of HER2 amplified cancer as HER2 mediated activation of HER3 occurs in a ligand- independent manner. LJM716 is a high affinity HER3- targeted antibody selected from a Human Combinatorial Antibody Library (HuCAL) specifically for its ability to neutralize multiple modes of HER3 activation. LJM716 is a potent inhibitor of HER3/ AKT phosphorylation and proliferation in a range of HER2 amplified and NRG expressing cell lines in vitro. LJM716 induced tumor regression in Fadu (NRG expressing, HNSCC) tumor xenografts and significant tumor growth inhibition (&amp;gt;80%) in a variety of xenograft models including BT474 (HER2 amplified breast). Furthermore, the combination of LJM716 with trastuzumab, cetuximab or PI3K- targeted agents was synergistic in a panel of in vitro cell lines while the in vivo combination of LJM716 with trastuzumab or erlotinib was efficacious in BT474 and L3.3 (pancreatic) tumor xenografts respectively. To further understand the mechanism by which LJM716 inhibits multiple modes of HER3 activation we solved the crystal structure of LJM716 bound to the HER3 extra-cellular domain. This data revealed that LJM716 binds to a novel conformational epitope contained within domains 2 and 4 and appears to trap HER3 in the inactive conformation. Interestingly, LJM716 does not block NRG binding to HER3 nor does it affect the binding affinity of the HER3/ NRG interaction. LJM716 therefore possesses a novel mechanism of action; it prevents the structural rearrangements required for HER3 activation induced by either HER2 or NRG. Thus LJM716 is the first HER3 antibody to display efficacy in both HER2 and ligand driven xenograft models. Based on preclinical data, combining LJM716 with either trastuzumab, cetuximab or PI3K- targeted agents may lead to greater and more sustained clinical efficacy in ErbB driven cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2733. doi:1538-7445.AM2012-2733

Abstract 2156: Preclinical combinations of vemurafenib, a selective BRAF inhibitor, with other targeted therapies in BRAFV600E colorectal cancer models

Abstract Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human (solid) tumors, including about 10% of colorectal cancers (CRCs). Vemurafenib (RG7204, PLX4032) is a first-in-class, BRAF-specific small molecule inhibitor that dose-dependently inhibits tumor growth in BRAFV600E CRC xenografts. Despite these encouraging preclinical findings, unlike the remarkable responses observed in melanoma, single agent vemurafenib in a Phase I extension trial of 21 patients with previously treated metastatic CRC resulted in a modest 5% response rate. We therefore explored a range of combinations of vemurafenib with different novel targeted therapies including a MEK inhibitor, an AKT inhibitor, a PI3K inhibitor, an mTOR/PI3K dual inhibitor and an EGFR inhibitor in BRAFV600E CRC cell lines. The consequences of these combinations on proliferation were analyzed by MTT assay and the combined effect was determined by combination index (CI) calculated using CalcuSyn software. Western analysis and Annexin V staining were utilized to evaluate combination effects on downstream signaling events and apoptosis induction. Optimized doses of both vemurafenib and a MEK inhibitor were tested as single agents and in combination in CRC xenograft models in nude mice. Synergistic anti-proliferative effects were observed with combinations of vemurafenib and other targeted therapies in the BRAFV600E positive CRC cell lines tested. More effective signaling inhibition and apoptosis induction were observed with the combinations than either agent alone. Combining vemurafenib with a MEKi delivered greater anti-tumor activity and increased life span of animals in the LS411N CRC xenograft model. In a BRAF-mutant CRC xenograft model with inherent resistance to vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced by combining with an AKT inhibitor. These in vitro and in vivo data suggest that the administration of vemurafenib in combination with novel targeted therapies may be effective in delivering enhanced and sustained clinical antitumor efficacy in colorectal cancers harboring the BRAFV600E mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2156. doi:1538-7445.AM2012-2156