31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Letrozole: A Pharmacoeconomic Review of its Use in Postmenopausal Women with Breast Cancer

Letrozole (Femara(R)), an aromatase inhibitor that blocks estrogen synthesis by inhibiting the final step of the estrogen biosynthetic pathway, is approved for use in a wide range of breast cancer settings. Randomised clinical trials in postmenopausal women with hormone-responsive early-stage breast cancer have demonstrated that, as adjuvant therapy, letrozole has greater efficacy than tamoxifen. It is also more effective than placebo as extended adjuvant therapy after completion of tamoxifen therapy in these patients. In women with hormone-responsive advanced breast cancer, letrozole is superior to tamoxifen in prolonging the time to disease progression and time to treatment failure in a first-line setting, and is at least as effective as anastrozole and more effective than megestrol for some endpoints (in one of two trials) in a second-line setting. Letrozole is generally well tolerated, and in a health-related quality-of-life analysis from a large clinical trial, patient well-being with letrozole as extended adjuvant therapy did not differ from that with placebo. Modelled analyses from the UK and the US suggest that, in postmenopausal women with hormone-receptor-positive early-stage breast cancer, letrozole is likely to be a cost-effective alternative to tamoxifen as adjuvant therapy; moreover, using letrozole as extended adjuvant therapy after tamoxifen, rather than no further treatment, is also a cost-effective treatment strategy. Sensitivity analyses have shown these results to be robust. In terms of direct healthcare costs, pharmacoeconomic models suggest that letrozole is a cost-effective alternative to tamoxifen as first-line therapy in postmenopausal women with hormone-responsive advanced breast cancer from the perspectives of the UK NHS, the Canadian and Italian public healthcare systems and the Japanese national health insurance system. Incremental costs per QALY or progression-free year gained over tamoxifen were well within the recommended limits for acceptability of new agents that are more effective and more expensive than existing therapies in the UK, Japan and Canada. Modelled analyses from the UK and Canada have also suggested that letrozole is cost effective as second-line therapy for advanced breast cancer in postmenopausal women who have disease progression following anti-estrogen therapy. In conclusion, letrozole is an effective and well tolerated treatment for postmenopausal women with early-stage or advanced hormone-responsive breast cancer. Pharmacoeconomic analyses from UK and North American perspectives support the use of letrozole in hormone-responsive early-stage breast cancer in both the adjuvant and extended adjuvant settings. In addition, other modelled analyses conducted in a variety of healthcare systems across different countries consistently suggest that letrozole is cost effective in advanced treatment settings.Adis-Drug-Evaluations, Breast-cancer, Letrozole

Bimatoprost: A Pharmacoeconomic Review of its Use in Open-Angle Glaucoma and Ocular Hypertension

Bimatoprost (Lumigan(R)) is a prostamide analogue used for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. In comparative clinical trials of up to 1 year in duration, administration of 0.03% bimatoprost ophthalmic solution once daily was more effective than 0.5% timolol twice daily and at least as effective as the prostaglandin analogues 0.005% latanoprost and 0.004% travoprost once daily in terms of reducing IOP and/or achieving target IOP levels. Bimatoprost was also more effective than twice-daily administration of 0.5%/2% timolol/dorzolamide in patients refractory to topical timolol therapy. Although generally well tolerated, bimatoprost is associated with a higher incidence of conjunctival hyperaemia than latanoprost, timolol or the combination of timolol and dorzolamide. Three fully published modelled cost-effectiveness analyses of bimatoprost evaluating cost per treatment success in patients with glaucoma or ocular hypertension have been conducted in the US. The analyses incorporated results of randomised, multicentre clinical trials and used a 1-year time horizon. In the treatment algorithm used in the models, patients not achieving target IOP levels with bimatoprost or comparator required additional medical visits and adjunctive therapy. Bimatoprost was associated with lower costs per treatment success than latanoprost, timolol or timolol/dorzolamide across a range of clinically relevant target IOPs. Results were sensitive to changes in treatment success rates and/or drug acquisition costs. Along with the inherent limitations of economic models, other possible criticisms of the analyses are the use of selected IOP data, and the lack of inclusion of costs associated with conjunctival hyperaemia or other adverse effects of therapy. Various other cost-effectiveness analyses of bimatoprost are available, primarily as abstracts and/or posters. In general, most of these studies have also been favourable for bimatoprost, despite having been conducted in different countries and/or from different perspectives. In conclusion, in patients with open-angle glaucoma or ocular hypertension, bimatoprost is an effective and generally well tolerated therapeutic option, albeit with a relatively high incidence of conjunctival hyperaemia. Although results of modelled cost-effectiveness analyses should be interpreted with due consideration of the limitations of the studies, available pharmacoeconomic data generally support the use of bimatoprost as a cost-effective treatment in this patient population.Adis-Drug-Evaluations, Bimatoprost, Dorzolamide/timolol, Glaucoma, Latanoprost, Ocular-hypertension, Timolol, Travoprost

Spotlight on the Pharmacoeconomics of Candesartan Cilexetil in Chronic Heart Failure and Hypertension

The addition of candesartan cilexetil (Atacand(R), Amias(R), Blopress(R), Kenzen(R), Ratacand(R)) to standard therapy for chronic heart failure (CHF) provided important clinical benefits at little or no additional cost in France, Germany, and the UK, according to a detailed economic analysis focusing on major cardiovascular events and prospectively collected resource-use data from the CHARM-Added and CHARM-Alternative trials in patients with CHF and left ventricular (LV) systolic dysfunction. Results of a corresponding cost-effectiveness analysis showed that candesartan cilexetil was either dominant over placebo or was associated with small incremental costs per life-year gained, depending on the country and whether individual trial or pooled data were used. Preliminary data from a US cost-effectiveness analysis based on CHARM data also showed favorable results for candesartan cilexetil. Two cost-effectiveness analyses of candesartan cilexetil in hypertension have been published, both conducted in Sweden. Data from the SCOPE trial in elderly patients with hypertension, which showed a significant reduction in nonfatal stroke with candesartan cilexetil-based therapy versus non-candesartan cilexetil-based treatment, were incorporated into a Markov model and an incremental cost-effectiveness ratio of _12_824 per quality-adjusted life-year (QALY) gained was calculated (2001 value). Another modelled cost-effectiveness analysis of candesartan cilexetil was based on the ALPINE trial, in which the incidence of new-onset diabetes was significantly lower in patients with newly diagnosed hypertension who were randomized to candesartan cilexetil (with or without felodipine) than among those who received hydrochlorothiazide (with or without atenolol). Although candesartan cilexetil was dominant over hydrochlorothiazide, the ALPINE cost-effectiveness analysis relied on a small number of clinical events and did not evaluate the incremental cost of candesartan cilexetil per life-year or QALY gained. In conclusion, despite some inherent limitations, economic analyses incorporating CHARM data and conducted primarily in Europe have shown that candesartan cilexetil appears to be cost effective when added to standard CHF treatment in patients with CHF and compromized LV systolic function. The use of candesartan cilexetil as part of antihypertensive therapy in elderly patients with elevated blood pressure was also deemed to be cost effective in a Swedish analysis, primarily resulting from a reduced risk of nonfatal stroke (as shown in the SCOPE study); however, the generalizability of results to other contexts has not been established. Cost-effectiveness analyses comparing candesartan cilexetil with ACE inhibitors or other angiotensin receptor blockers in CHF or hypertension are lacking, and results reported for candesartan cilexetil in a Swedish economic analysis of ALPINE data focusing on outcomes for diabetes require confirmation and extension.Adis-Spotlights, Candesartan-cilexetil, Chronic-heart-failure, Hypertension, Pharmacoeconomics

Prevention and Treatment of Osteoporosis in Postmenopausal Women: Defining the Role of Alendronate

Postmenopausal osteoporosis is characterized by an increased rate of bone turnover accompanied by a reduction in bone mineral density (BMD) that results in an increased risk of fracture, especially of the vertebrae, hip, or wrist. Alendronate (Fosamax(R), Fosamax Once-Weekly(R)), an oral bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism, is a first-line therapy for the management of postmenopausal women with, or at risk of developing, osteoporosis. Alendronate produces sustained increases in BMD and reductions in bone turnover from baseline, and reduces the risk of vertebral, hip, wrist, and other fractures in women with postmenopausal osteoporosis. It also prevents bone loss, and reduces the risk of radiographic or clinical vertebral fracture in postmenopausal osteopenia. Provided administration instructions are followed, alendronate is generally well tolerated. Adverse events are usually transient and are associated with the upper gastrointestinal tract (abdominal pain, nausea, acid regurgitation, dyspepsia); moreover, the incidence of these adverse events with alendronate was similar to those with placebo. More serious events (esophagitis, gastric or duodenal ulceration or bleeding) are uncommon. Once-weekly formulations are as effective and as well tolerated as once-daily alendronate in postmenopausal women. Pharmacoeconomic evaluations suggest that alendronate is a viable treatment option in postmenopausal osteoporosis. The reduction in fracture-related healthcare utilization seen with alendronate results in decreased direct costs, including inpatient or long-term care. Markov state-transition models suggest that this could at least partially offset costs incurred with alendronate therapy. Treatment of women with osteoporosis aged 65 years and older, and postmenopausal women with a previous osteoporotic fracture, are cost-effective strategies. Alendronate is also likely to increase quality-adjusted life-years in any postmenopausal women with osteoporosis. In conclusion, clinical and economic data support the use of alendronate in postmenopausal osteoporosis. It effectively reduces bone turnover, increases BMD, and reduces the risk of osteoporotic fracture in postmenopausal women with established osteoporosis, especially older women with a higher risk of fracture. Although its cost effectiveness in postmenopausal women with osteopenia is not clearly established, alendronate is clinically effective in these patients. In addition, it is generally well tolerated when taken as recommended. Consequently, alendronate should be considered a therapy of choice in the prevention and treatment of osteoporosis in postmenopausal women.Adis-Drug-Evaluations, Alendronic-acid, Osteoporosis, Postmenopausal-osteoporosis

Management of Overactive Bladder: Defining the Role of Extended-Release Tolterodine

Overactive bladder (OAB), a common condition affecting ~=16-17% of adult men and women in Europe and the US, is characterized by symptoms of urinary urgency, with or without urge urinary incontinence (UUI), usually with micturition frequency and nocturia. OAB is thought to result from abnormal, involuntary detrusor contractions during bladder filling. The symptoms of OAB have a considerable adverse effect on quality of life (QOL) in affected patients, and are associated with an increased risk of comorbidities, and increased direct and indirect costs. Management of OAB focuses on symptom improvement, and includes nonpharmacologic and pharmacologic therapy. Extended-release tolterodine (Detrusitol(R) XL, Detrol LA(R), Detrusitol SR(R), Detrusitol(R) Neo, Detrusitol(R) Retard, Unidet(TM)) is an oral, once-daily, nonselective, competitive antimuscarinic drug. It acts on smooth muscle motor efferent pathways, including bladder detrusor muscle, and is a first-line therapy for OAB. Extended-release tolterodine is at least as effective as immediate-release tolterodine in improving UUI and other symptoms associated with OAB (including urinary frequency, urgency symptoms, voided volume/micturition), and in improving health-related QOL. It has similar efficacy to oral immediate- or extended-release oxybutynin, or transdermal oxybutynin. The likelihood of dry mouth, the most bothersome anticholinergic adverse effect associated with antimuscarinic drugs, is significantly reduced with extended-release tolterodine in patients with OAB compared with immediate-release tolterodine. Dry mouth also occurs significantly less frequently with extended-release tolterodine than with immediate- or extended-release oxybutynin. The incidence of dry mouth with extended-release tolterodine or transdermal oxybutynin is similar. In economic models, extended-release tolterodine is more cost effective in patients with OAB than no treatment, or treatment with immediate-release tolterodine or immediate-release oxybutynin, and is as cost effective as extended-release oxybutynin. In conclusion, clinical and economic data support the use of extended-release tolterodine as a first-line therapy in the management of adult patients with OAB. It is at least as effective as immediate-release tolterodine, but is associated with a lower incidence of dry mouth. Moreover, the convenient once-daily administration regimen offers the potential for good compliance. The favorable efficacy and tolerability profile of extended-release tolterodine has been demonstrated for up to 12 months. Extended-release tolterodine is as effective as oral immediate- or extended-release oxybutynin, but is better tolerated in terms of dry mouth. It has similar efficacy and tolerability (including dry mouth) to transdermal oxybutynin. Extended-release tolterodine is, therefore, a valuable first-line therapy in the treatment of OAB.Adis-Drug-Evaluations, Overactive-bladder, Tolterodine

Management of Genital Herpes: Defining the Role of Valaciclovir

Genital herpes simplex virus (HSV) infection has substantial economic and quality-of-life consequences; not least is the risk of transmission to the fetus/infant during parturition with the subsequent effects on the family, society as a whole and healthcare providers. While general screening programs for HSV infection are not cost effective, screening of susceptible subgroups may be acceptable in some circumstances (e.g. immunocompromised patients, presumed discordant heterosexual couples, pregnant women) despite the high costs involved. First-line options for treatment and suppression of genital herpes in Europe and the US include valaciclovir, aciclovir and famciclovir. The established efficacy of valaciclovir, along with its potential for once-daily administration in many patients (versus administration up to five times daily for aciclovir), its positive effect on quality of life, its suppressive efficacy in late pregnancy and its proven reduction of viral transmission between heterosexual discordant partners support the drug's position as a first-line therapy and suppression option in patients with genital herpes. However, the high acquisition costs compared with aciclovir will affect formulary decisions in some patients, and the favored niche for this drug, at least until evidence of prevention of transmission is demonstrated for other antivirals, would seem to be in the prevention of transmission in susceptible subgroups such as couples discordant for HSV infection (especially male-positive/female-negative couples who are planning a pregnancy), and the treatment and suppression of genital herpes in patients particularly receptive to once-daily administration. Potential disease management programs for genital herpes would thus need to balance the high costs of HSV screening and the relatively high acquisition costs of valaciclovir against the convenience of once-daily administration, the improved quality of life and the proven potential for reduced viral transmission to susceptible partners (with potential for downstream reductions in the overall socioeconomic burden of the disease) associated with oral valaciclovir.Adis-Drug-Evaluations, Herpes-genitalis, Valaciclovir