The economic impact of biosimilars in Italy : a scenario analysis

Background: the first generation of biotechnology drugs is reaching, or has already reached, the patent expiry and a large number of biosimilars is entering the Italian pharmaceutical market. The objective of the analysis was to evaluate the economic impacts of biosimilars on the national health expenditure in Italy between 2014 and 2020. Methods: Based on the information deriving from consumption per standard unit and equivalent patients, it was estimated monthly expenditure for some of the biological drugs currently available in Italy that have had or will have a patent expiry within the analysis period (infliximab, etanercept, adalimumab, insulin glargine, trastuzumab, rituximab, bevacizumab and insulin aspart). Pharmaceutical expenditure was calculated on hospital sales prices net of transparent discounts required by law and visible from the AIFA database. Three alternative scenarios have been developed based on the perceptions of a board of clinical experts, pharmacologists and pharmacoeconomists involved in the study. The experts involved analyzed the estimates of treated patients between 2014 and 2017 and reports their hypothetical biosimilar penetration during the period 2018-2020. The results were represented as the difference between the estimated expenditure in the absence of biosimilars and the estimated expenditure in the presence of biosimilars with the real or hypothetical biosimilar penetration. Results: considering the standard units dispensed for each year, the economic model estimate an annual expenditure in 2014 equal to € 1.47 billion for the molecules considered in the analysis. These estimates rise to € 1.54, € 1.50 billion and € 1.51 billion during 2015, 2016 and 2017 in the scenario without biosimilar introduction. Biosimilar introduction generates cost savings between € 3.8 million in 2015 and € 32.9 million in 2017 if compared with the scenario without. Assuming an increasing biosimilar penetration between 2018 and 2020, scenario analysis estimates a cumulative cost reduction equal to € 597 million. Conclusions: Overall, biosimilar penetration generates important cost reduction that could be re-invested in the National Health Sistem

Pathologic response and survival after neoadjuvant chemotherapy with or without pertuzumab in patients with HER2-positive breast cancer: the Neopearl nationwide collaborative study

PurposeClinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with early-stage HER-2 positive breast cancer. To date, limited studies have examined comparative outcomes of neoadjuvant pertuzumab in real-world setting. The Neopearl study aimed to assess comparative real-life efficacy and safety of neoadjuvant pertuzumab for these patients.MethodsWe conducted a nationwide retrospective analysis involving 17 oncology facilities with a certified multidisciplinary breast cancer treatment committee. We identified patients with HER-2 positive stage II-III breast cancer treated with neoadjuvant chemotherapy based on trastuzumab and taxanes with or without pertuzumab. All patients underwent breast surgery and received a comprehensive cardiologic evaluation at baseline and after neoadjuvant treatment. Patients who received the combination of pertuzumab, trastuzumab, and chemotherapy constituted case cohort (PTCT), whereas those treated with trastuzumab and chemotherapy accounted for control cohort (TCT). The pCR rate and 5-year event free survival (EFS) were the primary outcomes. Secondary end-points were rates of conversion from planned modified radical mastectomy (MRM) to breast conservation surgery (BCS) and cardiotoxicities.ResultsFrom March 2014 to April 2021, we included 271 patients, 134 (49%) and 137 (51%) in TCT and PTCT cohort, respectively. Positive axillary lymph nodes and stage III were more frequent in PTCT cohort. The pCR rate was significantly increased in patients who received pertuzumab (49% vs 62%; OR 1.74, 95%CI 1.04-2.89) and with HER-2 enriched subtypes (16% vs 85%; OR 2.94, 95%CI 1.60-5.41). After a median follow-up of 5 years, the 5-year EFS was significantly prolonged only in patients treated with pertuzumab (81% vs 93%; HR 2.22, 95%CI 1.03-4.79). The same analysis performed on propensity score matched population showed concordant results. On univariate analysis, only patients with positive lymph nodes were found to benefit from pertuzumab for both pCR and 5-year EFS. The rates of conversion from MRM to BCS and cardiologic toxicities did not differ between the cohorts.ConclusionOur findings support previous data on improved outcomes with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy. This benefit seems to be more significant in patients with clinically positive lymph nodes

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: A real-world experience

We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-na\uc3\uafve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-na\uc3\uafve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-na\uc3\uafve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p < 0.0001), while overall survival was positively affected by lower ECOG PS (p < 0.0001), absence of brain metastases (p 0.05), and clinical benefit (p < 0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order

Percezione della numerosita' e del tempo in bambini nati pretermine

L’obiettivo del presente studio è stato quello di validare test per la percezione visiva di alto livello, quali la percezione del movimento, della numerosità e del tempo su un campione normativo (in età scolare) per poi applicarli a bambini nati pretermine di alto grado in assenza di lesioni cerebrali significative. Questi compiti sono tutti processati a livello della corteccia cerebrale parietale che sembra essere un’area particolarmente “a rischio” nei soggetti nati pretermine, anche in assenza di lesioni evidenti agli ultrasuoni o alla risonanza magnetica. La percezione del movimento è elaborata dalla corteccia parietale posteriore e l’informazione visiva del movimento è veicolata dalla via visiva dorsale che collega l’area visiva primaria con la corteccia parietale posteriore. La sede della percezione della quantità numerica coinvolge anch’essa la regione parietale, ed è localizzata in particolare a livello del “segmento orizzontale del solco intraparietale” (hIPS), sia nell’emisfero destro che in quello sinistro. Infine, la localizzazione della percezione del tempo appare ancora come un interrogativo a cui non è stata trovata una risposta definitiva. Anche in questo caso sembra essere presente un coinvolgimento delle aree cerebrali dorsali. Proprio queste regioni cerebrali sembrano essere delle strutture particolarmente vulnerabili nei soggetti nati pretermine, anche in quei bambini che non presentano un danno cerebrale evidente. Nel nostro studio abbiamo valutato, mediante test di psicofisica, la percezione visiva del movimento, della numerosità e del tempo in un gruppo costituito da 54 bambini nati a termine con un rendimento scolastico nella norma ed in un gruppo costituito da 8 bambini nati pretermine, con un’età gestazionale compresa tra le 24 e le 34 settimane

PANDAS and PANS: Clinical, Neuropsychological, and Biological Characterization of a Monocentric Series of Patients and Proposal for a Diagnostic Protocol

Whether PANS (pediatric acute-onset neuropsychiatric syndrome) and PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) represent true clinical entities is debated and data for a characteristic phenotype are still controversial. In this study, we aim to characterize clinical, neuropsychological, and biochemical aspects in a sample of PANS and PANDAS patients. Methods: Patients fulfilling a clinical diagnosis of PANS or PANDAS from 2014 to 2017 were enrolled. Neurological and psychiatric examination and biochemical and instrumental assessment results were collected. A neuropsychological battery was administered. For comparison purposes, a control group of patients with Sydenham's chorea (SC) was evaluated. Descriptive and comparative statistical analyses were performed. Results: Seven subjects received a diagnosis of PANS, 12 of PANDAS, and 11 of SC. Clinical presentation of PANS children showed statistically significant differences compared with both PANDAS and SC, in particular, with the presence of obsessive symptoms, behavioral regression, and somatic symptoms in the first group. Moreover, all PANS patients showed some neuropsychological deficits in visual-motor abilities, short- and long-term memory, and processing speed. Conclusions: Our experience confirms that patients with PANS had a complex clinical presentation and a compromised neuropsychological profile with respect to patients with PANDAS or SC. However, the absence of biological markers or instrumental alterations made the diagnosis of the two entities, PANS and PANDAS, a matter of exclusion. For these reasons, we propose a pilot diagnostic protocol that (when applied in a prospective manner) will allow comparison with similar childhood-onset neuropsychiatric disorders, such as obsessive-compulsive or tic disorders, and efficacy evaluation of different therapeutic approaches

Time to first tumor progression as outcome predictor of a second trasuzumab-based therapy beyond progression in HER-2 positive metastatic breast cancer

In a previous analysis performed on a cohort of 37 HER-2 positive metastatic breast cancer (MBC) patients treated with trastuzumab beyond progression, we found that a second trastuzumab-based therapy is associated with a considerable response rate and preserved time to progression as compared with a first trastuzumab-based therapy. In the present study, we extended the analysis to a total of 69 patients treated in four different italian Institutions, also trying to identify clinical predictors of sensitivity to a second trastuzumab-based therapy beyond progression. Efficacy results on the overall population confirmed that a second trastuzumab-based therapy beyond progression is an active regimen (27.5% of responses and 6.5 months of time to progression, respectively). Median time to progression to the first trastuzumab therapy (TTP1) identified two groups of patients with different sensitivity to trastuzumab beyond progression (group A, TTP1 >or= 8 months and group B, TTP1 < 8 months) in terms of time to second progression and post-progression survival (group A versus group B showed respectively a time to second progression of 7.6 versus 4.7 months, p = 0.05, and a post-progression survival of 31.7 months versus 21.8 months, p = 0.04). In the multivariate analysis, only TTP1 was a predictor of time to second progression and post-progression survival. Despite the recent approval of lapatinib plus capecitabine for trastuzumab-progressing patients, it is still reasonable to offer trastuzumab beyond progression to HER-2 positive MBC patients, because these data confirm the potential utility of such a conduct. In the clinic, time to first tumor progression may represent a useful tool to identify patients who are more likely to benefit from trastuzumab beyond progression

Optic Atrophy and Generalized Chorea in a Patient Harboring an OPA10/RTN4IP1 Pathogenic Variant

RTN4IP1 pathogenic variants (OPA10 syndrome) have been described in patients with early-onset recessive optic neuropathy and recently associated with a broader clinical spectrum, from isolated optic neuropathy to severe encephalopathies with epilepsy. Here we present a case of a patient with a complex clinical picture characterized by bilateral optic nerve atrophy, horizontal nystagmus, myopia, mild intellectual disability, generalized chorea, isolated small subependymal heterotopia, and asynchronous self-resolving midbrain MRI (magnetic resonance imaging) lesions. By using massive gene sequencing, we identified in this patient the c.308G>A (p.Arg103His) homozygous pathogenic variant in the RTN4IP1 gene. Complex movement disorders and relapsing-remitting neuroradiological lesions have not been previously reported in this condition. Our case expands the clinical spectrum of OPA10 syndrome and opens new opportunities for the molecular diagnosis

CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC

PONDx: real-life utilization and decision impact of the 21-gene assay on clinical practice in Italy

Clinicopathological prognostic features have limited value to identify with precision newly diagnosed patients with hormone receptor (HR)-positive, HER2-negative breast cancer (BC), who would benefit from chemotherapy (CT) in addition to adjuvant hormonal therapy (HT). The 21-gene Oncotype DX Breast Recurrence Score\uae (RS) assay has been demonstrated to predict CT benefit, hence supporting personalized decisions on adjuvant CT. The multicenter, prospective, observational study PONDx investigated the real-life use of RS\uae results in Italy and its impact on treatment decisions. Physicians' treatment recommendations (HT\u2009\ub1\u2009CT) were documented before and after availability of RS results, and changes in recommendations were determined. In the HR+ HER2- early BC population studied (N\u2009=\u20091738), physicians recommended CT\u2009+\u2009HT in 49% of patients pre-RS. RS-guided treatment decisions resulted in 36% reduction of CT recommendations. PONDx confirms that RS results provide clinically relevant information for CT recommendation in early-stage BC, resulting in a reduction of more than a third of CT use