HER2 in gastric adenocarcinoma: where do we stand today?

Aim: HER2 is a proto-oncogene expressed in 10–30% of gastric adenocarcinomas and is an ideal target for inhibition in malignancy with high recurrence and dismal survival rates. Materials & methods: A systematic search was conducted via PubMed, Google Scholar and the clinicaltrials.gov database to report the results of ongoing and past studies investigating HER2- inhibitors in gastric cancer. Results: Twenty-five studies were included; ToGA trial is the pivotal trial approving the use of trastuzumab in metastatic gastric cancer, followed by more studies investigating other HER2- inhibitors in this setting, as well as in local and locoregional malignancy. Conclusion: Anti-HER2 molecules are proving efficacy and safety in gastric cancer; the evidence is growing and association with other cancer agents is under investigation.

Safety of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis (HLH): Relationship to Treatment Exposure

Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which interferon gamma (IFNγ) is considered a key cytokine. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only curative therapy so far. Current conventional therapy for HLH is based on immunochemotherapies, namely etoposide and glucocorticoids; this treatment, however, is associated with opportunistic infections and severe myelotoxicity. Emapalumab, a fully human, anti-IFNγ monoclonal antibody that neutralizes IFNγ, is the only FDA-approved treatment for primary HLH patients with refractory, recurrent or progressive disease, or intolerance to conventional HLH therapy. In patients with primary HLH, the pharmacokinetics (PK) of emapalumab is highly influenced by body weight, and also by IFNγ production due to target-mediated drug disposition. In the pivotal trial (Locatelli et al NEJM 2020;382:1811-22), treatment of primary HLH patients with emapalumab was associated with a favorable safety and tolerability profile, with no unexpected safety concerns. Objective: To describe prespecified exploratory exposure-safety analyses that were performed on data from patients with primary HLH receiving emapalumab in the pivotal trial. Methods: Data from a multicenter, open-label, pivotal phase 2/3 study (NCT01818492) and its long-term follow-up study (NCT02069899) were included in this analysis. The safety of emapalumab was assessed in 34 patients (27 treatment experienced; 7 treatment naïve) with active primary HLH. Emapalumab was initiated at a dose of 1 mg/kg administered intravenously every 3 days, on a background of dexamethasone 5-10 mg/kg/day. Subsequent doses could be increased to 3, 6 and 10 mg/kg, if required, based on predefined laboratory and clinical response parameters. Treatment duration was up to 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to time of transplantation if needed. Exploratory graphical analyses were performed to determine the incidence of adverse events (AEs) as a function of the exposure parameters at the time of the AE. The relationship between emapalumab exposure and the incidence of treatment-emergent AEs, serious AEs, severe AEs, and AEs related to infections and infusion-related reactions (IRRs) was explored by logistic regression analyses. Selected parameters of renal (creatine clearance [CRCL]) and liver (total bilirubin [TBIL] and alanine aminotransferase [ALT]) function were explored graphically. Exposure parameters were obtained from the population PK/pharmacodynamic (PD) data file that was used for the population PK and PK/PD analyses. Observed individual concentration-time data were used to derive the individual exposure parameters as a function of time. The analyses considered AEs that emerged after the start of the first infusion until last infusion and prior to initiation of HSCT conditioning. Results: Exploratory graphical exposure-safety analyses did not reveal any apparent relationship between the number of AEs and exposure to emapalumab. Logistic exposure-safety regression analyses using the observed exposure to emapalumab at the time of an AE for patients experiencing an event and the highest observed exposure to emapalumab for those patients experiencing no AE, indicated that the incidence of AEs did not increase as a function of increasing emapalumab concentration. In fact, a statistically significant decrease in the incidence of severe AEs and the incidence of AEs related to IRRs was observed. No multivariate effects were identified in the multivariate regression analyses. No clear trend was observed for TBIL, ALT or CRCL as a function of the duration of emapalumab treatment. The exposure of emapalumab did not appear to influence the levels of TBIL, ALT or CRCL in individual patients during treatment. Conclusion: In this study, the exposure-safety evaluation did not reveal any significant relationships between exposure to emapalumab and observed incidence rates of AEs, serious AEs, infections, or IRRs. These findings support the primary evidence of a favorable benefit-risk profile of emapalumab across the dose range used in this fragile patient population. Disclosures Jordan: Sobi: Consultancy. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Jacqmin: Sobi: Consultancy. Laveille: Sobi: Consultancy. Snoeck: Sobi: Consultancy. de Min: Sobi: Consultancy, Ended employment in the past 24 months.

Demographic characteristics of the 1902 transthyretin amyloid cardiomyopathy patients treated by tafamidis through the French early access program

Background Transthyretin amyloidosis (ATTR) is a rare and serious, systemic disease characterized by deposits of amyloid fibrils in various tissues and organs. Tafamidis meglumine is a potent and selective stabilizer of TTR, indicated since 2011 in the treatment of neurological forms of the disease. The French “Agence Nationale de Sécurité du Médicament et des produits de santé” (ANSM) granted a temporary recommendation for use (RTU) on November 28th 2018, based on ATTR-ACT, the pivotal trial results, and designed to enable use of tafamidis meglumine in ATTR cardiomyopathy (ATTR-CM) patients with NYHA I, II and III before marketing authorization. This RTU has been a unique opportunity in France to collect real world data of ATTR-CM patients treated by tafamidis meglumine. Objective We aimed to describe the characteristics of ATTR-CM patient treated by tafamidis in the setting of the RTU, over 2 years from November 28th 2018 to November 27th 2020. Methods Demographic and clinical data about the diagnosis pathway of patients included in the RTU were prospectively collected using questionnaires, as requested by ANSM to be completed by physicians at the time of tafamidis prescription. A second version of the inclusion form, introduced in May 2020, has allowed collection of additional clinical information. Results Overall, 1902 ATTR-CM patients have been included by 189 physicians from 107 centers. Nine centers included each at least 50 patients, accounting for 1092, or 57.4% of all patients. The median age of the patients was 82 years (IQR=9 years), 82% were male, and, 12.4%, 58.8% and 28.7% of patients had a NYHA class of I, II and III, respectively. For almost all patients, the diagnosis of restrictive/infiltrative heart failure was based on heart MRI and/or echocardiography (98.5%; among the 601 patients included from May 2020 28.8% had both exams, 69.7% echo only and 1.6% MRI only), the infiltrative nature of the cardiomyopathy had been confirmed by bone scintigraphy (99.3%), and the absence of light chains had been confirmed by protein electrophoresis or Bence Jones proteinuria (96.6%). Genetic test was performed in 1205 patients (69.4%). Out of the 884 patients who had a genetic test result available at the time of initial prescription, 762 (86.2%) were affected with the wild-type form and 122 (13.8%) with the hereditary form. Among the 601 patients included from May 2020, a hospitalization for cardiovascular condition within the 6 months preceding tafamidis initiation was reported for 22.3% of them, and tafamidis was initiated within 12 months after diagnosis for 92% of them (only 8% initiated the treatment beyond that period). Conclusion The RTU program has provided 1902 ATTR-CM patients with early access to tafamidis over 24 months, in France. Overall, as compared to patients included in ATTR-ACT, the pivotal trial, RTU patients were older, the proportion of wild-type was slightly higher, and NYHA distributions were similar. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Early access program sponsored by Pfizer

Stroke in hemodialysis patients randomized to different intravenous iron strategies: a prespecified analysis from the PIVOTAL trial

Background: People with kidney failure treated with hemodialysis (HD) are at increased risk of stroke compared to similarly aged people with normal kidney function. One concern is that treatment of renal anemia might increase stroke risk. We studied risk factors for stroke in a prespecified secondary analysis of a randomized controlled trial of intravenous iron treatment strategies in HD. Methods: We analyzed data from the Proactive IV IrOn Therapy in HaemodiALysis Patients (PIVOTAL) trial focusing on variables associated with risk of stroke. The trial randomized 2,141 adults, who had started hemodialysis <12 months earlier and who were receiving an erythropoiesis-stimulating agent (ESA), to high-dose IV iron administered proactively or low-dose IV iron administered reactively in a 1:1 ratio. Possible stroke events were independently adjudicated. We performed analyses to identify variables associated with stroke during follow-up and assessed survival following stroke. Results: During a median 2.1 years follow-up, 69 (3.2%) patients experienced a first post randomization stroke. 57 (82.6%) were ischemic strokes and 12 (17.4%) hemorrhagic strokes. There were 34 post randomization strokes in the proactive arm and 35 in the reactive arm (hazard ratio (95% confidence interval): 0.90 (0.56, 1.44), p=0.66). In multivariable models, female gender, diabetes, history of prior stroke at baseline, higher baseline systolic blood pressure, lower serum albumin and higher C-reactive protein were independently associated with stroke events during follow up. Hemoglobin, total iron or ESA dose were not associated with risk of stroke. 58% of patients with a stroke event died during follow-up, compared to 23% without a stroke. Conclusions: In hemodialysis patients, stroke risk is broadly associated with risk factors previously described to increase cardiovascular risk in this population. Proactive intravenous iron does not increase stroke risk.