Long-term Safety Analysis Research Articles

Long-term safety of mepolizumab for up to ∼10 years in patients with severe asthma: open-label extension study

Objectives Long-term safety monitoring of mepolizumab is necessary to support real-world use for the treatment of severe asthma. This Long-Term Access Program assessed the safety and benefit:risk of mepolizumab in pediatric, adolescent, and adult patients with severe asthma. Materials and methods This was a multicenter, Phase IIIb safety, open-label extension study of multiple prior studies assessing mepolizumab in addition to standard of care (Aug 2015 − Aug 2022). Adults/adolescents (≥12 years of age) received mepolizumab 100 mg subcutaneously (SC) every 4 weeks until mepolizumab was commercialized. Pediatric patients (6–11 years of age) received mepolizumab 40 mg or 100 mg SC (bodyweight <40 or ≥40 kg, respectively) every 4 weeks. Safety was assessed every 4 weeks and benefit:risk every 12 weeks. Results Of the 514 patients enrolled, 57% were female and the mean age was 51.1 (standard deviation: 14.9) years; 24 (5%) patients were 6–17 years of age. Total cumulative mepolizumab exposure across all mepolizumab studies included in this analysis was 1500.59 patient-years; median exposure was 2.03 (range, 0.08 to 9.97) years. Overall, 37 (7%) patients experienced on-treatment serious adverse events (SAEs): 34/502 (7%) in the 100 mg SC group and 3/7 (43%) in the 40 mg SC pediatric group. Two patients experienced SAEs considered to be treatment-related by the investigator. Infections were the most common SAEs of special interest (9 [2%] patients). Physician-assessed benefit:risk of mepolizumab supported continued treatment over the study period. Conclusions This long-term safety analysis of mepolizumab was consistent with previous reports, with no emerging safety concerns; most patients had a favorable benefit:risk up to ∼10 years. Clinical trial identifier NCT00244686 (GSK ID 201956)

Long-term pooled safety analysis of tislelizumab as monotherapy or in combination with chemotherapy in patients with advanced cancers.

e14617 Background: The PD-1 inhibitor tislelizumab (TIS) has demonstrated efficacy and tolerability in patients (pts) with advanced cancers. To evaluate long-term safety of TIS as monotherapy (mono) or in combination (combo) with chemotherapy in pts with advanced gastrointestinal (GI) and lung cancers, data were pooled from 8 pivotal phase III studies conducted between 2017 and 2023. Methods: 2636 adult pts with GI (n=1415) or lung (n=1221) cancers and an ECOG PS of 0-1, who received ≥1 dose of study drug, were included. Endpoints included immune-mediated adverse events (imAEs) by tumor type, treatment (Tx) duration, and race. Early and delayed imAEs, defined as occurring within 1 year (yr) and &gt;1 yr after starting TIS, respectively, were also evaluated. Results: Median (range) Tx duration in the GI and lung cancer studies was 4.9 (0.1-50.4) and 6.2 (0.2-44.9) months, respectively, with 20.9% and 29.6% of pts, respectively, having ≥1 yr exposure. Most pts were Asian (GI mono: 76.4%; GI combo: 74.9%; lung mono: 79.2%; lung combo: 100%). ImAEs occurred in 32.5% of pts in the GI mono and combo studies (Table); most were low grade, with grade ≥3 imAEs reported in 6.2% (mono) and 8.2% (combo) of pts. Incidence of imAEs in the mono and combo lung studies, respectively, was 34.3% and 43.7% (grade ≥3: 6.4% and 9.6%). ImAE incidence was comparable between Asian and White race subgroups, respectively, in the GI mono (33.6% vs 29.5%), GI combo (34.9% vs 23.9%), and lung mono (35.5% vs 32.3%) studies. Most imAEs occurred within 1 yr of starting TIS in the GI (mono: 32.0%; combo: 32.4%) and lung (mono: 34.1%; combo: 42.2%) studies. Delayed imAEs occurred less often than early imAEs; of pts still on Tx or in study follow-up 1 yr after initial Tx, 54/757 (7.1%) in GI studies and 86/804 (10.7%) in lung studies experienced a delayed imAE. Frequently reported imAEs were consistent, regardless of time of onset (early vs delayed). Conclusions: This long-term, retrospective, pooled analysis supports TIS as a tolerable Tx for pts with advanced GI and lung cancers. Delayed imAEs were relatively infrequent and were consistent with the established safety profile of TIS. Clinical trial information: NCT03412773 ; NCT03430843 ; NCT03358875 ; NCT03663205 ; NCT03777657 ; NCT03783442 ; NCT03594747 ; NCT04005716 . [Table: see text]

RETRACTED ARTICLE: Long-Term Safety Analysis of the BBV152 Coronavirus Vaccine in Adolescents and Adults: Findings from a 1-Year Prospective Study in North India.

Evidence on the long-term safety of COVID-19 vaccines is scarce. Here, in continuation of our previously published results on short-term safety, we provide data on the long-term safety of the BBV152 vaccine in adolescents and adults. This was a prospective observational study conducted from January 2022 to August 2023. Adolescents and adults receiving the BBV152 vaccine were interviewed telephonically about long-term adverse events of special interest (AESIs) after 1 year of vaccination. Risk factors of AESIs and AESIs persistent for at least 1 month were identified. Out of 1024 individuals enrolled, 635 adolescents and 291 adults could be contacted during the 1-year follow-up. Viral upper respiratory tract infections were reported by 304 (47.9%) adolescents and 124 (42.6%) adults in this period. New-onset skin and subcutaneous disorders (10.5%), general disorders (10.2%), and nervous system disorders (4.7%) were the common AESIs in adolescents. General disorders (8.9%), musculoskeletal disorders (5.8%), and nervous system disorders (5.5%) were the common AESIs in adults. Menstrual abnormalities were noticed in 4.6% of female participants. Ocular abnormalities and hypothyroidism were observed in 2.7% and 0.6% of participants, respectively. Among serious AESIs (1%), stroke and Guillain-Barre syndrome were identified in 0.3% and 0.1% of participants, respectively. Among adolescents, female individuals, those with a history of allergy and post-vaccination typhoid were respectively at 1.6, 2.8, and 2.8 times higher risk of AESIs. The majority of the AESIs persisted at the 1-year follow-up. Female individuals, adolescents with pre-vaccination COVID-19, those with co-morbidities, and those with post-vaccination typhoid had respectively 1.6, 2, 2.7, and 3.2 times higher odds of persistent AESIs. Adults with co-morbidities had more than 2 times higher odds of AESIs and persistent AESIs. The patterns of AESIs developing after BBV152 differed from those reported with other COVID-19 vaccines as well as between adolescents and adults. With the majority of AESIs persisting for a significant period, extended surveillance of COVID-19-vaccinated individuals is warranted to understand the course and outcomes of late-onset AESIs. Serious AESIs might not be uncommon and necessitate enhanced awareness and larger studies to understand the incidence of immune-mediated phenomena post-COVID-19 vaccination. The relationship of AESIs with sex, co-morbidities, pre-vaccination COVID-19, and non-COVID illnesses should be explored in future studies.

A Retrospective Analysis of Safety in Participants Treated with a Hybrid Hyaluronic Acid and Calcium Hydroxyapatite Filler.

Limited long-term safety data are published on HA/CaHA/L, a hybrid dermal filler combining hyaluronic acid (HA), calcium hydroxyapatite (CaHA), and lidocaine (L). This retrospective multicenter study assessed treatment-emergent adverse events (TEAEs) in adults treated with HA/CaHA/L. The full analysis set (FAS) included eligible consented adults (N = 403); the long-term safety analysis (LTSA) set included FAS participants with greater than or equal to 12-months HA/CaHA/L exposure (n = 243). Participants were majority female (94.0%), with Fitzpatrick skin phototypes II/III (80.1%) and a mean age of 50.1 years. Most participants (86.4%) received one HA/CaHA/L treatment. The median time between participants' first HA/CaHA/L treatment and chart review was 15.4 months. Participants received a mean of 2.2 mL (0.5-8.9 mL) filler per treatment. Treated areas were predominantly malar (71.2%) and mandible (69.7%) regions. Most participants (95.0%) had one or more aesthetic treatments other than HA/CaHA/L [eg, other dermal fillers (84.1%), botulinum toxin (63.3%)]. Nineteen (4.7%) FAS participants had 20 documented TEAEs; most (3.5%, n = 14 participants) were mild in severity. Twelve TEAEs in 11 participants (2.7%) were related to HA/CaHA/L: induration (three, 0.7%), edema (3, 0.7%), and implant site nodules (five, 1.2%), which were noninflammatory and likely related to product placement. Among the LTSA, 15 (6.2%) participants had 16 documented TEAEs (six edema, five implant site nodules, one inflammation, three skin induration, one hypersensitivity); most were mild in severity. Nine TEAEs in eight participants (3.3%) were HA/CaHA/L-related. No treatment-emergent serious AEs were reported. The data from this noninterventional retrospective study support the favorable longer term (>12 month) safety profile of HA/CaHA/L.

A new method for long-term safety analysis of marine structures

This paper proposes to utilise a new adaptive kernel density estimation (KDE) method based on a linear diffusion process for fitting the significant wave height data in order to calculate the sea state parameter distribution tails more accurately, particularly the higher, more extreme values. The accuracy of the proposed method has been demonstrated based on fittings to two measured ocean wave datasets. This proposed method has subsequently been utilised for deriving accurate 50-year and 500-year environmental contour lines. The advantages of using a more reliable contour line derived from using the proposed new method for long-term safety analysis of marine structures have been substantiated.

Efficacy of progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing in vitro fertilization: a systematic review and meta-analysis.

NPLASY (202340059). https://inplasy.com/inplasy-2023-4-0059/.

Open-source Python library for modeling coupled thermo-hydro-mechanical (THM) processes

Abstract. The interactions between temperature, fluids, and mechanical properties in a repository system are essentially described scientifically by coupled thermo-hydro-mechanical (THM) processes. THM modeling, i.e., the prediction of the behavior of materials under different conditions, is the fundamental numerical tool here. The confident handling and deep understanding of numerical computation methods is thus the prerequisite for performing and evaluating preliminary safety analyses in the site selection process. At the Federal Office for the Safety of Nuclear Waste Management (BASE), a software library for the simulation of coupled THM processes is currently being developed. The main goal of the in-house development is an open-source toolbox in the scripting language Python and is motivated by several long-term sub-goals: targeted development of expertise within BASE regarding numerical modeling of safety-relevant aspects in the long-term safety analyses; diversification of the testing capabilities regarding the preliminary safety investigations by means of an in-house, independent modeling software; foundation of a library of known benchmarks and evaluation examples for the comparison of different software tools; documentation and processing of basic THM scenarios for internal or, if necessary, public technical training. The focus of this development is on creating a toolbox that is easy to use and at the same time highly flexible. The main methodical aspects are as follows: building a new library based on the pyGIMLi pre- and postprocessing framework (Rücker et al., 2017); creating a finite-element reference implementation in the Python scripting language for maximal transparency; creating an easy-to-use interface to the solution of the weak formulation for the finite-element theory with expressions of a symbolic manner allowing maximal flexibility; defining an interface to allow for the integration of alternative, third-party high-performance libraries; creating a collection of Jupyter notebooks of well-documented test cases and benchmarks. Choosing the open-source approach ensures the best possible transparency and, in the long term, also allows the provision of appropriately quality-assured and documented simulation tools to the public. The presented poster shows the current development status of the software library and the currently implemented quality assurance concepts and gives an outline of the potential applications of the library.

Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer: a long-term safety and overall survival update from the randomised, double-blind, placebo-controlled, phase 3 trial.

The ACE study previously demonstrated that tucidinostat (chidamide), a subtype-selective histone deacetylase (HDAC) inhibitor, plus exemestane significantly improved progression-free survival (PFS) in advanced hormone receptor-positive (HR+) breast cancer patients with a manageable safety profile. The analysis of long-term safety and overall survival (OS) is presented here. ACE is a randomized, double-blind, placebo-controlled, phase 3 trial comparing tucidinostat 30 mg/twice weekly plus exemestane 25 mg/day versus placebo plus exemestane 25 mg/day in postmenopausal patients with advanced, HR+ breast cancer. The primary endpoint was PFS, and OS was the secondary endpoint. Of the 365 patients enrolled between July 2015, and June 2017, 244 were assigned to tucidinostat plus exemestane (tucidinostat group) and 121 to placebo plus exemestane group (placebo group). Baseline characteristics were well balanced between groups. The median follow-up from randomization to data cut-off (February 25, 2021) of this analysis was 26.5 months (range, 13.9-45.5 months). A total of 231 deaths (63.3%) from 365 patients occurred, including 155 deaths (63.5%) in the tucidinostat group and 76 deaths (62.8%) in the placebo group. The median OS was 30.3 months (95% CI, 26.7-36.7) in the tucidinostat group and 30.3 months (95% CI, 24.8-38.1) in the placebo group. The safety profiles of both tucidinostat and placebo groups remained consistent with those previously reported, and no new safety signals were observed with longer follow-up. Neutropenia of grade 3 or 4 occurred in 51.6% of the patients in the tucidinostat group and 2.5% of the patients in the placebo group. Adverse events (AEs) that led to treatment discontinuations from any cause occurred in 28 (11.5%) patients in the tucidinostat group and 4 (3.3%) in the placebo group. Although tucidinostat in combination with exemestane had produced a clinically meaningful and statistically significant improvement in the primary endpoint PFS, the ACE study did not show a prolongation of the secondary endpoint OS in the tucidinostat combination regimen. Ongoing studies have been considered in terms of potential identification of what patient subpopulations could benefit most from the tucidinostat combination regimens in advanced HR+ breast cancer.

62: Long-term safety analysis of teduglutide treatment in adult patients with short bowel syndrome and intestinal failure (SBS-IF): analysis from a prospective, multinational SBS-IF registry

62: Long-term safety analysis of teduglutide treatment in adult patients with short bowel syndrome and intestinal failure (SBS-IF): analysis from a prospective, multinational SBS-IF registry

Long-Term Safety Analysis of the ChAdOx1-nCoV-19 Corona Virus Vaccine: Results from a Prospective Observational Study in Priority Vaccinated Groups in North India.

Various vaccines for protection against COVID-19 were provided emergency approval in late 2020 to early 2021. There is a scarcity of long-term safety data for many of these. The main aim of this study is to provide the one-year safety results of the ChAdOx1-nCoV-19/AZD1222 vaccine and determine the risk factors of adverse events of special interest (AESIs) and persistent AESIs. This was a prospective observational study conducted from February 2021 to April 2022 in a tertiary hospital in North India and its two associated centers. Health care workers, other frontline workers, and the elderly vaccinated with the ChAdOx1-nCoV-19 vaccine constituted the study population. Individuals were contacted telephonically at pre-decided intervals for one year and health issues of significant concern were recorded. Atypical adverse events developing after a booster dose of the COVID-19 vaccine were assessed. Regression analysis was conducted to determine risk factors of AESI occurrence and determinants of AESIs persisting for at least one month at the time of final telephonic contact. Of 1650 individuals enrolled, 1520 could be assessed at one-year post-vaccination. COVID-19 occurred in 44.1% of participants. Dengue occurred in 8% of participants. The majority of the AESIs belonged to the MedDRA® SOC of musculoskeletal disorders (3.7% of 1520). Arthropathy (knee joint involvement) was the most common individual AESI (1.7%). Endocrinal disorders such as thyroid abnormalities and metabolic disorders such as newly diagnosed diabetes developed in 0.4% and 0.3% of individuals, respectively. Regression analysis showed females, individuals with a pre-vaccination history of COVID-19, diabetes, hypothyroidism, and arthropathy had 1.78-, 1.55-, 1.82-, 2.47- and 3.9-times higher odds of AESI development. Females and individuals with hypothyroidism were at 1.66- and 2.23-times higher risk of persistent AESIs. Individuals receiving the vaccine after COVID-19 were at 2.85- and 1.94 times higher risk of persistent AESIs compared, respectively, to individuals with no history of COVID-19 and individuals developing COVID-19 after the vaccine. Among participants receiving a booster dose of the COVID-19 vaccine (n = 185), 9.7% developed atypical adverse events of which urticaria and new-onset arthropathy were common. Nearly half of the ChAdOx1-nCoV-19 vaccine recipients developed COVID-19 over one year. Vigilance is warranted for AESIs such as musculoskeletal disorders. Females, individuals with hypothyroidism, diabetes, and pre-vaccination history of COVID-19 are at higher risk of adverse events. Vaccines received after natural SARS-CoV-2 infection may increase the risk of persistence of adverse events. Sex and endocrinal differences and timing of the COVID-19 vaccine with respect to natural infection should be explored as determinants of AESIs in the future. Pathogenetic mechanisms of vaccine-related adverse events should be investigated along with comparisons with an unvaccinated arm to delineate the overall safety profile of COVID-19 vaccines.

Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study.

Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).

Comparative Analysis of Long-Term Efficacy, Safety, and Complications of Radiofrequency Ablation Versus Endovenous Laser Treatment of Varicose Veins

Comparative Analysis of Long-Term Efficacy, Safety, and Complications of Radiofrequency Ablation Versus Endovenous Laser Treatment of Varicose Veins

Abstract PD18-03: Final analysis of the Phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer

Abstract BACKGROUND In the Phase II NeoSphere study (NCT00545688), dual HER2 blockade with pertuzumab (P) + trastuzumab (H), + docetaxel (D) significantly increased pathologic complete response (pCR) vs. H+D in the neoadjuvant setting for HER2-positive early breast cancer (EBC), locally advanced (LA) BC, or inflammatory BC, with supportive progression- and disease-free survival (DFS) data. Consistently, the randomized, multicenter, double-blind, placebo (Pla)-controlled Phase III PEONY trial (NCT02586025) significantly improved total pCR (tpCR; primary endpoint) with P+H+D vs. H+D in an Asian population, and safety data were in-line with the known P safety profile. We present the final analysis of long-term efficacy (at 3 and 5 years) and safety from the study. METHODS Patients had centrally confirmed HER2-positive EBC (T2–3, N0–1) or LABC (T2–3, N2 or N3; T4, any N) and were randomized 2:1 to four neoadjuvant P+H+D or Pla+H+D cycles every 3 weeks. P: 840 mg loading/420 mg maintenance doses (or Pla); H: 8 mg/kg loading/6 mg/kg maintenance; D: 75 mg/m2. Patients then received three fluorouracil, epirubicin, and cyclophosphamide cycles, followed by 13 of P+H or Pla+H in the adjuvant setting for up to 1 year. Long-term outcomes (event-free survival [EFS], DFS, overall survival [OS]; all secondary endpoints) were assessed by Kaplan–Meier methods, Cox proportional hazards models, and a two-sided log-rank test (stratified by disease category and hormone receptor status). RESULTS Data cut-off was Mar 14, 2022, and 329 patients were randomized; 219 to P; 110, to Pla. Safety populations were 218 and 110 patients, respectively. Baseline characteristics were well balanced. Most patients received the full HER2-targeted cycles. Median follow-up was 62.9 months. Long-term efficacy data are shown in the table. During the overall treatment period, 70.6% of patients in the P+H+D arm and 68.2% in the Pla+H+D arm experienced grade ≥3 adverse events (AEs); the most common (in ≥5% of patients in either arm) being neutropenia (59.2% vs. 55.5%), leukopenia (34.4% vs. 34.5%), and febrile neutropenia (5.0% vs. 3.6%). Of the most common any-grade AEs (in ≥30% of patients in either arm), diarrhea was more common in the P+H+D arm (40.8% vs. 17.3% in the Pla+H+D arm). Serious AEs were reported in 17.0% and 13.6% of patients, respectively. No primary cardiac events (heart failure [New York Heart Association grade III or IV] or significant decline of left ventricular ejection fraction) or secondary cardiac events occurred during any study periods. CONCLUSIONS Long-term efficacy endpoints (EFS, DFS, and OS) were supportive of the primary endpoint results (tpCR) and suggested a clinically meaningful improvement with P+H vs. Pla+H when administered before and after surgery for one year of anti-HER2- therapy. Safety data were in-line with the known P safety profile and generally comparable between arms, with the exception of diarrhea. PEONY adds to the totality of data showing the benefit of the P+H+D regimen in HER2-positive EBC. Table 1: Long-term efficacy data Citation Format: Zhi-Ming Shao, Da Pang, Hongjian Yang, Wei Li, Shusen Wang, Shude Cui, Ning Liao, Yong-Sheng Wang, Chuan Wang, Yuan-Ching Chang, Hwei-Chung Wang, Seok Yun Kang, Jae Hong Seo, Kunwei Shen, Suphawat Laohawiriyakamol, Zefei Jiang, Liang Huang, Haiyan Wang, François Lamour, Grace Song, Eleonora Restuccia. Final analysis of the Phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-03.

OP39 Safety of ustekinumab in IBD: Final pooled long-term safety analysis through 5 years in CD and 4 years in UC

Abstract Background Long-term efficacy of ustekinumab (UST) has been reported in Crohn’s disease (CD) through 5 years (yrs)1 and in ulcerative colitis (UC) through 4 yrs.2 A previous pooled analysis of long-term safety data reported a favorable UST safety treatment profile for inflammatory bowel disease (IBD).3 Here, we present results of the final cumulative analysis of long-term safety data from UST studies through up to 5 yrs in CD and 4 yrs in UC. Methods Data from 6 phase 2/3 UST IBD studies were pooled. In phase 3, patients (pts) received a single IV placebo (PBO) or UST (130mg or ~6mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90mg q8w or q12w). Concomitant immunomodulators and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes are summarized and presented using number of events per 100 patient-years (PY) of follow-up and corresponding 95% confidence interval (CI). Results In this final pooled UST IBD safety data, 2575 pts were treated with UST with 4826 PYs of follow-up. Rates of key safety events, including MACE and malignancies, were similar between PBO and UST or not higher for UST (Table 1). The most frequently occurring adverse events (AEs) in either group (excluding diseases under study) were headache (PBO 16.66 vs. UST 11.60), arthralgia (PBO 15.91 vs. UST 11.23), abdominal pain (PBO 13.79 vs. UST 9.86), nausea (PBO 11.35 vs. UST 7.13), and pyrexia (PBO 11.35 vs. UST 5.91); infections were nasopharyngitis (PBO 17.82 vs UST 19.10) and upper respiratory tract infection (PBO 11.78 vs UST 9.80). The most frequently reported serious infections of anal abscess, pneumonia, cellulitis, and abdominal abscess were no higher in the UST group than PBO, except gastroenteritis (PBO 0.11 vs UST 0.25). No lymphomas were reported. Nine deaths were reported in UST-treated pts (0.00 [0.00, 0.32] PBO vs. 0.19 [0.09, 0.35] UST), 6 in CD and 3 in UC (all considered unrelated to study agent). Conclusion The final compilation of cumulative UST IBD safety data through 5 yrs in CD and 4 yrs in UC showed a safety profile that continued to be favorable and supports the well-established UST safety experience across all approved indications.

A synchronized approach between Emergency Department and Anemia Clinic to intravenous iron treatment for very severe (Hb

A synchronized approach between Emergency Department and Anemia Clinic to intravenous iron treatment for very severe (Hb <7.0 g/dL) and extreme (<5.0 g/dL) iron-deficiency anemia: short-, medium- and long-term efficacy and safety analysis.

Retrospective Observational Study of the Long-Term Safety and Efficacy Outcomes of Rituximab Biosimilar: Partial Data of RTXM83-AC-01-11 Subanalysis Study

Introduction Rituximab is a chimeric monoclonal antibody designed against the CD20 receptor displayed on the surface of B cells and used to treat nearly all B-cell non-Hodgkin lymphomas (NHLs). It was the first monoclonal antibody approved in oncology and it has improved outcomes in all B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. In recent years, the approval of several rituximab biosimilar molecules worldwide has further improved the patients' access to this drug, promoting cost-effective treatment. Biosimilar molecules are defined by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a biological molecule product highly similar to the approved reference product with no clinically meaningful differences. The multicentric double-blind international prospective pivotal study RTXM83-AC-01-11 led to the approval of rituximab biosimilar RTXM83. The study evaluated the efficacy, pharmacokinetics (PK)/pharmacodynamics (PD), safety, and immunogenicity profile of RTXM83 (rituximab biosimilar) vs reference rituximab (Mabthera®), both with CHOP, as first-line treatment of Diffuse-Large-B-Cell-Lymphoma (DLBCL). Participants from both arms received 6 cycles of R-CHOP followed by a 9-month follow-up (Candelaria et al., 2019). Data regarding long-term efficacy and safety events are of great relevance to demonstrate the strength of the clinical response and deepen the confidence in the use of biosimilar molecules. Here, we present a partial data analysis regarding the long-term safety of 11 patients included in this retrospective observational study. Aim This national retrospective observational study aimed to collect long-term data regarding safety e efficacy outcomes from Brazilian participants of the pivotal study RTXM83-AC-01-11 which led to the approval of biosimilar rituximab (Vivaxxia®) in Brazil. Methods All 28 Brazilian participants that were randomized and completed the phase III study RTXM83-AC-01-11 were eligible for this observational, retrospective LB2002 study (Clinical trial information: NCT04928573). Participants were invited to sign the consent form and share the disease history collected since their randomization on the RTXM83-AC-01-11 study. This partial analysis shows the participants' demographic and baseline characteristics, baseline disease characteristics, and the long-term safety data collected and monitored until July 1st, 2022. The long-term safety endpoint was the frequency of serious adverse events of interest, and we considered in this analysis the time between the end of the RTXM83-AC-01-11 study and the consent date of the LB2002 study. Results The intention to treat (ITT) and Safety populations comprised the partial analysis of the same 11 participants, 7 of them (63.6%) treated with biosimilar RTXM83 plus CHOP and 4 (36.4%) with Mabthera® plus CHOP. The median study follow-up time was 73.3 months, considered in this analysis as the time between the randomization of RTXM83-AC-01-11 study participants and the consent date of the LB2002 study. Overall, participants' median age was 55 years old, 63.6% were white, 54.5% were female, 18.8% were active smokers and the body mass index (BMI) ranged from 20 to 35.7 Kg/m² (Table 1). Regarding disease characteristics, 9,1% of the overall participants were classified as stage I DLBCL, 45.5% stage II and IV at the time of diagnosis. Of all 11 participants, 72.7% displayed extranodal lesions, and 18.2% had bulky lesions with a median body surface area (BSA) of 1.8 m2 (Table 1). As for prognostic factor and performance status, participants were classified with IPI 1 (45.5%) and 2 (54.5%), ECOG 1 (72.7%) and 2 (18.3%). The long-term safety analysis from the 11 participants revealed that 2 participants (18.2%) suffered from serious adverse events (SAE) among those of interest listed in Table 2. One participant of the RTXM83-CHOP arm had a SAE classified as severe infection related to rituximab (hypogammaglobulinemia). From the R-CHOP/MabThera® 1 participant displayed 1 SAE (secondary neoplasm) with a possible relationship to rituximab. Conclusion The partial analysis of the LB2002 has demonstrated thus far the safety profile of the biosimilar RTXM83 (Vivaxxia®) in the Brazilian population is consistent with the known safety profile of rituximab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Efficacy, Safety, and Subgroup Analysis of Savolitinib in Chinese Patients With NSCLCs Harboring MET Exon 14 Skipping Alterations

IntroductionSavolitinib has been found to have encouraging antitumor activity and a favorable safety profile in Chinese patients with pulmonary sarcomatoid carcinoma and other NSCLCs with MET exon 14 skipping alterations (MET ex14 positive) at the primary analysis of a phase 2 study. Here, we present the long-term efficacy and safety data of savolitinib, including subgroup analyses. MethodsThis multicenter, single-arm, open-label, phase 2 study in the People’s Republic of China enrolled MET inhibitor-naive adults with locally advanced or metastatic METex14-positive NSCLC (NCT02897479). Oral savolitinib at a dose of 400 or 600 mg was administered once daily (body weight dependent). The primary objectives of the final analysis were long-term overall survival (OS) and subgroup analyses by previous systemic treatment, NSCLC subtypes, and brain metastases. ResultsAt the final analysis cutoff date (June 28, 2021), a total of 70 patients were enrolled and receiving savolitinib, and median follow-up was 28.4 (interquartile range: 26.2–36.3) months. The median OS was 12.5 months (95% confidence interval [CI]: 10.5–21.4 [18- and 24-mo OS rates, 42.1% and 31.5%, respectively]). Median OS in pretreated or treatment-naive patients was 19.4 (95% CI: 10.5–31.3) and 10.9 (95% CI: 7.5–14.0) months, respectively; it was 10.6 months (95% CI: 4.6–14.0) in patients with pulmonary sarcomatoid carcinoma, 17.3 months (95% CI: 10.6–23.6) in other NSCLC subtypes, and 17.7 months (95% CI: 10.5–not evaluable) in patients with brain metastases. No new safety signals emerged with prolonged follow-up and exposure. ConclusionsThe updated results further confirm the favorable benefit and acceptable safety of savolitinib in Chinese patients with METex14-positive NSCLC.

979P Long-term intracranial safety and efficacy analyses from the phase III CROWN study

Updated results from the ongoing phase III CROWN study (NCT03052608) confirmed the durable systemic and intracranial (IC) benefit of lorlatinib (LOR), a 3rd generation anaplastic lymphoma kinase (ALK) inhibitor, vs crizotinib (CRIZ) in patients (pts) with treatment-naive ALK-positive non-small cell lung cancer. The 3-year follow up evaluated long-term IC safety and efficacy of LOR (data cutoff 20 September 2021).

Long-Term Clinical Outcomes and Safety Analysis of Superficial Esophageal Cancer Patients Treated with Definitive or Adjuvant Radiotherapy.

Simple SummaryFor superficial esophageal cancer, many tumor features have been identified as risk factors for lymph node metastasis, including depth of invasion, tumor size, the presence of lymphovascular invasion, etc. In such cases, endoscopic resection (ER) alone is not adequate for treatment coverage, and additional radiotherapy (RT)/concurrent chemoradiotherapy (CCRT) merits further investigation. On the other hand, esophagectomy has a high cure rate for early stage esophageal squamous cell cancer (ESCC); however, there are concerns of treatment complications and loss of esophagus preservation. Hence, definitive RT/CCRT may be a promising treatment alternative to esophagectomy, especially for those who are unable or unwilling to receive surgery. We retrospectively analyzed outcomes of patients with T1N0M0 staged ESCC treated with ER + RT/CCRT or RT/CCRT. We conclude that definitive or adjuvant RT/CCRT is an effective treatment alternative for superficial ESCC patients with satisfactory clinical outcomes and acceptable toxicities.(1) Background: The role of radiotherapy (RT) in superficial esophageal squamous cell cancer (ESCC) remains unclear. The objective of our study was to perform a detailed outcome and safety analysis of RT as a definitive or adjuvant treatment for T1N0M0 staged ESCC patients. (2) Methods: A total of 55 patients treated with endoscopic resection (ER) + RT/concurrent chemoradiotherapy (CCRT) or RT/CCRT from January 2011 to June 2021 were included in this study. Eighteen patients with risk factors received ER + RT/CCRT, and thirty-seven patients solely received RT/CCRT. Kaplan–Meier curves were used to calculate the clinical outcomes, and toxicities were scored. (3) Results: The median follow-up time was 51.9 months. The estimated 5-year local recurrence-free survival (LRFS) and overall survival (OS) were 88.9% and 94.4% in the ER + RT/CCRT group and 91.8% and 91.7% in the RT/CCRT group. The predominant failure pattern was in-field local failure (5.5%, 3/55), with one patient in the ER + RT/CCRT group and two patients in the RT/CCRT group. One patient (1.8%, 1/55) had lung metastasis in the RT/CCRT group. The most common toxicities were Grades 1–2 in all patients, including esophagitis (74.5%, 41/55), myelosuppression (49.1%, 27/55) and esophageal stricture after RT (27.3%, 15/55). Two patients (11.1%, 2/18) and four patients (10.8%, 4/37) had Grade 3 esophageal stricture after RT in the ER + RT/CCRT group and RT/CCRT group, respectively. No patients experienced a Grade 4 or higher toxicity, and there were no treatment-related deaths. (4) Conclusions: Definitive or adjuvant RT/CCRT is an effective treatment alternative for superficial ESCC patients with satisfactory clinical outcomes and acceptable toxicities.

Interim Analysis of Long-Term Safety and Efficacy of FINTEPLA (fenfluramine) in Patients with Lennox-Gastaut Syndrome (S13.010)

Interim Analysis of Long-Term Safety and Efficacy of FINTEPLA (fenfluramine) in Patients with Lennox-Gastaut Syndrome (S13.010)