Updated Safety Research Articles

Long-term three-year follow-up of mosunetuzumab in relapsed or refractory follicular lymphoma after ≥2 prior therapies (119/120)

Mosunetuzumab, a CD20xCD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate (ORR) were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7-not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of complete response was not reached (NR) (95% CI, 33.0-NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE-NE). Median progression-free survival was 24.0 months (95% CI, 12.0-NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) following 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or Grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe and effective treatment for patients with R/R FL, including those with high-risk disease. Trial registration: www.clinicaltrials.gov (NCT02500407).

514LBA (PB-514) LBA Posters: Updated safety and efficacy from a Phase 1 study of RMC-6236, a RAS (ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC)

514LBA (PB-514) LBA Posters: Updated safety and efficacy from a Phase 1 study of RMC-6236, a RAS (ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC)

P1.12B.07 Iruplinalkib in Patients with ALK-Positive Crizotinib-Resistant NSCLC: Updated Efficacy and Safety Data from a Phase 2 Trial

P1.12B.07 Iruplinalkib in Patients with ALK-Positive Crizotinib-Resistant NSCLC: Updated Efficacy and Safety Data from a Phase 2 Trial

MA06.12 Updated Efficacy, Safety, and Biomarker Analysis in Patients with TRK Fusion Lung Cancer Treated with Larotrectinib

MA06.12 Updated Efficacy, Safety, and Biomarker Analysis in Patients with TRK Fusion Lung Cancer Treated with Larotrectinib

Energy Content, Moisture Content, and Energy Assimilation Efficiency by Birds and Mammals of Oil-Containing Seeds and Implications for Seed Treatment Risk Assessments for Birds and Mammals.

Energy content, moisture content, and energy assimilation efficiency are essential parameters in the food intake rate (FIR) and exposure calculations for bird and mammal risk assessments. The updated European Food Safety Authority guidance document on risk assessment for birds and mammals summarizes these parameters for different food items. For seed treatments, values for cereal seeds are proposed as surrogates for other crops. Oil-containing seeds are expected to have a higher energy content than cereal seeds. This would result in lower FIR and, thus, exposure from consuming such seeds. To be able to calculate reliable exposure values for risk-assessment purposes, we conducted a systematic literature review to collect information on these three parameters for oil-containing seeds (sunflower, oilseed rape, soybean, peanut, sesame, safflower, linseed [flax], white mustard, and castor bean). The search yielded 401 papers, of which 151 contained values for at least one of the parameters of the crops in focus. The overall average energy content value of oil-containing seeds was 24.25 kJ/g (n = 124, SD = 3.00), whereas that for moisture content was 6.57% (n = 296, SD = 1.15). Energy assimilation values were only available for peanut, oilseed rape, soy, linseed, and sunflower for a limited number of bird and mammal species. Mean energy assimilation efficiency for mammals was 82.69% (n = 4, SD = 1.55), whereas values for birds were 57.54% (n = 2, SD = 6.77) for Galliformes and 79.25% (n = 2, SD = 1.82) for Passeriformes. The values presented can be used to calculate appropriate FIR values for future bird and mammal risk assessments. Environ Toxicol Chem 2024;43:2080-2085. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

1290P Updated efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC

1290P Updated efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC

LBA56 Updated efficacy and safety from the phase II PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC)

LBA56 Updated efficacy and safety from the phase II PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC)

LBA39 Updated efficacy and safety data from IMbrave050: Phase III study of adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in patients (pts) with resected or ablated high-risk hepatocellular carcinoma (HCC)

LBA39 Updated efficacy and safety data from IMbrave050: Phase III study of adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in patients (pts) with resected or ablated high-risk hepatocellular carcinoma (HCC)

1691P Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients (pts) with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Updated efficacy and safety results from CheckMate 67T

1691P Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients (pts) with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Updated efficacy and safety results from CheckMate 67T

LBA78 Updated efficacy and safety of vimseltinib in patients (pts) with tenosynovial giant cell tumor (TGCT): One-year follow-up from the MOTION phase III trial

LBA78 Updated efficacy and safety of vimseltinib in patients (pts) with tenosynovial giant cell tumor (TGCT): One-year follow-up from the MOTION phase III trial

983P Updated safety and efficacy of ABSK-011 in advanced hepatocellular carcinoma (aHCC) with FGF19 overexpression from a phase I study

983P Updated safety and efficacy of ABSK-011 in advanced hepatocellular carcinoma (aHCC) with FGF19 overexpression from a phase I study

1017P Updated safety and efficacy from the phase I study of givastomig, a novel claudin 18.2/4-1BB bispecific antibody, in claudin 18.2 positive advanced gastroesophageal carcinoma (GEC)

1017P Updated safety and efficacy from the phase I study of givastomig, a novel claudin 18.2/4-1BB bispecific antibody, in claudin 18.2 positive advanced gastroesophageal carcinoma (GEC)

1603P Updated safety and efficacy of tazemetostat (TAZ) plus enzalutamide (ENZ) in patients with metastatic castration-resistant prostate cancer (mCRPC)

1603P Updated safety and efficacy of tazemetostat (TAZ) plus enzalutamide (ENZ) in patients with metastatic castration-resistant prostate cancer (mCRPC)

MHRA Drug Safety Update - topical steroids.

MHRA Drug Safety Update - topical steroids.

Evaluation of Safety Issues for Workers by Applying Safety Management System and Risk Assessment at Metro Rail Construction Work Project

Construction industry is one of the top dangerous industries in India because there is a high risk of accident occurrence where the construction workers are exposed to accidents such as fall from height. The awareness of safety at workplace in India has emerged since 1967 with the introduction of the Factories Act 1948 (FA), followed by The Act is administered by the Ministry of Labour and Employment. Rapid transportation system becomes a significant factor for the developing country. Apart from that it is very essential to control the traffic in the high dense and populated country like India. So this where the need of metro rail is generated. A metro project is carried out in Pune under Pune Metro Rail Project. This thesis work is carried out for a part of Pune metro project. In the present scenario, in India maximum accident occurs in construction industry as the Indian construction company is lacking a huge with updated safety instrument and lack of knowledge about safety. This studies is deals with the safety policies, there work environment, responsibilities of a safety personnel in company. The company has a very strict and well defined safety rules which follows BIS standard, OSAH standard and BOCW. The duty of safety engineer is to look after whether any activity, in the site or out of the site, related to the project is going safely or not. It has to be checked by safety personnel as well as the engineer whether any work is following the safety integral management system of the company. At the design stage different activities must kept in mind and a safe design must be given so that to reduce the accidents. All activities must have the instructions separately to check the accidents like earthwork in it’s as a unique activity so it requires the separate instructions. Some work could be done on the selection process of labour and supervisors and a good communication and better behavior could again check the follow up of different tools and equipment and precautions while working on the site. Training classes must be done on the site with proper process so that the importance of the safety gets clear to the labour with the benefits of that.

Establishing Updated Safety Standards for Independent 99mTc-MAA SPECT/CT Treatment Planning in Radioembolization

Significant improvements within radioembolization imaging and dosimetry permit the development of an accurate and personalized pretreatment plan using technetium 99m-labeled macroaggregated albumin (99mTc-MAA) and single-photon emission computed tomography (SPECT) combined with anatomical CT (SPECT/CT). Despite these potential advantages, the clinical transition to pretreatment protocols with SPECT/CT is hindered by their unknown safety constraints. This study aimed to address this issue by establishing novel dose limits for 99mTc-MAA SPECT/CT to enable quantitative pretreatment planning. Stratification criteria to determine images most viable for dosimetry analysis were created from a cohort of 85 patients. SPECT/CT, cone beam CT, and activity calculations derived from the local deposition method were used to create an accurate pretreatment protocol. Planar and SPECT/CT images were compared using linear regression and modified Bland-Altman analyses to convert accepted planar dose limits to SPECT/CT. To validate these new dose limits, activity calculations based on SPECT/CT were compared with those calculated with the body surface area and planar methods for three treatment plans. A total of 38 of 85 patients were deemed viable for dosimetry analysis. SPECT yielded greater lung shunt fractions (LSFs) than planar imaging when LSFs were <4.89%, whereas SPECT yielded lower LSFs than planar imaging when LSFs were >4.89%. Planar to SPECT/CT dose conversions were 0.76×, 0.70×, and 0.55× for the whole liver, normal liver, and lungs, respectively. Patients with SPECT LSFs ≤4.89% were safely treated with the direct application of planar lung dose limits. Activity calculations with the newly established SPECT/CT dose limits were greater than those of the body surface area method by a median range of 33.1% to 61.9% and were lower than planar-based activity calculations by a median range of 12.5% to 13.7% for the whole liver and by 29.4% to 32.2% for the normal liver. This study demonstrated a safe method for translating dose limits from 99mTc-MAA planar imaging to SPECT/CT. A robust pretreatment protocol was further developed guided by the current knowledge in the field. Established SPECT/CT dose limits safely treated 97.5% of patients and permitted the application of independent pretreatment planning with 99mTc-MAA SPECT/CT.

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial

Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24–0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56–0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110.

Updated efficacy and safety results of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

7078 Background: Lisaftoclax is a novel, oral, highly selective, potent BCL-2 inhibitor in development. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax + ibrutinib has a strong synergistic effect. This report provides updated efficacy and safety data of lisaftoclax-based therapies (including combinations with ibrutinib) in pts with WM. Methods: In this global, open-label, phase 1b/2 multicenter study, pts with WM were enrolled in 3 arms: Arm A (lisaftoclax) included BTKi-resistant/intolerant pts; Arm B (lisaftoclax + ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax + rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high risk of tumor lysis syndrome (TLS). Objectives were efficacy, safety, and pharmacokinetics (PK) assessments (responses assessed per IWWM criteria). Results: As of January 25, 2024, 46 pts were enrolled and treated at doses of up to 1,000 (Arm A), 1,200 (Arm B), and 800 mg (Arm C; Table). The median (range) treatment duration was 11 (1-28; Arm A), 23.5 (1-34; B), and 11.5 (5-33; C) months. Objective response rates (PR, VGFR, CR) were: 41.7% (Arm A), 90.9% (B), and 37.5% (C). In Arm A, pts with wild-type CXCR4 (n = 7) had better overall response to lisaftoclax than the CXCR4mut group (n = 3). No significant difference was observed between pts with/without CXCR4mut in Arms B and C. In Arm B, 1 DLT (grade 3 clinical TLS due to preexisting renal impairment) was reported at 1,200 mg; 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmia was not observed. One pt required dose reduction because of neutropenia. The MTD was not reached. Lisaftoclax + ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential drug-drug interactions. Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. (CT.gov: NCT04260217; Internal ID: APG2575WU101) *Co-first authors: ML and SA. Clinical trial information: NCT04260217 . [Table: see text]

Updated results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager in patients (pts) with small cell lung cancer (SCLC) and other neuroendocrine cancers (NEC).

8090 Background: Delta-like canonical Notch ligand 3 (DLL3) is highly expressed on the cell surface of neuroendocrine carcinomas, which have few approved treatment options in the refractory, metastatic setting. HPN328 is DLL3-targeting T-cell engager. HPN328 has 3 binding domains including anti-DLL3 for target engagement, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. Methods: Pts with relapsed/refractory, metastatic SCLC, neuroendocrine prostate cancer (NEPC) and other NEC associated with DLL3 expression are eligible. Primary objectives are safety, maximum tolerated dose (MTD) and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. Overall response rate (ORR) is determined using modified RECIST v1.1 to include extracranial response assessment for pts treated with radiotherapy for brain metastases while on treatment. HPN328 is administered IV QW or Q2W with priming dose preceding target dose in higher dose cohorts. Results: As of January 5, 2024, 86 pts received HPN328 doses of 0.015-24 mg across 14 cohorts (SCLC [n = 54;63%]; other NEC [n = 32;37%]). The median (range) number of prior regimens was 3 (1-7); 83% previously received a PD-1/PD-L1 blocker. Treatment is ongoing in 24 of 46 (52%) pts in the dose optimization cohorts (1 mg priming dose with 12 or 24 mg target doses QW or Q2W). Treatment-related AEs in ≥ 10% of pts included CRS (59% [30% G1, 26% G2, 3% G3+]), dysgeusia (36%), fatigue (34%), diarrhea (19%), nausea (17%), vomiting (14%), decreased appetite and decreased neutrophil count (13% each), and weight decreased (11%). No G3-4 CRS was seen at target doses. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9% of pts, all G1-2. The maximum tolerated priming dose was 1 mg; dose escalation of target dose continued up to 24 mg QW without reaching a maximum tolerated target dose. Among efficacy evaluable pts treated in dose optimization cohorts, the confirmed ORR in SCLC was 50% (12/24), with one complete response (CR). In NEC (other than NEPC) the confirmed ORR was 44% (4/9), with one CR. Four of eleven pts with NEPC had unconfirmed PRs in 1 mg priming dose cohorts, with 5 NEPC pts remaining on treatment &gt; 20 weeks. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T1/2 of 71 hrs. Transient increases in cytokines up to 24 hrs post-dose and T-cell activation were observed. Conclusions: HPN328 is well tolerated and clinically active in SCLC, NEC, and NEPC. Current dose optimization cohorts have completed enrollment and data continue to mature; selection of a recommended phase 2 dose will be made based upon complete mature data. Updated safety and efficacy results will be presented. Clinical trial information: NCT04471727 .

Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.

3091 Background: RYZ101 (225Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improved therapeutic index. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177Lu-SSA therapy. Herein, we report updated results from the phase Ib portion of the trial. Methods: The phase Ib portion of the trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level –1 90 kBq/kg; Level –2 60 kBq/kg. DLT was assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions/safety data were overseen by a Data Review Committee. Tumor response was assessed locally by RECIST v1.1. Results: 17 patients have received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 30 June 2023, the most frequent TEAEs were nausea (58.8%) and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (none were treatment related); grade ≥3 AEs occurred in 9 patients (5 were treatment related). No AEs led to treatment discontinuation. 4 patients had TEAEs leading to dose modification, dose hold, and/or delays. The confirmed objective response rate was 29.4% (n=5; all partial responses); 1 patient had an unconfirmed partial response. 8 patients (47.1%) had stable disease and 3 patients (17.6%) had progressive disease. Updated safety and efficacy data, including duration of response and progression-free survival, will be presented. Conclusions: RYZ101 was well tolerated and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy. Longer-term safety and efficacy data will be presented. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576 .