Pooled Safety Analysis Research Articles

Pooled safety analysis and management of sotorasib-related adverse events in KRAS G12C-mutated advanced non-small cell lung cancer.

We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks. Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment. In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT;68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of >90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy <3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause. Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification.

Pooled safety analysis of two phase 3 studies investigating trifluridine/tipiracil plus bevacizumab in patients with metastatic colorectal cancer

Pooled safety analysis of two phase 3 studies investigating trifluridine/tipiracil plus bevacizumab in patients with metastatic colorectal cancer

Tenapanor Improves Abdominal Symptoms Irrespective of Changes In Complete Spontaneous Bowel Movement Frequency in Adults With Irritable Bowel Syndrome With Constipation.

Tenapanor is a first-in-class, minimally absorbed intestinal sodium/hydrogen exchanger isoform 3 inhibitor approved by the U.S. Food and Drug Administration for adults with irritable bowel syndrome with constipation (IBS-C). Pooled data from the phase 2b (NCT01923428) and phase 3 T3MPO-1 (NCT02621892) and T3MPO-2 (NCT02686138) studies examined the effects of tenapanor on abdominal symptoms independent of tenapanor's effect on complete spontaneous bowel movement (CSBM) frequency in adults with IBS-C. This post hoc analysis was performed for patients with no CSBMs in ≥6 of the first 12 weeks of treatment (no-CSBM subgroup). The three-item Abdominal Score (AS3; the average of weekly abdominal pain, bloating, and discomfort scores) measured abdominal symptom response in tenapanor vs. placebo. The overall change from baseline and response rate (improvement of ≥2 points or a reduction of ≥30%) in AS3 and individual abdominal scores during the 12 weeks were assessed. In the pooled safety analysis set (N = 1,382), 641 patients were classified as no-CSBM patients and 640 were included in the efficacy analysis. Among the no-CSBM subgroup, tenapanor-treated patients experienced a greater improvement in AS3 in week 12 vs. placebo-treated patients (least squares mean change, -1.74 vs. -1.29; p = 0.007), and the AS3 responder rate was higher for tenapanor (40.2% vs. 29.6%; p = 0.008). Similar improvements were displayed across individual abdominal symptom scores. Diarrhea was the most common adverse event in tenapanor-treated patients. Tenapanor was observed to improve abdominal symptoms independent of its effect on bowel symptoms in adults with IBS-C.

Pooled safety analysis from the VOLTAIRE clinical trials of adalimumab-adbm and adalimumab reference product in patients with rheumatoid arthritis, Crohn’s disease, and chronic plaque psoriasis

ABSTRACT Objectives This analysis reported the incidence of safety endpoints across five phase 3 randomized controlled clinical trials in patients with rheumatoid arthritis (RA), Crohn’s disease (CD), and chronic plaque psoriasis (PsO) who received ≥ 1 dose of adalimumab-adbm or adalimumab reference product (RP). Methods Exposure-adjusted incidence rates for safety endpoints were calculated per 100 patient-years and reported by disease indication and treatment arm. Subgroup analyses by patient age and sex were also conducted. Results The mean length of follow-up was 62 weeks, 48 weeks, and 32 weeks for patients with RA, CD, and PsO, respectively. Rates of serious adverse events (SAEs) and discontinuations due to adverse events (AEs) were similar among patients with RA and PsO, but slightly higher among those with CD. Incidence rates of all safety endpoints were consistent between the adalimumab-adbm and adalimumab RP treatment arms within each indication Subgroup analyses of patients with RA, CD, and PsO showed no between-group differences by age and sex. Conclusions In patients with RA, CD, and PsO, there were no differences between biosimilar adalimumab-adbm or the adalimumab RP regarding the rate of AEs, SAEs, discontinuations due to AEs, deaths, or any AEs of special interest.

Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.

2067-LB: Pooled Safety Analysis of Enobosarm from Phase 2 and Phase 3 Placebo-Controlled Clinical Trials

2067-LB: Pooled Safety Analysis of Enobosarm from Phase 2 and Phase 3 Placebo-Controlled Clinical Trials

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]

Pooled safety analysis of sacituzumab govitecan (SG) in multiple solid tumor types.

Pooled safety analysis of sacituzumab govitecan (SG) in multiple solid tumor types.

Safety Profile and Adverse Event Management for Futibatinib, An Irreversible FGFR1-4 Inhibitor: Pooled Safety Analysis of 469 Patients.

Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA. Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose of 20 mg once every day. In total, 469 patients with one of 33 known tumor types were analyzed, including 318 patients who received futibatinib 20 mg every day. AEs of clinical interest (AECI; any grade/grade ≥3) in the overall population included hyperphosphatemia (82%/19%), nail disorders (27%/1%), hepatic AEs (27%/11%), stomatitis (19%/3%), palmar-plantar erythrodysesthesia syndrome (PPES; 13%/3%), rash (9%/0%), retinal disorders (8%/0%), and cataract (4%/1%). Median time to onset of grade ≥3 AECIs ranged from 9 days (hyperphosphatemia) to 125 days (cataract). Grade ≥3 hyperphosphatemia, hepatic AEs, PPES, and nail disorders resolved to grade ≤2 within a median of 7, 7, 8, and 28 days, respectively. Discontinuations due to treatment-related AEs were rare (2%), and no treatment-related deaths occurred. AE management included phosphate-lowering medication and dose adjustments. Futibatinib showed a consistent and manageable safety profile across patients with various tumor types. AECIs were mostly reversible with appropriate clinical management.

Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis Through 5 Years in Crohn's Disease and 4 Years in Ulcerative Colitis.

Previously published long-term safety data reported a favourable ustekinumab safety profile for the treatment of inflammatory bowel disease [IBD]. We present the final cumulative safety data from pooled ustekinumab IBD phase 2/3 clinical studies through 5 years in Crohn's disease [CD] and 4 years in ulcerative colitis [UC]. In phase 3 studies, patients received a single intravenous placebo or ustekinumab [130 mg or ~6 mg/kg] induction dose followed by subcutaneous maintenance doses of placebo or ustekinumab [90 mg q8w or q12w]. Analyses included all patients who received one dose of study treatment and included patients who were biologic-naïve and patients with a history of biologic failure. Safety outcomes are summarized and presented using number of events per 100 patient-years of follow-up and corresponding 95% confidence intervals. In this final pooled safety analysis, 2575 patients were treated with ustekinumab with 4826 patient-years of follow-up. Rates of key safety events, including major adverse cardiac events and malignancies, were similar between placebo and ustekinumab or not higher for ustekinumab. Opportunistic infections, including tuberculosis, and malignancies were reported infrequently. Rates of key safety events in the IBD group were no higher in the ustekinumab group than in the placebo group for both patients who were biologic-naïve or who had a history of biologic failure. No lymphomas or cases of posterior reversible encephalopathy syndrome [formerly known as reversible posterior leukoencephalopathy syndrome] were reported. The final cumulative ustekinumab safety data through 5 years in CD and 4 years in UC demonstrated favourable safety compared to placebo and continue to support the well-established safety profile across all approved indications. NCT00265122, NCT00771667, NCT01369329, NCT01369342, NCT01369355, NCT02407236.

Pooled safety analysis of incobotulinumtoxina in the treatment of neurological disorders in adults

Pooled safety analysis of incobotulinumtoxina in the treatment of neurological disorders in adults

Deucravacitinib, an Oral, Selective, Allosteric Tyrosine Kinase 2 Inhibitor, in Moderate to Severe Plaque Psoriasis: Evaluation of Creatine Phosphokinase Elevations in the Phase 3 POETYK PSO-1 and PSO-2 Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the US, EU, and other countries for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. In the phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) trials, deucravacitinib was significantly more efficacious than placebo or apremilast and was well tolerated. This pooled safety analysis of POETYK PSO-1 and PSO-2 assessed changes from baseline in creatine phosphokinase (CPK) levels and CPK elevations and rhabdomyolysis adverse events (AEs) in patients receiving placebo, deucravacitinib, or apremilast.&#x0D; Methods: Patients with moderate to severe plaque psoriasis were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. Shifts from baseline in severity grade (Common Terminology Criteria for Adverse Events [CTCAE] version 5) of CPK levels were analyzed. Elevated CPK and rhabdomyolysis adverse events (AEs) were reported.&#x0D; Results: The pooled population included 1683 patients (placebo, n=419; deucravacitinib, n=842; apremilast, n=422). At baseline, the proportions of patients with grade ≥1 CPK levels were comparable (placebo, 6.3%; deucravacitinib, 5.9%; apremilast, 7.4%). During Weeks 0-16, worsening of CPK levels by &gt;1 CTCAE grade from baseline occurred at similar rates in patients receiving placebo (2.2%), deucravacitinib (2.5%), and apremilast (1.4%). Most deucravacitinib-treated patients maintained their baseline CPK CTCAE grade or shifted to a lower grade through Week 52. Elevated CPK AEs were reported in 1.2% (placebo), 2.7% (deucravacitinib), and 0.7% (apremilast) of patients through Week 16. Exposure-adjusted incidence rates (EAIRs) of elevated CPK AEs through Week 52 were comparable across treatments (placebo, 4.5/100 person-years [PY]; deucravacitinib, 4.7/100 PY; apremilast, 3.6/100 PY). Two deucravacitinib-treated patients (0.2/100 PY) and 1 apremilast-treated patient (0.4/100 PY) discontinued due to AEs of asymptomatic elevated CPK. Two deucravacitinib-treated patients had rhabdomyolysis with potential inciting events, one of which was associated with CPK elevation.&#x0D; Conclusion: Most deucravacitinib-treated patients maintained their baseline CPK grade or shifted to a lower grade through Weeks 16 and 52. The EAIR of CPK elevation AEs were comparable across treatment groups over 52 weeks.

Pediatric model-based dose optimization using a pooled exposure-response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma.

An exposure-response (E-R) safety analysis was conducted across adult and pediatric (<18 years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to <18 years) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab-ipilimumab daily average exposure and time to grade 2+ immune-mediated adverse events (gr2+ IMAEs). Results from the E-R safety model showed ipilimumab, but not nivolumab, exposure to be a statistically significant predictor of gr2+ IMAEs. Significant covariates included sex (41% higher risk for women than men), line of therapy (19% higher for first-line than later-line), and treatment setting (26% lower for adjuvant than advanced melanoma). Younger age and lower body weight (BW) were each associated with a lower risk of gr2+ IMAEs (hazard ratio [HR]: 0.830 for 15-year-olds versus 60-year-olds and 0.84 for BW 52 kg versus 75 kg). For adolescents with melanoma treated with nivolumab in the advanced or adjuvant settings, these results are supportive of nivolumab flat dosing regimens for adolescents greater than or equal to 40 kg and BW-based dosing for adolescents less than 40 kg. These results also support adult weight-based dosing regimens for nivolumab plus ipilimumab in adolescents with advanced melanoma. This analysis suggests that although higher exposures are predicted in adolescents with lower weight compared with adults, there is no predicted immune-mediated safety risk when treated with the approved adult dosing of nivolumab with/without ipilimumab.

Pooled Analysis of Safety from Birtamimab Phase 1-3 Studies in Patients with Light Chain (AL) Amyloidosis

Introduction: SystemicAL amyloidosis is a progressive and often fatal disease caused by misfolded light chains that aggregate into amyloid fibrils and deposit in vital organs, leading to organ dysfunction. Current standard of care (SoC) therapies for AL amyloidosis target the plasma cell clone to reduce or eliminate light chain production, but do not remove soluble toxic light chain aggregates or insoluble amyloid deposits. Early mortality remains high for patients with advanced disease (e.g., Mayo 2012 Stage IV disease, median overall survival &amp;lt;6 months). Birtamimab - a humanized monoclonal antibody that neutralizes soluble, toxic light chain aggregates and depletes insoluble amyloid deposits by inducing phagocytosis - is under investigation for the treatment of AL amyloidosis. Here, we present a pooled safety analysis from previous Phase 1-3 clinical trials, with a focus on the 2 double-blind randomized controlled trials (RCTs): PRONTO (NCT02632786) and VITAL (NCT02312206). Methods: Patients with AL amyloidosis were treated with intravenous birtamimab up to 24 mg/kg every 28 daysin the non-placebo-controlled Phase 1/2 open-label trial (NCT01707264) with open-label extension (OLE; NCT02613182) and 2 RCTs (Phase 2 PRONTO with OLE [NCT03154047] and Phase 3 VITAL). In PRONTO, patients had received ≥1 previous systemic therapy with at least a partial hematologic response and persistent cardiac dysfunction, and received birtamimab or placebo. In VITAL, newly diagnosed treatment-naïve patients with cardiac involvement received birtamimab + SoC or placebo + SoC (where SoC was a bortezomib-containing chemotherapy regimen). The analysis included all patients who received ≥1 dose of birtamimab. Pooled median exposure times were calculated, and baseline characteristics and demographics were summarized. For VITAL and PRONTO, pooled rates and severity of treatment-emergent adverse events (TEAEs) with birtamimab were compared with rates in the placebo arms. In addition, safety data from the non-placebo-controlled studies were summarized. Results: The median (range) exposure to birtamimab among 302 patients pooled from the Phase 1-3 trials was 12.24 (0.03-57.72) months. Of the 302 patients exposed to birtamimab, 295 received at least one 24-mg/kg infusion, up to 2500 mg. Analysis of the 2 randomized, placebo-controlled trials included data from 196 patients treated with birtamimab from the PRONTO (n=66) and VITAL (n=130) trials and 193 patients who received placebo (PRONTO, n=63; VITAL, n=130). Both trials had comparable treatment durations overall. The rates of TEAEs, serious and grade ≥3 TEAEs were similar between birtamimab and placebo arms within each trial and between treatment arms in the placebo-controlled pooled analysis set (PRONTO and VITAL; Table 1). Higher rates of treatment-related, serious, and grade ≥3 TEAEs were reported in VITAL compared with PRONTO, presumably due to the treatment-naïve population and receipt of concomitant SoC therapy in VITAL. In the pooled analysis set, the most common TEAEs that occurred with greater frequency in the birtamimab vs placebo arms in either trial were, respectively, fatigue (36.2%, 34.2%), diarrhea (33.2%, 33.7%), nausea (31.6%, 30.1%), constipation (31.1%, 31.6%), and dyspnea (25.0%, 24.9%). The most commonly reported (≥5%) serious and grade ≥3 TEAEs were primarily cardiac disorders (cardiac failure, syncope, cardiac arrest), consistent with the underlying disease. Infusion-associated TEAE rates were low in the pooled birtamimab and placebo arms (5.1% vs 3.6%, respectively) and were generally mild to moderate. The safety profile observed in the non-placebo-controlled Phase 1/2 trial plus OLE and PRONTO OLE (n=106) was consistent with the safety data reported in the placebo-controlled studies. Conclusions: Birtamimab was well tolerated in patients with AL amyloidosis when administered as monotherapy and did not demonstrate additive toxicity when given with SoC chemotherapy. Rates of TEAEs in the birtamimab arm were similar to rates in the placebo arm in the PRONTO and VITAL trials. The safety and efficacy of birtamimab is being further investigated in an ongoing confirmatory Phase 3 double-blind RCT in patients with Mayo Stage IV AL amyloidosis (AFFIRM-AL; NCT04973137), which is currently enrolling.

330MO Pooled safety analysis of zanubrutinib monotherapy in Asian patients with B cell malignancies

330MO Pooled safety analysis of zanubrutinib monotherapy in Asian patients with B cell malignancies

Underwater versus conventional endoscopic mucosal resection for colorectal lesions: a systematic review and meta-analysis of randomized clinical trials.

Conventional endoscopic mucosal resection (CEMR) is the established method for the resection of non-pedunculated colorectal lesions (NPCRL) ≥ 10mm. In the last decade, underwater endoscopic mucosal resection (UEMR) has been introduced as a potential alternative. The aim of this systematic review with meta-analysis is to compare the recurrence and safety of UEMR and CEMR by analyzing only randomized controlled trials (RCTs). We systematically searched PubMed, Cochrane Library and EMBASE until April 2023. Studies met the following inclusion criteria: (1) RCTs, (2) comparing UEMR with CEMR, (3) NPCRL ≥ 10mm, and (4) reporting the outcomes of interest. Primary outcomes were recurrence and safety. Secondary outcomes were en bloc, R0, complete resection, clipping and adverse events per type. Five RCTs were included. UEMR was associated with a lower recurrence rate (OR: 0.56; 95% CI: 0.32-0.97). Thus, the RR of recurrence was 1.7 times higher in the CEMR group (95% CI, 1.04-2.77). There was no significant difference in the pooled safety analysis. UEMR showed better en bloc resection rates (OR: 1.54; 95% CI: 1.15-2.07), but subgroup analysis showed comparable rates in lesions ≥ 20mm. R0 resection was higher in UEMR (OR: 1.72; 95% CI: 1.23-2.41). Other outcomes were not different between the 2 groups. UEMR is as safe as CEMR, with a higher overall R0 rate and a higher en bloc resection rate for lesions < 20mm, leading to a lower overall recurrence rate. The results of this meta-analysis support the widespread use of UEMR.

Pooled Safety Analysis of Single-Agent Lurbinectedin in Patients With Advanced Solid Tumours

BackgroundLurbinectedin was approved by FDA and other health regulatory agencies for treating adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Safety profile at approved dose (3.2 mg/m2 every 3 weeks) was acceptable and manageable in 105 adult SCLC patients from a phase II basket trial. This study analyses safety data from several solid tumours treated at the lurbinectedin-approved dose. MethodsData were pooled from 554 patients: 335 from all nine tumour-specific cohorts of the phase II basket trial and 219 from a randomised phase III trial (CORAIL) in platinum-resistant ovarian cancer. Events and laboratory abnormalities were graded using NCI-CTCAE v.4. ResultsMost common tumours were ovarian (n = 219, 40%), SCLC (n = 105, 19%) and endometrial (n = 73, 13%). Transient haematological laboratory abnormalities were the most frequent grade 3 or more events: neutropenia (41%), leukopenia (30%), anaemia (17%) and thrombocytopenia (10%). Most common treatment-emergent non-haematological events (any grade) were transient transaminase increases (alanine aminotransferase [66%], aspartate aminotransferase [53%]), fatigue (63%), nausea (57%), constipation (32%), vomiting (30%) and decreased appetite (25%). Dose reductions were mostly due to haematological toxicities, but most patients (79%) remained on full lurbinectedin dose. Serious events mostly consisted of haematological disorders. Eighteen treatment discontinuations (3%) and seven deaths (1%) were due to treatment-related events. ConclusionsThis analysis confirms a manageable safety profile for lurbinectedin in patients with advanced solid tumours. Findings are consistent with those reported in patients with relapsed SCLC, Ewing sarcoma, germline BRCA1/2 metastatic breast cancer, neuroendocrine tumours and ovarian cancer.

Pooled Safety Analysis of Inclisiran in 3,576 Patients With Approximately 10,000 Person Years of Exposure From Seven Trials

Pooled Safety Analysis of Inclisiran in 3,576 Patients With Approximately 10,000 Person Years of Exposure From Seven Trials

Secukinumab in Pediatric Patients with Plaque Psoriasis: Pooled Safety Analysis from Two Phase 3 Randomized Clinical Trials.

Plaque psoriasis affects ~ 1% of the pediatric population, negatively impacting quality of life. The efficacy and safety of secukinumab in pediatric patients with moderate to severe or severe chronic plaque psoriasis have been established in two pivotal phase 3 trials (open-label, NCT03668613; double-blind, NCT02471144). The aims were to report the pooled safety of secukinumab up to 52 weeks from two studies in subgroups of pediatric patients stratified by age and bodyweight, and to present, alongside the pediatric data, the pooled safety data from four pivotal adult secukinumab trials. The safety of secukinumab was evaluated in subgroups of pediatric patients defined by age (6 to <12 and 12 to <18 years) and bodyweight (<25 kg, 25 to <50 kg, and ≥50 kg) in the pooled population. Patients received secukinumab low dose (LD; 75/75/150 mg), secukinumab high dose (HD; 75/150/300 mg), placebo, or etanercept (0.8 mg/kg). For safety analyses, data were pooled from the pediatric studies NCT03668613 and NCT02471144, and presented alongside the pooled data from four adult pivotal studies (NCT01365455, NCT01636687, NCT01358578, NCT01555125). A total of 198 pediatric patients (overall exposure: 184.6 patient-years [PY]) and 1989 adult patients (1749.5 PY) receiving secukinumab up to week 52 were included in this analysis. At week 52, the incidence of adverse events (AEs) was lower in the lower age and bodyweight subgroups. The AEs reported within these subgroups were consistent with the overall AEs reported in this analysis. Overall, exposure-adjusted incidence rates for treatment-emergent AEs were lower in the secukinumab-treated pediatric pool (198.8/100 PY) compared with the etanercept (266.3/100 PY) and adult pools (256.1/100 PY). Up to 52 weeks, the incidence rates of the AEs in the secukinumab-treated patients in the 6 to <12 years subgroup and 12 to <18 years subgroup were 167.7/100 PY and 214.7/100 PY, respectively. Similarly, incidence rates of the AEs in the secukinumab-treated patients in the <25 kg, 25 kg to <50 kg, and ≥50 kg subgroups were 177.3/100 PY, 192.5/100 PY, and 206.8/100 PY, respectively. Nasopharyngitis was the most frequently reported AE in secukinumab-treated pediatric patients across age (<12 years: 11.8/100 PY; ≥12 years: 42.4/100 PY) and bodyweight (<25 kg: 22.8/100 PY; 25 kg to <50 kg: 19.0/100 PY; ≥50 kg: 43.0/100 PY). Of the 198 secukinumab-treated pediatric patients, one reported nail Candida, one reported skin Candida, and two reported vulvovaginal Candida. Transient and mostly mild events of neutropenia were observed with secukinumab, none leading to study treatment discontinuation. No incidence of treatment-emergent anti-drug antibodies was reported in pediatric patients treated with secukinumab. Secukinumab was well tolerated in pediatric patients with moderate to severe and severe plaque psoriasis across age and bodyweight subgroups. The overall safety profile of secukinumab in pediatric patients was consistent with that of adult patients. NCT03668613 (Novartis Study Code CAIN457A2311, referred to as A2311), actual study start date: August 29, 2018; actual primary completion date: September 19, 2019; estimated study completion date: September 14, 2023. NCT02471144 (Novartis Study Code CAIN457A2310, referred to as A2310), study start date: September 29, 2015; primary completion date: December 13, 2018; estimated study completion date: March 31, 2023.

399 Pooled safety analysis of lebrikizumab in patients with uncontrolled asthma from three randomized clinical trials

Abstract LAVOLTA (L)I, LII and ACOUSTICS were randomized, placebo-controlled, double-blinded, Phase 3 trials of lebrikizumab, a monoclonal antibody targeting interleukin-13, in patients with uncontrolled asthma (LI, NCT01867125; LII, NCT01868061; ACOUSTICS, NCT01875003). These studies failed to provide consistently significant efficacy results in uncontrolled asthma. This study aims to report pooled safety analysis of lebrikizumab in patients during the 52-week placebo-controlled period from the three clinical trials. Adults in LI and LII, adolescents (12–17 years) in ACOUSTICS, with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40–90% predicted and stable background therapy were randomized 1 : 1 : 1 to lebrikizumab 125 or 37·5 mg or placebo (PBO) subcutaneously once every 4 weeks. Safety analyses were based on all patients who received at least one dose of study drug, with patients grouped by assigned treatment. Safety was assessed using summary of adverse events (AEs). The proportions of patients who experienced treatment-emergent AEs [combined lebrikizumab doses (LEB), 1281 (77%) of 1661 patients vs. PBO, 650 (78%) of 883 patients], serious AEs (7.6% vs. 8.5%) and AEs leading to study drug discontinuation (3.4% vs. 3.6%) were similar between LEB and PBO. One death occurred in the PBO group. Similar frequencies of key safety events, including conjunctivitis (LEB, 1.6%; PBO, 1.7%), infections and infestations (LEB, 51.6%; PBO, 50.7%), and eosinophil-related disorders (LEB, 0.2%; PBO, 0.2%) were noted; higher frequency of eosinophilia (&amp;gt;500 eosinophils/mm3) was reported (LEB, 1.1%; PBO, 0%). The safety profile was similar between lebrikizumab and placebo in adults and adolescents with uncontrolled asthma.