Fatal Adverse Events Research Articles

A tumor-responsive nanostrategy for reducing the risk of immunotherapy-related myocarditis

Immune checkpoint blockade (ICB) therapy using anti-programmed cell death 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTLA4), either individual or in combination, has emerged as a pioneer in clinical immunotherapy for various human cancers. However, immune-related adverse effects (irAEs) remain the significant hindrances to their clinical development. In particular, immune-related myocarditis has emerged as a fatal adverse event with the highest fatality rate. For this purpose, we report herein the first example of uncoupling efficacy and myocarditis toxicity in checkpoint blockade cancer therapy. This efficient, yet highly safe access to ICB therapy was achieved by a simple nanoplatform that masked anti-PD1/CTLA4 antibodies to albumin via a ROS-cleavable linker. An in-depth investigation of the experimental autoimmune myocarditis (EAM) mouse model revealed the avoiding exacerbation of myocarditis of our nanomedicine. Notably, the on-demand release of antibodies at the tumor sites enables the combined checkpoint antibody activity. The present study uncouples the ICB efficacy and toxicity, and highlights the irresistible charm of TME-responsive nanoantibodies in clinical cancer immunotherapy, offering solutions to challenges in the advancement of TME-responsive drug delivery toward clinical application.

Cardiotoxic profiles of CAR-T therapy and bispecific T-cell engagers in hematological cancers

BackgroundChimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers, which redirect T-cells to tumor antigens, have immensely benefitted patients with relapsed/refractory B-cell cancers. How these therapies differ in cardiotoxicity is underexplored. We used the World Health Organization pharmacovigilance database, VigiBase, to compare cardiotoxicity profiles between CD19-targeted CAR-T therapy and blinatumomab (a CD19/CD3-targeted bispecific T-cell engager).MethodsSafety reports in VigiBase were filtered for diffuse large B-cell lymphoma (DLBCL, n = 17,479) and acute lymphocytic leukemia (ALL, n = 28,803) for all adverse reactions. Data were further filtered for patients taking CAR-T therapy or blinatumomab. Reporting odds ratios (ROR) and fatality rates were compared between CAR-T cell products (e.g. tisagenlecleucel and axicabtagene ciloleucel), and between CAR-T therapy and blinatumomab.ResultsTisagenlecleucel is associated with cardiac failure (IC025 = 0.366) with fatality rates of 85.7% and 80.0% in DLBCL and pediatric ALL patients respectively. For DLBCL patients, axicabtagene ciloleucel has greater reporting for hypotension than tisagenlecleucel (ROR: 2.54; 95% CI: 1.28–5.03; p = 0.012), but tisagenlecleucel has higher fatality rates for hypotension than axicabtagene ciloleucel [50.0% (tisagenlecleucel) vs 5.6% (axicabtagene ciloleucel); p < 0.001]. Blinatumomab and tisagenlecleucel have similar fatality rates for hypotension in pediatric ALL patients [34.7% (tisagenlecleucel) vs 20.0% (blinatumomab); p = 0.66].ConclusionsTisagenlecleucel is associated with severe and fatal adverse cardiac events, with higher fatality rates for hypotension compared to axicabtagene ciloleucel in DLBCL patients, but similar hypotension fatality rates compared to blinatumomab in pediatric ALL patients. Effective management necessitates experienced physicians, including cardio-oncologists, skilled in interdisciplinary approaches to manage these toxicities.

Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology . We focus specifically on the application of immune checkpoint inhibitors (ICIs) and microsatellite instability (MSI) in gastric cancer (GC). The four pillars of GC management have long been considered, including surgery, chemotherapy, radiotherapy and targeted therapy. However, immunotherapy has recently emerged as a ”fifth pillar”, and its use is rapidly expanding. There are four principal strategies for tumor immunotherapy: ICIs, tumor vaccines, adoptive immunotherapy and nonspecific immunomodulators. Of them, ICIs are the most advanced and widespread type of cancer immunotherapy for GC. Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy. In particular, inhibition of the PD-1/PD-L1 axis with ICIs, including nivolumab and pembrolizumab, has emerged as a novel treatment strategy for advanced GC. Unfortunately, these therapies are sometimes associated with often subtle, potentially fatal immune-related adverse events (irAEs), including dermatitis, diarrhea, colitis, endocrinopathy, hepatotoxicity, neuropathy and pneumonitis. We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges, emergency department revisits, and downstream complications. Recent studies have revealed that MSI-high or mismatch- repair-deficient tumors, regardless of their primary site, have a promising response to ICIs. So, it is important to detect MSI before applying ICIs for treatment of GC.

Efficacy and safety evaluation of Allisartan Isoproxil in patients with hypertension: a meta-analysis.

This study aimed to evaluate the effectiveness and safety of Allisartan Isoproxil in the management of hypertension. A comprehensive search was conducted across both English and Chinese databases, including the Cochrane Library, Embase, PubMed, Web of Science, Chinese Journal Full Text Database (CNKI), Wanfang Digital Periodical Full Text Database, and VIP Chinese Periodical Database (VIP), up to March 24, 2024. Randomized controlled trials (RCTs) investigating alisartan axetil for hypertension management were selected. Literature quality was assessed, and data were extracted for meta-analysis using Stata 15.1 software. The quality of evidence for outcome indicators was evaluated using the GRADE system level. Six RCTs involving 767 participants were included. Meta-analysis revealed that, compared to placebo, the Allisartan Isoproxil group exhibited a significant reduction in systolic blood pressure (SBP) [WMD = -8.08, 95% CI (-11.81, 4.10), p = 0.000] and brachial-ankle pulse wave velocity (baPWV) [SMD = -0.69, 95% CI (-1.17, 0.20), p = 0.006]. However, the reduction in diastolic blood pressure (DBP) was not statistically significant [WMD = -5.48, 95% CI (-11.07, 0.10), p = 0.054]. Additionally, compared to calcium channel blockers (CCB) and angiotensin II receptor blockers (ARB), Allisartan Isoproxil did not significantly affect SBP [WMD = 0.20, 95% CI (-3.71, 4.10), p = 0.921] or DBP [WMD = 0.16, 95% CI (-2.11, 2.43), p = 0.891]. Allisartan Isoproxil demonstrated superior effects in increasing nitric oxide (NO) levels and decreasing endothelin (ET) levels compared to control groups [WMD = 9.56, 95% CI (6.42, 12.71), p = 0.000], [WMD = -7.42, 95% CI (-11.13, -3.71), p = 0.000], and showed a higher effective control rate of blood pressure [RR = 1.26, 95% CI (1.13, 1.41), p = 0.000]. Subgroup analysis did not reveal significant differences. Regarding safety, there were no statistically significant differences in adverse events between the Allisartan Isoproxil group and the control groups [RR = 0.99, 95% CI (0.74, 1.32), p = 0.928], and no fatal adverse events were reported. Allisartan Isoproxil is effective in reducing SBP and baPWV, increasing NO, decreasing ET, and achieving a higher control rate of blood pressure in patients with essential hypertension. These benefits are achieved with minimal adverse reactions. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023467869, identifier PROSPERO CRD42023467869.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Lenvatinib (Lenv) plus tislelizumab (Tis) combined with or without transarterial chemoembolization (TACE) in first-line treatment of unresectable hepatocellular carcinoma (uHCC): A prospective, non-randomized, open-label, phase II cohort study.

e16169 Background: The synergistic potential of programmed death protein-1 inhibitors and tyrosine kinase inhibitors in treating uHCC has been established. TACE, a cornerstone in uHCC therapy, primes the tumor microenvironment for immunotherapy by releasing neoantigens and inducing ischemia. This study explores the efficacy and safety of Lenv plus Tis, combined with or without TACE, in a first-line setting. Methods: This phase II study enrolled patients (pts) with pathologically and/or radiologically diagnosed uHCC eligible for embolization, with at least one measurable lesion, Child-Pugh class A/B, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Pts received Tis (200mg every 3 weeks) and Lenv (oral dose adjusted by weight: 8mg for &lt;60kg and 12mg for ≥60kg) with or without conventional TACE, as determined by the treating physician. The primary endpoint was the objective response rate (ORR), with secondary endpoints including overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: By the data cutoff on January 27, 2024, 37 pts were enrolled: 12 received Lenv+Tis (cohort 1), and 25 received Lenv+Tis+TACE (cohort 2). Median follow-up time was 10.66 months. The ORR was 33.3% in cohort 1 and 68.0% in cohort 2, with DCRs of 100% and 96%, respectively (mRECIST). Median OS was 10.85 months (95% CI, 4.76-16.95) for cohort 1 and 13.61 months (95%CI, NE-NE) for cohort 2. Median PFS was 10.85 months (95% CI, NE-NE) for cohort 1, and 11.86 months (95% CI, 6.49-16.73) for cohort 2. Grade 3-4 treatment-emergent adverse events (teAE) occurred in 50% of cohort 1 and 68% of cohort 2. No fatal adverse event was reported. The most common grade 3-4 teAE (incidence &gt;10%) were anaemia (17%) in cohort 1, and decreased platelet count (16%), hypertension (16%), rash (16%), fatigue (12%), elevated ALT (12%) in cohort 2. Conclusions: Both Lenv+Tis and Lenv+Tis+TACE showed promising efficacy and manageable safety in the first-line treatment of uHCC. More pts were recruiting to further prove these results. Clinical trial information: NCT05842317 . [Table: see text]

Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): Updated analysis from a phase I/II study.

7008 Background: Glofitamab, a bispecific antibody with a novel 2:1 (CD20:CD3) format, engages and redirects T cells to eliminate malignant B cells. In a Phase I/II study (NCT03075696), fixed-duration glofitamab monotherapy showed high, durable complete responses (CR) and manageable safety in patients (pts) with heavily pretreated R/R MCL (Phillips et al. ASH 2022). We report updated efficacy and safety data for pts with R/R MCL. Methods: Pts received obinutuzumab pretreatment (Gpt; 1000mg or 2000mg) 7 days before their first glofitamab dose. Glofitamab step-up dosing was given on Cycle (C) 1 Day (D) 8 (2.5mg) and D15 (10mg), and target dose (16mg or 30mg) from C2D1 to C12 as a fixed-duration therapy. Efficacy endpoints were CR, overall response rate (ORR), duration of CR (DOCR), duration of response (DOR) and progression-free survival (PFS). Post-hoc PFS and overall survival (OS) landmark analyses were performed in pts with a CR at end of treatment (EOT). Results: As of Sept 4, 2023, 61 pts were enrolled; 60 received study treatment (1000mg Gpt, n=16; 2000mg Gpt, n=44). Median number of prior lines of therapy was 2 (range: 1–5); 73.3% were refractory to the last line of prior therapy. Median duration of glofitamab therapy was 7.4 months; median number of cycles was 12. Of the 31 pts (51.7%) who received prior Bruton’s tyrosine kinase inhibitor (BTKi) therapy, 29 (93.5%) were BTKi refractory; median number of prior lines of therapy was 3 (range: 1–5); 90.0% were refractory to the last line of prior therapy. At a median PFS follow-up of 17.2 months, ORR and CR rate were 85.0% and 78.3%, respectively. Median DOCR was 15.4 months; the majority of CRs (28/47; 59.6%) were ongoing at data cut-off. Of 19 pts with a CR, 9 had disease progression and 10 died (fatal adverse event [AE], n=8; COVID, n=7; septic shock, n=1). Estimated 12-month DOCR and DOR rates were 71.0% and 66.6%, respectively. Median PFS was 16.8 months. Landmark analyses indicated that most pts with a CR at EOT were alive and progression free 15 months post-EOT (OS rate, 72.7%; PFS rate, 59.2%). Observed efficacy data were consistent across both Gpt cohorts. In post-BTKi pts after a median PFS follow-up of 26.1 months, ORR and CR rate were 74.2% and 71.0%, respectively. Median DOCR was 12.6 months; median PFS was 8.6 months. No new safety signals were observed. Cytokine release syndrome (CRS) remained the most common AE (42/60, 70.0%; Grade 1/2, 58.3%) and was lower in the 2000mg (63.6%) vs the 1000mg (87.5%) Gpt cohort. Glofitamab monotherapy (2000mg Gpt) is currently under investigation in the Phase III GLOBRYTE study (NCT06084936). Conclusions: Fixed-duration glofitamab continues to demonstrate compelling response rates that are maintained beyond EOT, with long-term durability observed in heavily pretreated pts with R/R MCL, including pts with prior BTKi therapy. The safety profile was manageable and CRS mainly low grade. Clinical trial information: NCT03075696 .

Safety, tolerability and efficacy of 212Pb-DOTAMTATE as a targeted alpha therapy for subjects with unresectable or metastatic somatostatin receptor-expressing gastroenteropancreatic neuroendocrine tumors (SSTR+ GEP-NETs): A phase 2 study.

4020 Background: 212Pb-DOTAMTATE is a Targeted Alpha Therapy (TAT) in clinical development for subjects with SSTR+ neuroendocrine tumors. A phase I dose-escalation study has already been completed (Delpassand et al. J Nucl Med 2022). TAT holds the promise to improve outcomes versus Peptide Receptor Radionuclide Therapy (PRRT) with beta-emitters like 177Lu-DOTATATE, currently considered the standard of care for subjects with GEP-NETs. Methods: ALPHAMEDIX 02 is a Phase II, open-label, multicenter study evaluating the safety, tolerability and efficacy of 212Pb-DOTAMTATE in PRRT-naïve (Cohort 1, N = 36) and PRRT-refractory (Cohort 2, Target N = 30) subjects with histologically confirmed unresectable or metastatic GEP-NETs, positive somatostatin analogue imaging and at least 1 site of measurable disease per RECIST 1.1. 212Pb-DOTAMTATE was administered at 67.6 μCi/kg per cycle, with a maximum activity administered per cycle of 5.5 mCi every 8 weeks, for up to 4 cycles. Primary endpoints include overall response rate (ORR) per RECIST1.1, and incidence and severity of adverse events (AEs). Secondary endpoints include progression free survival, overall survival , and health-related quality of life. Initial results of the already completed cohort 1 are presented. Results: In cohort 1, 17 out of 36 subjects with metastatic SSTR+ GEP-NETs achieved a confirmed response (ORR 47.2% (32.0-63.0%)). In the Phase I trial, five out of eight PRRT- naïve subjects with SSTR+ GEP-NETs treated with the same regimen of 212Pb-DOTAMTATE achieved a response (ORR 62.5% (30.6-86.3%)): the combined ORR from both studies is 50% (22 out of 44, 95%-CI:36% - 64%). Median Duration of Response (DOR) has not been reached in both studies. Four out of five subjects (80%) with confirmed response in Phase I had a DOR of ≥ 12 months. In the ongoing Phase II study the response follow-up for 10 subjects with confirmed response is currently shorter than 6 months: so far 7 out of 17 subjects (41%) with confirmed response had a DOR of ≥ 6 months, and one of these subjects had a DOR of ≥ 12 months. Lymphocytopenia is a lead cause of the 59% grade 3 and 4 AEs reported in subjects in cohort 1. Overall, 4 fatal AEs were reported: death / progressive disease (N = 2), carcinoid syndrome (N = 1) and sepsis (N = 1). Conclusions: In PRRT-naïve subjects with SSTR+ unresectable or metastatic GEP-NETs treatment with up to 4 cycles of ²¹²Pb-DOTAMTATE (67.6 μCi/kg/cycle) was well-tolerated, with a safety profile consistent with the underlying disease and expected toxicities of radioligand therapy, similar to 177Lu-DOTATATE. The ORR of 47.2% in cohort 1 (50% in the pooled dataset) appears to be substantially higher than the ORR previously reported for 177Lu-DOTATATE in the pivotal NETTER-1 study (ORR 18% (10–25%)). Clinical trial information: NCT05153772 .

Safety of tabelecleucel with pembrolizumab in recurrent/metastatic Epstein–Barr virus-associated nasopharyngeal carcinoma.

6096 Background: Despite standard treatment with radiation and/or chemotherapy, approximately one in four patients (pts) with nasopharyngeal carcinoma (NPC) will develop recurrent/metastatic (RM) disease that is associated with poor prognosis. Programmed cell death ligand 1 (PD-L1) expression is upregulated in NPC due to Epstein–Barr virus (EBV) activation. Tabelecleucel (tab-cel), an off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy, has shown promising antitumor activity in pts with RM EBV+NPC (Prockop, JCO 2016). The anti-PD-1 antibody pembrolizumab (pembro) is also active in NPC. To characterize the safety profile and preliminary efficacy of tab-cel combined with pembro in RM EBV+NPC, we initiated a phase 1b/2 study (NCT03769467). Here we report safety outcomes in 12 subjects treated in the phase 1b portion of the study. Methods: The multicenter, open-label, single-arm phase 1b portion of the study was designed to evaluate the safety of tab-cel in combination with pembro in pts with incurable RM EBV+NPC previously treated with platinum-containing therapy. Pts were either checkpoint-inhibitor naïve (n=6) or experienced to anti-PD-1/PD-L1 therapy (n=6). Tab-cel was administered intravenously (IV) on days 1, 8, and 15 of a 21-day cycle. Initial tab-cel dose was 2x106 cells/kg. Pembro was administered at 200 mg IV Q3W. Primary endpoints of phase 1b focused on assessing safety. Results: As of the final data cutoff, 12 subjects were treated as part of the phase 1b portion of the study. Subjects were 75% Asian and 50% male, with a median age (min, max) of 51 (20, 72) years and a median time from initial diagnosis to first dose of tab-cel (min, max) of 47.7 (8.0, 221.8) months. All subjects had received prior platinum-based chemotherapy/chemoradiation. No dose-limiting toxicities or fatal treatment-emergent adverse events (TEAEs) were identified. All 12 subjects reported ≥1 TEAE; the most common TEAEs reported by ≥4 subjects were disease progression (8 subjects, 66.7%), myalgia (5 subjects, 41.7%), pyrexia, arthralgia, and hyponatremia (4 subjects, 33.3%, each). No ≥ grade 3 TEAEs were considered related to tab-cel or pembro. No TEAEs considered related to tab-cel or pembro led to study discontinuation. No clinically significant abnormal trends were identified in laboratory parameters or vital signs. Although the phase 1b portion of the study was not designed to assess efficacy, the best response seen was stable disease in 6 of 12 pts (50%). Conclusions: Phase 1b data demonstrated combination therapy of tab-cel and pembro to be well tolerated and identified a recommended phase 2 dose in subjects with platinum-pretreated RM EBV+NPC. The study was discontinued after the phase Ib portion due to an evolving immunotherapy treatment landscape for this disease, which would need to be considered for further clinical development. Clinical trial information: NCT03769467 .

Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-Related Macular Degeneration

ObjectiveTo evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DesignPhase 1, open-label, single-center, first-in-human clinical study. SubjectsAdult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included. MethodsPatients (N=17) were sequentially enrolled into low (3.56×1010 viral genome [vg]/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. Main Outcome MeasuresSafety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. ResultsBaseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center–involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24. ConclusionsAll 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.

Safety and time to response of [177Lu]Lu-DOTATATE in patients with newly diagnosed advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Sub-analysis of the phase 3 randomized NETTER-2 study.

4131 Background: NETTER-2 (NCT03972488) is the first randomized study to evaluate radioligand therapy ([177Lu]Lu-DOTA-TATE; hereafter 177Lu-DOTATATE) at first line (1L) in patients (pts) with advanced, well-differentiated higher grade (G2 and G3) gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Significant improvements in progression-free survival and objective response rate (ORR) were observed for pts receiving 177Lu-DOTATATE. This sub-analysis of NETTER-2 assessed safety and time to response (TTR). Methods: Eligible pts (n=226) were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki67 ≥10% and ≤55%) advanced GEP-NETs and were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq every 8 weeks [Q8W]) plus 30 mg octreotide long-acting repeatable (LAR) Q8W during 177Lu-DOTATATE treatment then Q4W (177Lu-DOTATATE arm), or 60 mg octreotide LAR Q4W (control arm). Hematologic adverse events (AEs) and laboratory toxicities were scored according to CTCAE grade. Response was assessed centrally based on conventional imaging (RECIST 1.1 criteria). Results: The AE pattern in the 177Lu-DOTATATE arm was consistent with the established safety profile. Among laboratory abnormalities, grade 3/4 decreases in lymphocytes (38.1% vs 2.7%), leukocytes (4.1% vs 0), neutrophils (3.4% vs 0), platelets (2.0% vs 0) and hemoglobin (1.4% vs 2.7%) were observed in 177Lu-DOTATATE (n=147) and control (n=73) arms, respectively; median time to first occurrence of hematologic toxicities was 4.4 months among pts with immediate hematotoxicities. These events were transient and manageable. There was no notable difference in infection rates between treatment arms (31.3% 177Lu-DOTATATE and 27.4% control). One case of myelodysplastic syndrome was observed (177Lu-DOTATATE arm ~14 months after first cycle). Five fatal AEs occurred during the randomized treatment period; all considered unrelated to treatment and attributed to GEP-NET progression. AEs leading to 177Lu-DOTATATE dose interruption, reduction and discontinuation occurred in 14 (9.5%), 2 (1.4%) and 3 (2.0%) pts, respectively. Among 65 responders in the 177Lu-DOTATATE arm (ORR 43 %), median TTR (Q1, Q3) was 5.7 months (4.1, 8.3). Most responses occurred during the 4-cycle treatment with 177Lu-DOTATATE. Conclusions: In pts with advanced G2 and G3 (Ki67 ≥10% and ≤55%) GEP-NETs treated with 177Lu-DOTATATE at 1L the most common hematologic toxicity was lymphopenia, but infection rates were similar vs control. With a median TTR of 5.7 months, most responses to 177Lu-DOTATATE occurred during scheduled treatment. Overall, the study confirmed the safety profile of 177Lu-DOTATATE and supports its use at 1L for this pt population. Clinical trial information: NCT03972488 .

Efficacy and safety of EUS-guided hepatogastrostomy: A systematic review and meta-analysis.

EUS-guided hepaticogastrostomy (EUS-HGS) is one of the preferred methods in biliary drainage where ERCP fails or is contraindicated. The clinical outcomes of EUS-HGS are not well studied because of variability in procedure technique. We conducted a search of multiple electronic databases and conference proceedings from inception through January 2023. The clinical outcomes studied were pooled technical success, clinical success, and adverse events. Standard meta-analysis methods were used using the random-effects model, and heterogeneity was studied by I 2 statistics. We analyzed 44 studies, which included 19 prospective and 25 retrospective studies. The pooled technical success rate of EUS-HGS was 94.4% (confidence interval [CI], 92.4%-95.9%; I 2 = 0%), and the pooled clinical success rate was 88.6% (CI, 83.7%-92.2%; I 2 = 0%). The pooled adverse outcomes with EUS-HGS were 23.8% (CI, 19.6%-28.5%; I 2 = 0%). The mild adverse event rate associated with HGS was 5.8% (4.2%-8.1%; I 2 = 0%), moderate adverse event rate was 12.1% (9.1%-15.8%; I 2 = 16%), and severe adverse event rate was 4.2% (3.0%-5.7%; I 2 = 61%), whereas fatal adverse event rate was 3.2% (1.9%-5.4%; I 2 = 62%). On subgroup analysis, the pooled rate of adverse events of EUS-guided hepaticogastrostomy with antegrade stenting was 13.3% (95% CI, 8.2%-21.0%). The pooled technical success with EUS-guided hepaticogastrostomy with antegrade stenting was 89.7% (95% CI, 82.6%-94.2%), and clinical success was 92.5% (95% CI, 77.9%-97.7%). On the basis of our analysis of EUS-HGS, the overall technical success was 94.4%, and the clinical success rate was 88.6%, and the overall adverse events were reported to be 23.8%. These data can also help improve the clinical benefits of EUS-HGS in the selected patients in whom it is performed.

Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial

A standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC. This single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0-1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1-4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1-day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4-5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed. Between Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72-79). The median number of chemotherapy cycles received was five (IQR 3-6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30-51]) and morbidity events were observed in 24 patients (31% [22-42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3-4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3-4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%). The study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE. French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC, and the Ligue Contre le Cancer), Sandoz, GEFLUC, and GEMLUC. For the French translation of the abstract see Supplementary Materials section.

Long-term efficacy and immunogenicity of Ad26.RSV.preF–RSV preF protein vaccine (CYPRESS): a randomised, double-blind, placebo-controlled, phase 2b study

Ad26.RSV.preF-RSV preF protein showed 80·0% vaccine efficacy against respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in older adults during one RSV season. No RSV vaccines have shown three-season efficacy. We aimed to evaluate efficacy of Ad26.RSV.preF-RSV preF protein over three RSV seasons. CYPRESS was a randomised, double-blind, placebo-controlled, phase 2b study done at 40 US clinical research centres wherein adults aged 65 years or older were centrally randomly assigned 1:1 by computer algorithm to receive Ad26.RSV.preF-RSV preF protein or placebo (one intramuscular injection) on day 1. Investigators, participants, site personnel, and the sponsor were masked to vaccine allocation, except for individuals involved in preparation of study vaccinations. The primary endpoint (first occurrence of RSV-mediated LRTD meeting one of three case definitions) was previously reported. Here, the predefined exploratory endpoint of vaccine efficacy against RSV-positive LRTD was assessed in the per-protocol efficacy set (all participants randomly assigned and vaccinated without protocol deviations affecting efficacy) through season 1 and from day 365 until the end of season 3. Humoral and cellular immunogenicity was assessed in a subset of randomly assigned and vaccinated participants. The secondary endpoint of safety through the first RSV season was previously reported; follow-up for selected safety outcomes (fatal adverse events, adverse events leading to study discontinuation, serious adverse events, and vaccine-related serious adverse events) until study completion is reported here in all randomly assigned and vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT03982199 and is complete. Of 6672 adults screened, 5782 participants (2891 each receiving vaccine or placebo) were enrolled and vaccinated between Aug 5 and Nov 13, 2019. The season 2 per-protocol efficacy set included 2124 vaccine recipients and 2126 placebo recipients (season 3: 864 and 881; across three seasons: 2795 and 2803, respectively). Vaccine efficacy against RSV LRTD was 76·1% (95% CI 26·9-94·2) over seasons 2 and 3 and 78·7% (57·3-90·4) across three seasons. For those in the immunogenicity subset (vaccine n=97; placebo n=98), immune responses remained above baseline for at least 1 year. Serious adverse events occurred in 47 (2·1%) and 12 (1·3%) vaccine recipients and 45 (2·1%) and 10 (1·1%) placebo recipients during seasons 2 and 3, respectively. No treatment-related serious or fatal adverse events were reported. Ad26.RSV.preF-RSV preF protein maintained high efficacy against RSV LRTD in older adults across three RSV seasons. Janssen Vaccines & Prevention.

Phase Ib/II Study of Lacnotuzumab in Combination with Spartalizumab in Patients with Advanced Malignancies.

Blocking the colony-stimulating factor 1 (CSF-1) signal on tumor-associated macrophages can lead to an upregulation of checkpoint molecules, such as programmed cell death ligand 1 (PD-L1), thus causing resistance to this blockade. Combining spartalizumab (PDR001), a high-affinity, ligand-blocking, humanized anti-PD-1 immunoglobulin G4 antibody, with lacnotuzumab (MCS110), a high-affinity, humanized monoclonal antibody directed against human CSF-1 can potentially overcome this resistance. This was a multicenter, phase Ib/II trial using a combination of spartalizumab with lacnotuzumab in patients with advanced cancers, including anti-PD-1/PD-L1 treatment-resistant melanoma, and anti-PD-1/PD-L1 treatment-naïve triple-negative breast cancer, pancreatic cancer, and endometrial cancer (ClinicalTrials.gov identifier: NCT02807844). The primary objective of dose escalation phase Ib was to assess safety, tolerability, and recommended phase II dose. The primary objective of the phase II expansion study was to assess the combination's antitumor activity, including objective response rate and clinical benefit rate. A total of eight patients (five in phase Ib and three in phase II) were evaluable for adverse events (AEs) at our study site. All eight patients experienced at least grade 1 AE. The most common treatment-related AEs were increased serum aspartate aminotransferase (38%), fatigue (38%), anemia (25%), increased alkaline phosphatase (25%), hyperbilirubinemia (25%), hypocalcemia (25%), and hypoalbuminemia (25%). Most of these AEs were grade 1 or 2. None of the patients experienced grade 4 AEs and no drug-related fatal AEs were reported among the eight patients treated in the study. One (13%) patient had stable disease (SD) (captured as unknown by the study sponsor because the evaluation criteria set per protocol was not met) and three (38%) patients had progressive disease. Four (50%) patients developed clinical disease progression based on investigator evaluation. One patient with pancreatic cancer achieved immune-related SD for 26 months while on the study treatments. The study completed phase Ib dose escalation and phase II. However, gating criteria for efficacy were not met for expansion beyond 80 patients in phase II and the sponsor did not continue development of the combination of spartalizumab and lacnotuzumab for oncology indications. The potential signal of activity in pancreatic cancer should be further explored.

Abstract CT113: A dose-exploring, randomized, open-label, Phase I study for toripalimab subcutaneous injection in patients with advanced nasopharyngeal carcinoma

Abstract Background Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, in combination with gemcitabine and cisplatin (GP) has been approved as a first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) by the US FDA in October 2023. This is the first-in-human clinical trial (NCT05751486) to investigate the pharmacokinetics of toripalimab subcutaneous (SC) formulation in RM-NPC and determine the appropriate subcutaneous administration regimen for subsequent clinical trials. Methods Patients with histologically confirmed RM-NPC and without previously systemic therapy for RM disease were enrolled. Eligible patients were assigned to receive toripalimab SC 240 mg every 3 weeks (Q3W), 360 mg Q3W or 480 mg Q6W, in combination with GP for up to 6 cycles, followed by toripalimab SC monotherapy until disease progression, intolerable toxicity, or completion of 2 years of treatment. Tumor response was assessed per RECIST v1.1. The primary endpoint was pharmacokinetic (PK) profile. Secondary endpoints included safety, efficacy, and immunogenicity. Results From November 24, 2022 to November 20, 2023, a total of 38 patients (240 mg cohort, n=12; 360 mg cohort, n=13; 480 mg cohort, n=13) were enrolled, the median follow-up time was 6.8 months. The median age was 49 years, and 28 (73.7%) patients were males. PK analysis showed that in the first cycle, the exposure (AUC0-21days and Ctrough) of toripalimab 360 mg Q3W SC regimen was comparable to that of 240 mg Q3W intravenous (IV) regimen (table 1). Objective Response Rates (ORR) in 240 mg, 360 mg and 480 mg cohorts were 100%, 92.3% and 92.3%, respectively. By November 20, 2023, 71.1% (27/38) patients have ongoing responses. No new safety signal was identified. The incidence of Grade ≥3 adverse events (AEs) was 76.3% with no fatal AEs. The incidence of investigator-determined immune-related AEs was 36.8% with 1 (2.6%) Grade ≥3. Conclusions Toripalimab SC formulation showed similar safety and clinical efficacy with toripalimab IV formulation when combined with GP in patients with RM-NPC. The exposure of toripalimab 360 mg Q3W SC was comparable to that of 240 mg Q3W IV. Toripalimab SC formulation is planned for phase III clinical development. Table 1. PK parameters of each dose cohort. Parameters JS001sc Cohorts (N = 36) IV ref-model based 240 mg SC Q3W, n=12 480 mg SC Q6W, n=12 360 mg SC Q3W, n=12 240 mg IV Q3W, n=1014 Cycle 1 Ctrough, μg/mL GM (% CV) 10.2 (57.1) 8.4 (43.5) 18.6 (50.1) 10.2 (61.8) Cycle 1 AUC (0-Xd), μg•d/mL GM (% CV) 8376 (0-21 d) (39.3) 25316 (0-42 d) (35.4) 14229 (0-21 d) (58.2) 13386 (27.0) Bioavailability 62.6% (25.3%-100.0%) Citation Format: Hai-Qiang Mai, Ya-Qian Han, Guo-Wu Wu, Kun-Yu Yang, Chuan-Ben Chen, Mo Wang, Xian-Ming Luo, Shuang-Hui Wei, Xi Tan, Peng Xue, Rui-Hua Xu. A dose-exploring, randomized, open-label, Phase I study for toripalimab subcutaneous injection in patients with advanced nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT113.

CAR‐T‐cell products in solid tumors: Progress, challenges, and strategies

AbstractT cells engineered to express chimeric antigen receptors (CARs) with specificity toward tumor cells have led to promising outcomes in patients with hematological malignancies. Nevertheless, the application of CAR‐T cell therapy in solid tumors encounters several obstacles. These include tumor heterogeneity and immune escape, T cell exhaustion and restricted infiltration into the tumors that affect the therapeutic efficacy of CAR‐T cells, as well as “on‐target, off‐tumor” toxicities that can lead to severe and even fatal adverse events. In recent years, clinical trials and new approaches of CAR‐T cell therapy for solid tumors have made certain progress. Here, we update the outcomes of related clinical trials and summarize engineered strategies aiming to improve the efficacy and therapeutic safety of CAR‐T cells based on experimental and clinical studies.

PD-1 inhibition with retifanlimab and/or arginase inhibition with INCB001158 in Japanese patients with solid tumors: A phase I study.

Retifanlimab is a humanized monoclonal antibody targeting programmed death protein-1, and INCB001158 is an oral arginase inhibitor. This phase Ib study investigated retifanlimab, INCB001158, and their combination in Japanese patients with advanced solid tumors. Patients received retifanlimab (500 mg every 4 weeks [Q4W] i.v.) or escalating doses of INCB001158 (75 or 100 mg twice daily [BID]) monotherapy in Part 1 and combination of retifanlimab (500 mg Q4W) and INCB001158 (100 mg BID) in Part 2. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of recommended phase II doses in Japanese patients. Eighteen patients (retifanlimab or INCB001158 monotherapy and combination; n = 6 each) were enrolled at 2 sites in Japan. There were no DLTs, fatal adverse events (AEs), or discontinuations due to AEs. Rash (all grade 1) was the most common treatment-emergent AE with retifanlimab (n = 6). Treatment-related AEs were reported with retifanlimab (n = 4) or INCB001158 (n = 2) monotherapy and with combination (n = 4); an immune-related AE (thyroid disorder, grade 2) was reported with combination. Two responses were observed with retifanlimab monotherapy (1 complete, 1 partial) and 1 stable disease (SD), for an overall response rate of 33.3% (95% confidence interval [CI], 4.3-77.7) and disease control rate (DCR) of 50% (95% CI, 11.8-88.2). Three patients had SD with INCB001158 monotherapy (DCR 50%; 95% CI, 11.8-88.2). No responses or SD were observed with combination therapy. Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients.

“Through-stent enterography”: first experience with a novel technique intended to improve safety in endosonography-guided gastroenterostomy

Background and AimsEndosonographic-guided gastroenterostomy (EUS-GE) is a novel technique to manage symptoms of gastric outlet obstruction. Major challenges are the high mobility of intestinal loops and the transient loss of endosonographic visibility during the puncture. This can lead to stent-misdeployment, which can be associated with potentially fatal adverse events. By injecting contrast medium through the guidewire-channel of the lumen apposing metal stent (LAMS) application system under fluoroscopic guidance, a positive enterogram can confirm the position of the stent inside the intestinal lumen before its deployment. The aim of this study was to describe this novel technique and to assess its feasibility. MethodsThe data of 39 consecutive patients undergoing EUS-GE with “through-stent-enterography” between July 2020 and March 2022 were retrospectively collected and analyzed. Primary endpoint was to assess the technical success. Secondary endpoints were to assess adverse events, rate of reinterventions and clinical success. ResultsTechnical success was achieved in all cases (n=39). In two cases a second puncture was required to place the stent successfully. In one case, misdeployment could be avoided after a negative enterogram. In the other case, misdeployment occurred despite a positive enterogram a reintervention was needed. Clinical success was achieved in 92.3% (n=36). No major adverse events or mortalities were encountered. Conclusions“Through-stent-enterography” after the puncture to confirm the correct position of the stent in the small bowel is a novel and simple technique, which can potentially reduce the risk of misdepolyment of the stent.

Signal mining and risk analysis of Alprazolam adverse events based on the FAERS database

This study aims to evaluate the safety of Alprazolam by analyzing the FAERS database, provide data analysis for monitoring adverse drug reactions. This research encompasses adverse event (AE) reports related to Alprazolam from the first quarter of 2004 to the second quarter of 2023. Four signal mining and analysis methods were utilized, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Further exploration was conducted regarding patient characteristics and types of AEs. A total of 23,575 AE reports in which Alprazolam was the primary suspect drug were collected, identifying 347 Preferred Term (PT) signals and 27 System Organ Classes (SOCs). The number of AE reports increased annually, especially in 2015, 2018, 2019, and 2020. The main affected groups were females and the age range of 18 to 45. Psychiatric disorders, Nervous system disorders, and Gastrointestinal disorders were the most common the organ system in which the AEs occurred. There is a certain risk of drug abuse and suicide with Alprazolam. Most notably, several AEs not recorded in the Alprazolam leaflet appeared among the top 30 PTs in signal strength, including but not limited to Benzodiazepine drug level abnormal, Acquired amegakaryocytic thrombocytopenia, Cutaneous T-cell dyscrasia, and Coronary No-reflow Phenomenon. For the first time, AEs related to the cardiovascular system and platelet function were unveiled. The severe AE reports that resulted in "hospitalization" and "death" accounted for 30.96% and 21.86%. This study highlights the risks of suicide and misuse of Alprazolam. Other potential severe or fatal AEs, such as those related to the cardiovascular system, platelet function, and others, require further research to determine their precise mechanisms and risk factors.