Citations

Abstract Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.

Abstract There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder with oftentimes an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in bipolar disorder (BD). We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association with a subset of BD-I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement (response- emergent mania).

AbstractBackgroundCardiometabolic disorders (CMD) and Mild Cognitive Impairment (MCI) have been associated with an increased risk of developing dementia. However, brain glucose metabolism has not been compared between patients with CMD and MCI, and little is known about its associations with global cognitive performance. Here we examined regional brain 18F – FDG uptake in patients with CMD and MCI, and analyzed its potential associations with global cognitive performance.Methods55 patients with increased risk for developing dementia were recruited (MCI = 22; CMD = 33) in this cross‐sectional study. As a measure of brain glucose metabolism, PET/CT was performed and the mean uptake value in brain regions of interest (ROI) was obtained and standardized by whole brain uptake. Global cognitive performance was examined using the Mini‐Mental State Examination (MMSE). Group differences in brain metabolism and cognitive performance were examined. We conducted separate linear regression models considering standardized MMSE as the dependent variable, and mean 18F – FDG uptake in each of the ROI (and its CMD/MCI group‐interactions) as independent variables. Our models were adjusted by age, gender, years of education, and presence of at least one APOE e4 allele, and corrected for multiple testing with the False Discovery Ratio (FDR < 0.01).ResultsThe CMD and MCI groups were comparable in age, gender, education, and mean 18F‐FDG uptake across all the ROIs, but significantly different in MMSE (Table 1). Adjusted models for global cognitive performance showed significant group interactions with the mean 18F – FDG uptake in bilateral caudate and hippocampus, as well as in left‐hemisphere amygdala, cuneus, fusiform gyrus, and opercular part of the inferior frontal gyrus. Thus, significant negative associations of 18F – FDG uptake in the above ROIs and cognitive performance was observed in the MCI group (Figure 1 & Table 2).ConclusionsIn MCI patients, reduced global cognitive performance was significantly associated with high brain glucose metabolism in bilateral caudate and hippocampus, and with the left fusiform gyrus, cuneus, and inferior frontal gyrus (opercular part). These asymmetric associations between high metabolism and low cognitive performance could suggest compensatory effects in MCI patients but further research is needed to confirm this hypothesis.

Abstract Introduction Prospective data about quality of life (QoL) in men with breast cancer (BC) are lacking. A prospective registry (EORTC10085) of men with all BC stages, including a QoL correlative study, was performed as part of the International Male Breast Cancer Program. Methods Questionnaires at BC diagnosis included the EORTC QLQ-C30 and BR23 (BC specific module), adapted for men. High functioning and global health/QoL scores indicate high functioning levels/high QoL; high symptom-focused measures scores indicate high symptoms/problems levels. EORTC reference data for healthy men and women with BC were used for comparisons. Results Of 422 men consenting to participate, 363 were evaluable. Median age was 67 years, and median time between diagnosis and survey was 1.1 months. A total of 114 men (45%) had node-positive early disease, and 28 (8%) had advanced disease. Baseline mean global health status score was 73 (SD: 21), better than in female BC reference data (62, SD: 25). Common symptoms in male BC were fatigue (22, SD: 24), insomnia (21, SD: 28), and pain (16, SD: 23), for which women’s mean scores indicated more burdensome symptoms at 33 (SD: 26), 30 (SD: 32), and 29 (SD: 29). Men’s mean sexual activity score was 31 (SD: 26), with less sexual activity in older patients or advanced disease. Conclusions QoL and symptom burden in male BC patients appears no worse (and possibly better) than that in female patients. Future analyses on impact of treatment on symptoms and QoL over time, may support tailoring of male BC management.

SummaryBackgroundThere is limited real‐world data on comparative effectiveness of different biologic or small molecule agents as second‐line therapies in patients with ulcerative colitis (UC) with prior exposure to a tumour necrosis factor inhibitor (TNFi).MethodsWe conducted a retrospective cohort study using TriNetX, a multi‐institutional database to assess the efficacy of tofacitinib, vedolizumab and ustekinumab in patients with ulcerative colitis (UC) with prior exposure to a TNFi. Failure of medical therapy was defined as a composite outcome of intravenous steroids or colectomy within 2 years. One‐to‐one propensity score matching was performed for demographics, disease extent, mean haemoglobin, C‐reactive protein, albumin and calprotectin, prior IBD medications and steroid use between cohorts.ResultsAmong 2141 patients with UC and prior exposure to TNFi, 348 (16.2%), 716 (33.4%) and 1077 (50.3%) were switched to tofacitinib, ustekinumab and vedolizumab, respectively. After propensity‐score matching, there was no difference in the composite outcome (aOR: 0.77, 95% CI: 0.55–1.07) but higher risk of colectomy (aOR: 2.69, 95% CI: 1.31–5.50) in the tofacitinib cohort than the vedolizumab cohort. There was no difference in the risk of composite outcome (aOR: 1.29, 95% CI: 0.89–1.86) but higher risk of colectomy (aOR: 2.63, 95% CI: 1.24–5.58) in the tofacitinib cohort than the ustekinumab cohort. The vedolizumab cohort had a higher risk of composite outcome (aOR: 1.67, 95% CI: 1.29–2.16) than the ustekinumab cohort.ConclusionUstekinumab might be the preferred second‐line therapy over tofacitinib and vedolizumab in patients with UC that were previously exposed to a TNFi.

4006 Background: Liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Here, we present results from NAPOLI 3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1; stratified by Eastern Cooperative Oncology Group [ECOG] performance status, geographic region and presence/absence of liver metastases) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or Gem+NabP on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when at least 543 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. Median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gem+NabP group; median PFS was 7.4 months versus 5.6 months. Median (95% CI) duration of response was 7.3 (5.8–7.6) and 5.0 (3.8–5.6) months in patients who received NALIRIFOX and Gem+NabP, respectively. Grade 3/4 treatment-emergent adverse events occurring in at least 10% of patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in patients with mPDAC. The NALIRIFOX safety profile was consistent with the profiles of the regimen components and generally manageable. Clinical trial information: NCT04083235 . [Table: see text]

2517 Background: Approximately 50% to 60% of pts with r/r LBCL will either not achieve a complete response (CR) or will relapse with current treatments and require additional therapy. Autologous anti-CD19 chimeric antigen receptor T (CAR T) therapies have revolutionized the care of patients whose disease progresses following standard therapies, but patient-specific manufacturing processes and long wait times to treatment present challenges for their broad clinical use. Allogeneic (healthy-donor-derived), off-the-shelf, anti-CD19 (CAR T) treatment promises broader and more rapid access to one-dose treatment with curative intent. Initial phase 1 data for the anti-CD19 AlloCAR T cell product ALLO-501 (NCT03939026) and successor, ALLO-501A (NCT04416984), demonstrated a manageable safety profile with no dose-limiting toxicities (DLTs), and efficacy comparable to autologous CAR T therapy in pts with r/r LBCL who were autologous CAR T-naïve. This update provides additional follow up and a focus on participants who received the conditioning regimen and cells made with an optimized manufacturing process currently under study in the first potentially pivotal trial for an allogeneic CAR T product. Methods: In these two multicenter, single-arm, open-label, phase 1 trials, a cohort of autologous CAR T-naïve pts with r/r LBCL underwent 3-day lymphodepletion (LD) with FCA90, fludarabine (F, 30 mg/m2/day), cyclophosphamide (C, 300 mg/m2/day), and ALLO-647 (A [anti-CD 52 mAb] 30 mg/day; total dose: 90 mg) followed by a single dose of ALLO-501 or ALLO-501A produced by the Alloy manufacturing process. Results: As of Jan 26, 2023, 12 pts received the FCA90 LD regimen and CAR T therapy with 100% receiving product per specifications with a median time from enrollment to LD of 3 days. Median follow-up time (actual) was 7.1 months (range: 1.4, 36.0). No DLTs, severe (Gr3+) cytokine-release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) events occurred. An overall response rate and a CR rate of 66.7% and 58.3%, respectively, were observed. Median DOR was 23.1 months. Among 8 pts with the opportunity to be followed for 6 months, 5 (62.5%) had achieved CR and 4 (50.0%) sustained CR through 6 months. Analyses of vector copy number pharmacokinetics at Days 28 and 56 documented substantial and sustained expansion of CAR T cells. Conclusions: A one-time dose of allogeneic CAR T therapy following LD with FCA90 provided durable responses with a manageable safety profile in patients with r/r/ LBCL comparable to those treated with autologous CAR T cells. This treatment enables rapid access to off-the-shelf treatment with a median time from trial enrollment to treatment of 3 days. These findings support broader evaluation of ALLO-501A in the ongoing, first potentially pivotal phase 2 trial (ALPHA2) of off-the-shelf allogeneic CAR T cells. Clinical trial information: NCT03939026 .

TPS1115 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T + P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T + P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T + P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), PFS by Blinded Independent Central Review (BICR), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, Canada, Brazil, APAC and EU countries with additional sites planned. Clinical trial information: NCT05132582 .