Baseline Eastern Cooperative Oncology Group Research Articles

Exposure-Response Relationships for Pralsetinib in Patients with RET-Altered Thyroid Cancer or RET Fusion-Positive Nonsmall Cell Lung Cancer.

Pralsetinib is a highly potent oral kinase inhibitor of oncogenic RET (rearranged during transfection) fusions and mutations. Pralsetinib received approval from the United States Food and Drug Administration for the treatment of patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), and received accelerated approval for the treatment of patients with RET fusion-positive thyroid cancer. Exposure-response (ER) analyses of efficacy were performed separately in patients with thyroid cancer and in patients with NSCLC, but data for all patients were pooled for the safety analysis. ER models were developed with time-varying exposure; the effect of covariates was also examined. For patients with NSCLC, a higher starting dose was associated with improved progression-free survival (PFS), but this improvement did not correlate with a higher exposure overall. Significant covariates included sex and baseline Eastern Cooperative Oncology Group (ECOG) score. For patients with thyroid cancer, a higher exposure was associated with improved PFS. Significant covariates included prior systemic cancer therapy and ECOG score. For safety, higher exposure was associated with a greater risk of grade≥3 anemia, pneumonia, and lymphopenia. Patients with an ECOG score of ≥1 had an increased risk of grade≥3 pneumonia. Non-White patients had a lower risk of grade≥3 lymphopenia. ER analysis revealed that higher pralsetinib exposure was associated with improved PFS in thyroid cancer, but not in NSCLC. However, a higher starting dose (ie, 400 vs ≤300mg daily) was correlated with better PFS for all indications. Higher exposure was also associated with an increased risk of grade≥3 adverse events (AEs); however, the overall incidence of these events was acceptably low (≤20%). This analysis supports the use of a 400mg starting dose of pralsetinib, allowing for dose reduction in the event of AEs.

Harnessing physical activity monitoring and digital biomarkers of frailty from pendant based wearables to predict chemotherapy resilience in veterans with cancer

This study evaluated the use of pendant-based wearables for monitoring digital biomarkers of frailty in predicting chemotherapy resilience among 27 veteran cancer patients (average age: 64.6 ± 13.4 years), undergoing bi-weekly chemotherapy. Immediately following their first day of chemotherapy cycle, participants wore a water-resistant pendant sensor for 14 days. This device tracked frailty markers like cadence (slowness), daily steps (inactivity), postural transitions (weakness), and metrics such as longest walk duration and energy expenditure (exhaustion). Participants were divided into resilient and non-resilient groups based on adverse events within 6 months post-chemotherapy, including dose reduction, treatment discontinuation, unplanned hospitalization, or death. A Chemotherapy-Resilience-Index (CRI) ranging from 0 to 1, where higher values indicate poorer resilience, was developed using regression analysis. It combined physical activity data with baseline Eastern Cooperative Oncology Group (ECOG) assessments. The protocol showed a 97% feasibility rate, with sensor metrics effectively differentiating between groups as early as day 6 post-therapy. The CRI, calculated using data up to day 6 and baseline ECOG, significantly distinguished resilient (CRI = 0.2 ± 0.27) from non-resilient (CRI = 0.7 ± 0.26) groups (p < 0.001, Cohen’s d = 1.67). This confirms the potential of remote monitoring systems in tracking post-chemotherapy functional capacity changes and aiding early non-resilience detection, subject to validation in larger studies.

Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer.

Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC), at the dose of 600mg once daily (QD) during cycles of 21days on/7days off, with optional dose reduction to 400 mgand 200mg. Ribociclib is rapidly absorbed with a median time to reach maximum plasma concentration of 2.4h, mean half-life of 32.0h and oral bioavailability of 65.8% at 600mg. It is eliminated mainly by hepatic metabolism (~84% of total elimination), mostly by cytochrome P450 (CYP) 3A4. Age, body weight, race, baseline Eastern Cooperative Oncology Group status, food, mild hepatic impairment, mild-to-moderate renal impairment, proton pump inhibitors, and combination partners (non-steroidal aromatase inhibitors or fulvestrant) have no clinically relevant impact on ribociclib exposure. Ribociclib inhibits CYP3A at 600mg leading to increased exposure of CYP3A substrates. Strong CYP3A inhibitors or inducers increase or decrease, respectively, ribociclib exposure. Exposure-safety and exposure-efficacy analyses support the clinical benefit of the 600mg QD starting dose, with potential individualized dose reductions to 400 mgand 200mg for effective management of the adverse events neutropenia and QTcF interval prolongation, while maintaining efficacy, in patients with HR+/HER2- ABC. Overall, these clinical pharmacology data informed ribociclib dose justification and clinical development, as well as its prescribing information for clinical use in advanced breast cancer patients.

Impact of Patient Subgroups on the Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients with Advanced Illness.

We evaluated the impact of baseline patient characteristics on safety and efficacy of methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, in patients with advanced illness with opioid-induced constipation (OIC). This analysis pooled data from 2 randomized, double-blind, placebo-controlled studies (study 302: NCT00402038; study 4000: NCT00672477) in patients with advanced illness, including cancer, and OIC. Patients were randomized to receive subcutaneous methylnaltrexone (study 302: 0.15 mg/kg; study 4000: 8 or 12 mg based on weight) or placebo every other day for 2 weeks. The proportions of patients achieving rescue-free laxation within 4 or 24 hours after the first dose of study drug were assessed in patient subgroups stratified by baseline age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, laxative type, and opioid requirement. Treatment-emergent adverse events (TEAEs) were evaluated. Overall, 363 patients were included in this analysis (methylnaltrexone, 178; placebo, 185). Mean (SD) age was 66.3 (13.7) years and 48.5% were men overall. A significantly greater proportion of patients receiving methylnaltrexone versus placebo achieved rescue-free laxation within 4 hours (111/178 [62.4%] vs 31/185 [16.8%]; P<0.0001) and 24 hours (135/178 [75.8%] vs 81/185 [43.8%]; P<0.0001) of the first dose. These trends were consistent across all subgroups. Most patients experienced ≥1 TEAE in the overall population (methylnaltrexone, 82.1%; placebo, 76.2%), which remained consistent when stratified by baseline characteristics. More than half of TEAEs were gastrointestinal in nature. Abdominal pain was more common in patients receiving methylnaltrexone than placebo across baseline characteristic subgroups. Methylnaltrexone treatment was superior to placebo in achieving rescue-free laxation within 4 and 24 hours after the first dose, irrespective of patients' cancer status, baseline ECOG performance status, or baseline opioid or laxative use. The methylnaltrexone safety profile remained consistent across baseline characteristic subgroups.

R‐CHOP WITH SINTILIZUMAB IN FIRST‐LINE TREATMENT OF LARGE B‐CELL LYMPHOMA PATIENTS WITH TP53 MUTATIONS AND PD‐L1 EXPRESSION: A RANDOMIZED, MULTICENTER CLINICAL STUDY

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma, which accounts for approximately 30%–40% of all cases of non-Hodgkin lymphoma (NHL). Although 60% of patients can be cured by standard R-CHOP (rituximab plus cyclophosphamide, doxoru bicin, vincristine, and prednisone) as frontline therapy, patients with resistance to primary chemoimmunotherapy have a poor prognosis. It has been well demonstrated that TP53mutations and PD-L1 expression correlate with therapeutic resistance. Accordingly, in our preliminary observation, we found that sintilizumab (a PD-1 inhibitor) exerts remarkable efficacy and acceptable tolerance in PD-L1 expressing patients with relapsed or refractory (R/R) DLBCL. Therefore, we further initiate a clinical trial to investigate if sintilizumab can enhance the efficacy of R-CHOP in untreated DLBCL patients with TP53 mutations and PD-L1 expression. Methods: This randomized, multicenter study performs in at least 10 clinical sites in China. Patients aged 18 years or older with histologically diagnosed with DLBCL, untreated and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 are eligible for inclusion. Patients will receive one cycle of R-CHOP regimen and TP53 status and PD-L1 expression will be examined by PCR and immunohistochemistry (IHC), respectively. Afterwards, patients with TP53 mutations and PD-L1 expression (≥30% by IHC) are randomly assigned (1:1) to receive either sintilimab plus R-CHOP regimen (group A) or R-CHOP only (group B) for 5 cycles, until disease progression, unacceptable toxicity or withdrawal of consent. To avoid the interference of prednisolone, sintilizumab (200mg, every 3 weeks) is administered intravenously at day 10 after chemotherapy. Patients achieving CR in group A will continue to receive sintilizumab for 8 cycles. The primary endpoint of this study is complete response rate (CR) according to Lugano classification. Secondary endpoints include objective response rate (ORR) and 1-year progression free survival (PFS). Tumor measurements are assessed by PET/CT at baseline, at weeks 9 and 18, and then by CT scan every 3 months for 1 year. In addition, blood circulating tumor DNA (ctDNA) and PD-L1 are also under evaluation accordingly. Safety was assessed in all treated patients. The study is registered with www.chictr.org, NCT05280626 and is ongoing. Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, ongoing trials No conflicts of interests pertinent to the abstract.

Association of enfortumab vedotin (EV) toxicity with baseline parameters and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC).

e16585 Background: EV is an antibody-drug conjugate approved for the treatment of mUC. Toxicities of special interest with EV are neuropathy, rash, and hyperglycemia. While it has been reported that EV-related skin toxicity may be associated with better responses to EV, the relationship of EV-related adverse events (AEs) with clinical outcomes is still unclear. The aim of this study is to investigate the association of EV-related toxicity and clinical outcomes among pts with mUC. Methods: We retrospectively reviewed demographic, clinical and laboratory data from pts with mUC who were treated with &gt; 1 dose of EV at Dana-Farber Cancer Institute. AEs were graded per the CTCAE V5.0. A multivariable Cox regression analysis was performed to analyze overall survival (OS) and the occurrence of AEs while accounting for age, sex, and baseline peripheral neuropathy (BPN). A landmark analysis was performed to evaluate the association of toxicity occurrence and clinical outcomes, accounting for guarantee-time bias. Results: Our cohort included 54 pts with a median age of 72 years, of which 72.2% (n = 39) were male. Median follow-up was 18.6 months. Neuropathy was the most common AE occurring in 66.7% (n = 36) pts with 7.4% (n = 4) grade 3-4. Skin toxicity occurred in 57.4% (n = 31) pts with 3.7% (n = 2) grade 3-4. There were no recorded grade 5 AEs. Worse baseline Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was associated with the development of more AEs (HR = 2.8; 95% CI = 1.2-6.3; p = 0.01). Decreased baseline hemoglobin (Hb) was associated with more EV-related neuropathy (1/HR = 1.25; 95% CI = 1.1-1.4; p = 0.01) and higher neuropathy grade (1/HR = 1.7; 95% CI = 1.1-2.5; p = 0.01). Moreover, pts who have previously received immune checkpoint inhibitors (ICI) were more likely to develop EV-related rash (HR = 5.4; 95% CI = 1.1-26.2; p = 0.03; Table 1). Overall, 30 deaths were observed, and median OS was 13.3 months (95% CI = 9.5-NA). A landmark analysis at 2 weeks of therapy (marking the final infusion of the 1st cycle of EV therapy) showed that in 16 pts who developed early skin toxicity, OS was improved vs. 38 pts who did not develop early skin toxicity (HR = 0.4; 95% CI = 0.2-0.9; p = 0.04). Conclusions: To our knowledge, this is the first study to investigate the association of EV-related AEs and clinical outcomes of pts with mUC using a landmark analysis. ECOG-PS and baseline Hb may be predictors of EV-related AEs. The incidence of early skin toxicity may be associated with improved OS. [Table: see text]

Ramucirumab, avelumab and paclitaxel (RAP) as second line treatment in esophagogastric adenocarcinoma: Final results of the phase 2 RAP trial (AIO-STO-0218).

4032 Background: The addition of immune checkpoint inhibitors to chemotherapy has improved outcomes in patients (pts) with metastatic esophagogastric adenocarcinoma (EGA), but treatment combinations and optimal pt selection need to be established. Objective: To investigate efficacy and tolerability of the programmed death-ligand 1 (PD-L1) inhibitor avelumab with ramucirumab and paclitaxel in the second line treatment of pts with metastatic EGA (NCT03966118). Methods: In this phase 2 multicenter single-arm clinical trial the reported results are based on a median follow-up of 27.4 months. Patients with previously treated metastatic EGA, adequate organ function, and eligibility for immunotherapy were included. Interventions: Pts with metastatic EGA after progression on platinum/ fluoropyrimidine based palliative first line treatment, checkpoint-inhibitor naive, received ramucirumab 8 mg/kg (d1,15), avelumab 10 mg/kg (d1,15) and paclitaxel 80 mg/m² (d1,8,15) q4w. Results: The pre-specified primary end point was overall survival rate at 6 months (mo) (H0≤50%, H1≥65%). A total of 60 patients (pts) were enrolled, 59 were evaluable (intention to treat, ITT). Participants had a median age of 64.0 yrs (range 18-81) and 80% were men. Baseline Eastern Cooperative Oncology Group performance status was 0 in 23 pts (39.0%) and 1 in 36 pts (61.0%); 29 pts (48.2%) had EGA localized in the esophagogastric junction and 30 in the stomach (51.8%). all pts had received prior platin/ 5-FU based chemotherapy, 40pts (67.8%) had prior taxanes. Central post-hoc biomarker analysis (56 pts) showed PD-1 ligand 1 (PD-L1) combined positive score of 5 or greater in 24 pts (42.9%). The observed overall survival (OS) rate at 6 mo was 71% (95% CI 61-84%) and at 12 mo 43% (95% CI 32-58%). The median OS (ITT) was 10.6 mo (95% CI 8.4-12.8); 9.4 mo (95% CI 7.2-11.7) in pts with PD-L1 CPS &lt; 5 and 14.0 mo (95% CI 6.0-22.1; p = 0.25) in those with PD-L1 CPS≥5. Treatment was generally well tolerated without unexpected toxicities. Translational research identified subgroups with a longer survival possibly due to a higher treatment benefit. Pts with higher than median T cell repertoire (TRB) richness showed an elevated median OS of 20.4 mo compared to pts with lower than median TRB richness (med OS 8.3 mo; HR 0.43, 95% CI 0.23-0.81; p = 0.0079). Pts with lower than median cfDNA burden had a median OS of 19.2 mo compared to pts with higher than median cfDNA (med OS 7.3 mo; HR 0.30, 95% CI 0.16-0.59; p = 0.00022). Conclusions: In this multicenter clinical trial, ramucirumab and paclitaxel combined with avelumab showed favorable efficacy and tolerability in the second line treatment of pts with metastatic EGA. PD-L1 CPS≥ 5, cfDNA below the median or T cell richness above the median seem to predict for even better outcomes with median OS hardly seen before in the second line setting. Clinical trial information: NCT03966118 .

Neoadjuvant chemotherapy followed by definitive chemoradiation in technically unresectable oral cavity squamous cancers.

e18073 Background: Definitive Chemoradiation has dismal outcomes in very advanced oral cavity cancers. Surgical resection is the preferred modality of treatment . NACT followed by assessment for surgery is the standard algorithm used in technically unresectable oral cavity squamous cancers. Patients who are not amenable for surgery or not willing for the same are subjected to definitive Chemoradiation. There is very limited data about the outcomes of these patients and hence we have performed this analysis. Methods: This is an institutional review board approved retrospective analysis of a prospectively collected dataset of borderline resectable oral cavity squamous patients who received NACT. Adults patients with an eastern co-operative oncology group (ECOG) performance status (PS) 0-2 who were deemed as technically unresectable in a multi-disciplinary clinic (MDC) were included. These patients received 2-3 cycles of NACT (3-weekly) and underwent a response assessment. Depending on response and general condition, they were re-assessed in MDC and further therapy was decided. Patients who were not amenable to surgery and not willing for the and considered for definitive Chemoradiation were included in this analysis. Overall survival (OS) was calculated from date of diagnosis to date of death. Kaplan-meier method was used for estimation of 5 years OS. Impact of response to neoadjuvant chemotherapy on overall survival was calculated using log-rank method. Results: A total of 429 patients were analysed of which 387 (90.2%) were males The median age was 40 years (IQR; 40-54 years). The baseline ECOG PS was 0 in 163 (38%), 1 in 257 (59.9%) and 2 in 9 (2.1%) patients. The clinical stage at presentation was IVA in 257 (59.9%) patients and IVB in 172 (40.1%). The neoadjuvant regimen received were TPF regimen in 162 (37.8%) patients and two drug Taxane- Platinum regimen in the rest. The response rate to neoadjuvant therapy was 35.9% (N=154). Three thirty nine patients had an event with a median survival of 10 months (95%CI-;8.6-11.4). The five year survival was 15.6 % (Standard error 2%), while the 10 year OS was 9.6% (standard error 2.6%). On multivariate analysis, the only factor impacting the OS was response to neoadjuvant chemotherapy (HR: 0.54, 95% CI; 0.43-0.69; P=0.000). Conclusions: Neoadjuvant Chemotherapy followed by definitive Chemoradiation (who are not amenable for surgical resection or not willing) leads to dismal outcomes and further strategies to improve the outcomes are warranted.

Cohort study on immune checkpoint inhibitor-associated acute kidney injury: Incidence, risk factors, and management strategies.

Case studies and retrospective chart reviews of health system data have demonstrated an increased risk of nephrotoxicity in patients receiving immune checkpoint inhibitors compared to clinical trials. This study investigated the frequency, causes, and risk factors for acute kidney injury in a real-world, rural setting. This was a retrospective cohort study of patients who received at least one dose of a checkpoint inhibitor at a rural health system from May 2013 to February 2020 and who received at least one dose of a checkpoint inhibitor. Electronic and manual chart review helped to determine the incidence of, risk factors for, and renal outcomes and management strategies of checkpoint inhibitor-related acute kidney injury. Multivariable Fine and Gray subdistribution hazard models were used to assess the impact of patient characteristics on the incidence of sustained acute kidney injury and checkpoint inhibitor-induced acute kidney injury. After exclusion criteria, 906 patients who received at least one dose of a checkpoint inhibitor at Marshfield Clinic Health System during the study period were included. The incidence of acute kidney injury of any duration and due to any cause was 36.1%, while sustained acute kidney injury occurred in 28.7% of patients. Checkpoint inhibitor-related acute kidney injury was thought to have occurred in 2.7% of patients. Baseline estimated glomerular filtration rate < 60 was the sole predictor of checkpoint inhibitors-related acute kidney injury. Most patients with suspected checkpoint inhibitor-related acute kidney injury were managed with corticosteroids, and 62.5% experienced complete renal recovery. Ours is the first retrospective cohort study to test whether baseline Eastern Cooperative Oncology Group score and checkpoint inhibitor place in therapy were associated with checkpoint inhibitor-related acute kidney injury, and neither of these data points were found to be predictive. Even after expanding the parameters and methodologies of our study as compared to other retrospective cohort studies, we found only three baseline characteristics to be predictive of sustained acute kidney injury: Baseline eGFR, loop diuretic, and spironolactone use. For checkpoint inhibitor-related baseline, eGFR alone was predictive.

Improved uptake and survival with systemic treatments for metastatic non-small cell lung cancer: younger versus older adults

BackgroundOver the past decade, there has been increasing availability of novel therapeutics with improved tolerability and efficacy for advanced non-small cell lung cancer (NSCLC). The study goals were: to compare the uptake of systemic therapy (ST) before and after the availability of targeted tyrosine kinase inhibitors (TKI) and immunotherapy and to examine the changes in overall survival (OS) over time between younger and older adults with advanced NSCLC.MethodsAll patients with advanced NSCLC referred to British Columbia (BC) Cancer in 2009, 2011, 2015 and 2017 were included. One-year time points were based on molecular testing implementation and funded drug availability: baseline (2009), epidermal growth factor receptor TKI (2011), anaplastic lymphoma kinase TKI (2015) and Programed Death-1 (PD-1) inhibitors (2017). Age groups were <70years and ≥70years. Baseline demographics, simplified comorbidity scores (SCS), disease characteristics, and ST details were collected retrospectively. Variables were compared using X2, Fisher’s exact tests and logistic-regression analysis. OS was calculated using the Kaplan-Meier method and compared using the log-rank test.Results3325 patients were identified. Baseline characteristics were compared between ages < 70 years and ≥ 70 years for each time cohort with significant differences noted in baseline Eastern Cooperative Oncology Group (ECOG) performance status and SCS. The rate of ST delivery trended upwards over time with age <70 years: 2009 44%, 2011 53%, 2015 50% and 2017 52% and age ≥70 years: 22%, 25%, 28% and 29% respectively. Predictors for decreased use of ST for age <70 years: ECOG ≥2, SCS ≥9, year 2011, and smoking history; and age ≥70 years: ECOG ≥2, years 2011 and 2015, and smoking history. The median OS of patients who received ST improved from 2009 to 2017: age <70 years 9.1 m vs. 15.5 m and age ≥70 years 11.4 m vs. 15.0 m.ConclusionsThere was an increased uptake of ST for both age groups with the introduction of novel therapeutics. Although a smaller proportion of older adults received ST, those who received treatment had comparable OS to their young counterpart. The benefit of ST in both age groups was seen across the different types of treatments. With careful assessment and selection of appropriate candidates, older adults with advanced NSCLC appear to benefit from ST.

Outcomes of lenvatinib therapy in poorly differentiated thyroid carcinoma.

Lenvatinib showed promising results in a subgroup of patients with poorly differentiated thyroid carcinoma (PDTC) in the SELECT trial. Our aim was to report the effectiveness and tolerability of lenvatinib in our series of PDTC patients. Medical records of eight consecutive patients with PDTC treated with lenvatinib in a single center between January 2019 and October 2022 were retrospectively reviewed. Inclusion criteria were PDTC diagnosis based on Turin criteria and evidence of disease progression in the previous 6 months. Eight PDTC patients received an average dose of lenvatinib of 18.1 mg for a median duration of treatment of 10.3 months. The baseline Eastern Cooperative Oncology Group performance status was ≥2 in 50% of patients. Two patients had unresectable primary tumor. Seven patients showed extrathyroidal disease, particularly mediastinal lymph nodes (85.7%), lung (71.4%), and bone (71.4%). The disease control rate was 100%, with partial response and stable disease in 12.5 and 87.5%, respectively. The median time to best overall response was 3 months, and the median duration of response was 7.5 months. Median progression-free survival was 12 months and median overall survival was not reached. At 6, 12, and 18 months, overall survival was 87.5, 71.4, and 57.1%, respectively. All patients experienced drug-related adverse effects (AEs). Four (50%) had dose reductions and two (25%) had temporary treatment interruptions. Lenvatinib was stopped in two patients due to grade ≥3 AEs. Lenvatinib is an effective treatment for real-world PDTC patients. Adequate management of comorbidities and AEs increases treatment tolerability and minimizes dose reductions.

High risk of infection in 'real-world' patients receiving ibrutinib, idelalisib or venetoclax for mature B-cell leukaemia/lymphoma.

The infection risk in patients receiving ibrutinib, idelalisib or venetoclax for chronic lymphocytic leukaemia (CLL) or B-cell lymphoma treated outside of clinical trials is incompletely defined. We sought to identify the severe infection rate and associated risk factors in a 'real-world' cohort. We conducted a retrospective cohort study of adult patients with CLL or lymphoma treated with ibrutinib, idelalisib or venetoclax. Of 67 patients identified (ibrutinib n=53, idelalisib n=8 and venetoclax n=6), 32 (48%) experienced severe infection. Severe infection occurred at a rate of 65 infections per 100 person-years, with a median of 17.8months of therapy. Median time to first infection (IQR) was 5.4months (1.4-15.9). Poor baseline Eastern Cooperative Oncology Group (ECOG) performance status and high Charlson Comorbidity Index (CCI) score associated with increased risk of severe infection [hazard ratios (95% CI) 1.57 (1.07-2.31, p=.018) and 1.3 (1.05-1.62, p=.016) respectively]. The severe infection rate for patients receiving ibrutinib, idelalisib or venetoclax for lymphoma and CLL exceeded those reported in clinical trials. Patients with poor ECOG or high CCI should be closely monitored for early signs of infection and prevention strategies actively pursued. Further prospective research is required to define optimal antimicrobial prophylaxis recommendations.

Blastic Plasmacytoid Dendritic Cell Neoplasm Treated with Approved CD123-Targeted Therapy Tagraxofusp: The First European Real-World Evidence Prospective Registry of First-Line Adult Patients

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic malignancy derived from plasmacytoid dendritic cells (pDC) that overexpress CD123, the interleukin-3 (IL-3) receptor alpha. Patients with BPDCN have a poor prognosis, with median overall survival (OS) of 8-14 months. Tagraxofusp (TAG; Elzonris®), a first-in-class CD123-targeted therapy comprising human IL-3 fused to a truncated diphtheria toxin payload, is currently the only approved first-line (1L) treatment for adult patients with BPDCN. TAG demonstrated clinically relevant efficacy as well as a manageable safety profile in the 0114 pivotal trial conducted in the United States (US), with an overall response rate of 75% and complete response (CR)/CRc (CR with residual skin abnormality not indicative of active disease) rate of 57% in 1L patients. Herein, we describe the first European (EU) real-world evidence prospective registry in patients with BPDCN who received TAG, with a focus on the effectiveness and safety of receiving TAG in a real-world setting. Enrolled patients will meet the updated diagnostic classification profile recently outlined by the World Health Organization (WHO) 2022 guidance. Currently, no published treatment outcomes data exist from prospective interventional clinical trials of 1L or relapsed/refractory (R/R) BPDCN outside the US. Data collected here will increase understanding of clinical outcomes in TAG-treated patients. The registry was designed to meet the requirements outlined in the marketing authorization of the EU Commission for further evaluation of safety and efficacy in patients with 1L or R/R BPDCN. Methods: This is a single-arm, postauthorization, noninterventional study (EudraCT: 2021-001684-24) in patients ≥18 years with a confirmed diagnosis of BPDCN (immunophenotypic analysis positive for CD123, CD4, and CD56, plus 1 additional pDC marker [TCF4, TCL1, CD303, or CD304], or a combination of 3 pDC markers, according to WHO 2022 classification). Patients will receive TAG under real-world routine clinical practice conditions: 12 mcg/kg/day intravenously (IV) on days 1-5 of a 21-day cycle (which corresponds to the approved dosage). The study will enroll a minimum 80 patients from 40-50 sites across EU, who are to be treated or who have recently (within 3 months) started treatment with TAG over an ~4-year period. Patients with R/R BPDCN will comprise an exploratory cohort. Primary objectives of the study are rates of CR after 3 months (± 1 month) of TAG and the incidence and severity of capillary leak syndrome (CLS). Secondary objectives are rates of patients bridged to stem cell transplant (SCT), OS, progression-free survival (PFS), best overall response (BOR), and duration of response (DOR). Secondary safety assessments are incidence and severity of adverse events of special interest: hepatic-, renal-, and cardiac-related events, and choroid plexitis events. TAG dose interruptions, number of TAG doses/cycles administered, and rates of IV albumin supplementation for diagnosed, or symptoms of, CLS will also be assessed. Data collection is anticipated quarterly, as well as at screening, enrollment, early discontinuation, and/or study end. A list of the assessments taken at each time point are shown in the Figure. Safety data collection will end 18 months after the last enrolled patient's first visit (LPFV). Interim analyses will be performed annually, with an effectiveness interim analysis scheduled for 12 months post-LPFV. Demographic, safety, and efficacy data will be summarized descriptively. The Kaplan-Meier method will be used to summarize PFS, OS, and DOR. The Clopper-Pearson exact method will determine the rates of patients bridged to SCT and BOR. Subgroup analyses for effectiveness and safety may also be performed on the basis of gender, age, or baseline Eastern Cooperative Oncology Group performance status. Enrollment is due to start in Q3-Q4 2022. Taking the registry as the basis, upon study finalization a complementary comparative analysis of effectiveness and safety from the TAG registry with a retrospective clinical cohort will be undertaken using appropriate methodology. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Health-Related Quality of Life for Frail Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Daratumumab, Lenalidomide and Dexamethasone: Subgroup Analysis of MAIA Trial

Introduction: In the primary analysis of the phase 3 MAIA trial (NCT02252172), daratumumab, lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) in transplant-ineligible (TIE) patients (pts) with newly diagnosed multiple myeloma (NDMM) vs Rd. With longer follow-up (median: 56.2 months [mo]), D-Rd continued to demonstrate PFS benefit, conferred an overall survival benefit, induced deeper responses, and was associated with clinically meaningful improvements in patient-reported outcomes (PROs) vs Rd. The median age of these pts was 73 years with 43.6% of pts aged ≥75 years. Consistent with the overall population, in a frailty subgroup analysis (median age: 77 years), D-Rd also demonstrated deeper responses and PFS benefit vs Rd (not reached [NR] vs 30.4 mo; HR, 0.62; P = 0.003) in frail pts at a median follow-up of 36.4 mo. Although, D-Rd improved clinical outcomes in these elderly frail pts, little is known about health-related quality of life (HRQoL) outcomes. In frail pts, improving HRQoL and minimizing the risk of toxicity is paramount. Here, we assess PROs in the frail pts in the MAIA trial. Methods: Pts were randomized 1:1 to D-Rd or Rd until disease progression (PD) or unacceptable toxicity. Frailty assessment was performed on all randomized pts using age, Charlson Comorbidity Index, and baseline (BL) Eastern Cooperative Oncology Group performance status score. Based on this assessment, pts were categorized into frail and non-frail subgroups. PROs were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30). Questionnaires were completed at BL, on day 1 of cycles (Cyc) 3, 6, 9, and 12 for year 1, and every 6 mo thereafter until PD. Analyses were conducted on all pts with a BL and ≥1 post-BL PRO assessment. Meaningful thresholds for improvement and worsening were defined a priori based on published literature (≥10-point change). Treatment effect was assessed by a mixed-effects model for repeated measures. Time to first worsening was estimated using the Kaplan Meier method and Cox proportional hazards regression was used to compute hazard ratio (HR) and associated 95% confidence interval (CI) where worsening was defined using a distribution-based method. Results: In the MAIA trial, 737 pts were randomized (D-Rd, n=368; Rd, n=369). Of these, 341 pts were classified as frail (D-Rd, n=172; Rd, n=169,). At a median follow-up of 64.5 mo, frail pts treated with D-Rd reported greater improvements from BL vs Rd in EORTC QLQ-C30 Global Health Status (GHS) scores (Figure 1A) and physical functioning (LS mean change from BL for D-Rd at Cyc 12: 12.7 [9.0-16.3] vs Rd, 9.8 [5.9-13.7]) at several time points, with 39% of pts treated with D-Rd staying on treatment with PRO assessment at Cyc 48 vs 17% in the Rd group. Additionally, pts treated with D-Rd showed notably large reductions (≥20-point change) in pain symptoms over time and larger than that seen in pts treated with Rd (Figure 1B). No meaningful changes from BL were observed in fatigue symptoms for either treatment group. Results for emotional functioning, social functioning, and nausea and vomiting also numerically favored D-Rd at several time points. The median time to first improvement was numerically shorter with D-Rd vs Rd for GHS (D-Rd: 2.38 mo vs Rd: 4.67 mo), physical functioning (2.60 mo vs 4.65 mo), pain (2.07 mo vs 2.83 mo), and fatigue symptoms (2.04 mo vs 3.09 mo). The median time to first worsening was longest for physical functioning (D-Rd: 68.14 mo vs Rd: 39.62 mo; HR [95%CI] 0.66 [0.45-0.95]; P=0.023) and pain symptoms (D-Rd: NR vs Rd: 60.48 mo; 0.66 [0.44-1.00]; P=0.045). The median time to first worsening was longer with D-Rd vs Rd for GHS (D-Rd: 29.31 mo vs Rd: 21.62 mo; HR 0.91 [0.65-1.26]). The median time to first worsening for the other functional (emotional, social, role) and symptom (nausea and vomiting) scales numerically favored D-Rd vs Rd, except cognitive functioning and fatigue. Conclusions: D-Rd demonstrates clinical benefit in all pts, including frail pts. In addition, frail pts treated with D-Rd reported sustained improvements in global health (overall HRQoL) and physical functioning, with notable reduction in pain through the duration of therapy. Additionally, higher percentage of frail pts continued on D-Rd vs Rd. D-Rd regimen is not only clinically effective but also results in a sustained improvement in HRQoL for TIE frail pts with NDMM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Performance Status and Long-Term Outcomes in Cancer-Associated Pulmonary Embolism: Insights From the Hokusai-VTE Cancer Study

BackgroundPerformance status (PS) is a reliable prognostic tool for overall survival in patients with cancer-associated pulmonary embolism (PE). However, its association with venous thromboembolism (VTE) recurrence and bleeding remains unclear. ObjectivesThe aim of this study was to investigate whether PS at the time of PE diagnosis and its course during follow-up are linked to VTE-related outcomes. MethodsIn this post hoc analysis of the Hokusai-VTE Cancer study, multivariable survival analysis was used to examine the association of PS with anticoagulation discontinuation and the composite primary outcome of VTE recurrence or major bleeding in patients with cancer-associated PE. PS was assessed using the Eastern Cooperative Oncology Group (ECOG) scale at baseline and at predefined study follow-up visits. ResultsOverall, 652 patients with cancer-associated PE were included. During 12-month follow-up, PS worsened in 317 of 642 patients (49.4%) with complete ECOG data at the end of follow-up. Those with worse ECOG values over follow-up were more likely to discontinue anticoagulation for any reason apart from death (adjusted HR: 1.59; 95% CI: 1.31-1.93). The composite primary outcome occurred in 57 of 500 patients with baseline ECOG status 0 or 1 and in 32 of 152 patients with ECOG status 2 (cumulative incidence at 12 months 10.7% [95% CI: 8.2%-13.9%] vs 14.4% [95% CI: 9.7%-21.3%]). Worse ECOG values during follow-up were associated with greater risk for the composite outcome (adjusted HR: 2.13; 95% CI: 1.24-3.67). ConclusionsECOG PS is a valuable indicator for predicting VTE-related outcomes and may inform decision making regarding anticoagulation during follow-up in patients with cancer-associated PE.

S165 Impact of Patient Subgroups on the Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients With Advanced Illness

Introduction: Methylnaltrexone (MNTX) is a peripherally acting µ-opioid receptor antagonist indicated for opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care and in patients with chronic noncancer pain. We investigated if baseline patient characteristics impact the safety and efficacy of MNTX in those with advanced illness and OIC. Methods: This analysis pooled data from 2 randomized, double-blind, placebo (PBO)-controlled studies (study 302–NCT00402038; study 4000‒NCT00672477) in patients with advanced illness, including cancer. Study 302: Patients were randomized to receive subcutaneous (SC) MNTX 0.15 mg/kg or PBO every other day (QOD) for 2 weeks, with possible dose escalation to 0.30 mg/kg at week 2. Study 4000: Patients received weight-based SC MNTX 8 mg or 12 mg QOD or PBO for 2 weeks. The proportion of patients achieving a rescue-free laxation within 4 or 24 hours after the first dose of study drug was assessed in patient subgroups stratified by baseline age (< 65 vs ≥ 65), Eastern Cooperative Oncology Group (ECOG) status (≤ 2 vs > 2), cancer status, laxative type (osmotic agents, stimulants, stool softeners), and opioid requirement (oral morphine equivalent dose < 80 mg/d, 80 ‒ < 150 mg/d, and ≥ 150 mg/d). Treatment-emergent AEs (TEAEs), gastrointestinal (GI) TEAEs, and abdominal pain were evaluated. Results: Overall, 363 patients were included in this analysis (MNTX = 178; PBO = 185). Mean age was 67.8 years in the MNTX group and 66.7 years in the PBO group; 46.8% were men across all groups. A significantly greater proportion of patients receiving MNTX achieved rescue-free laxation within 4 hours (n = 111/178, 62.4% vs n = 31/185, 16.8%, P < .0001) and 24 hours (n = 135/178, 75.8% vs n = 81/185, 43.8%, P < .0001) of the first dose vs PBO. These trends were consistent across all subgroups (Table). Most patients experienced ≥ 1 TEAE in the overall population (MNTX 82.1%; PBO 76.2%); results were similar when stratified by baseline cancer, ECOG, opioid, or laxative group (Table). More than half of TEAEs were GI in nature; abdominal pain was more common in patients receiving MNTX across subgroups. Conclusion: MNTX treatment was superior to PBO in achieving RFL within 4 and 24 hours after the first dose, irrespective of patients’ cancer status, baseline ECOG status, or baseline opioid or laxative use. MNTX remained consistently safe across different baseline clinical and demographic characteristics. Table 1. - Rescue-free laxation response and treatment-emergent events by demographic and clinical characteristics subgroup Rescue-free laxation TEAEs Within 4 hours of the first dose Within 24 hours of the first dose Patients with ≥ 1TEAE Patients with gastrointestinal TEAE Patients with abdominal pain MNTX PBO MNTX PBO MNTX PBO MNTX PBO MNTX PBO Age, n (%) < 65 years 53 (63.9) 13 (14.6) 66 (79.5) 36 (40.4) 70 (84.3) 65 (73.0) 48 (57.8) 37 (41.6) 21 (25.3) 8 (9.0) ≥ 65 years 58 (61.1) 18 (18.8) 69 (72.6) 45 (46.9) 77 (80.2) 76 (79.2) 43 (44.8) 47 (49.0) 18 (18.8) 11 (11.5) Cancer status, n (%) Cancer 74 (63.8) 17 (14.9) 88 (75.9) 53 (46.5) 102 (87.9) 91 (79.8) 67 (57.8) 57 (50.0) 28 (24.1) 11 (9.6) Noncancer 37 (59.7) 14 (19.7) 47 (75.8) 28 (39.4) 44 (69.8) 50 (70.4) 24 (38.1) 27 (38.0) 11 (17.5) 8 (11.3) Functional status, n (%) ECOG ≤ 2 52 (66.7) 18 (22.5) 60 (76.9) 42 (52.5) 67 (85.9) 58 (72.5) 43 (55.1) 37 (46.3) 23 (29.5) 8 (10.0) ECOG > 2 59 (59.0) 13 (12.4) 75 (75.0) 39 (37.1) 80 (79.2) 83 (79.0) 48 (47.5) 47 (44.8) 16 (15.8) 11 (10.5) Baseline opioid dose in OME, n (%) < 80 mg/d 24 (57.1) 7 (12.3) 29 (69.0) 24 (42.1) 30 (71.4) 42 (73.7) 16 (38.1) 26 (45.6) 7 (16.7) 5 (8.8) 80 to < 150 mg/d 24 (61.5) 8 (19.0) 29 (74.4) 22 (52.4) 37 (94.9) 31 (73.8) 22 (56.4) 17 (40.5) 8 (20.5) 6 (14.3) ≥ 150 mg/d 63 (64.9) 16 (18.6) 77 (79.4) 35 (40.7) 80 (81.6) 68 (79.1) 53 (54.1) 41 (47.7) 24 (24.5) 8 (9.3) Baseline laxative regimen, n (%) Stimulants 86 (63.2) 21 (14.1) 104 (76.5) 64 (43.0) 113 (82.5) 118 (79.2) 73 (53.3) 68 (45.6) 29 (21.2) 17 (11.4) Osmotic agents 56 (65.9) 17 (20.7) 64 (75.3) 38 (46.3) 75 (88.2) 63 (76.8) 53 (62.4) 38 (46.3) 25 (29.4) 12 (14.6) Stool softeners 58 (63.0) 15 (15.3) 69 (75.0) 46 (46.9) 72 (78.3) 78 (79.6) 42 (45.7) 46 (46.9) 18 (19.6) 12 (12.2) ECOG = Eastern Cooperative Oncology Group; OME = oral morphine equivalent dose; MNTX = methylnaltrexone; PBO = placebo; TEAE = treatment-emergent adverse event.

64-Year-Old Woman With Aphasia and Troponin Elevation

64-Year-Old Woman With Aphasia and Troponin Elevation

P947: COMPARATIVE EFFECTIVENESS OF ORAL IXAZOMIB-LENALIDOMIDE-DEXAMETHASONE (IRD) AFTER INITIAL BORTEZOMIB (V)-BASED INDUCTION VS PARENTERAL V-BASED THERAPY IN NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM)

Background: Long-term proteasome inhibitor (PI)-based treatment can improve outcomes for patients (pts) with multiple myeloma (MM). However, prolonged parenteral PI therapy (e.g. with V) can be challenging to achieve in routine clinical practice, and outcomes for pts are often poorer in this setting compared with clinical trials. The phase IV, community-based, single-arm US MM-6 study (NCT03173092) is assessing in-class transition (iCT) from V-based induction to all-oral IRd in transplant ineligible NDMM pts treated in routine clinical practice, with the objective of increasing the duration of PI-based treatment while maintaining quality of life. INSIGHT MM is the largest global, prospective, observational study of MM pts (>4,200), and provided a subset of patients as the comparator cohort. This enabled assessment of iCT vs V-based therapy in NDMM pts in routine clinical practice in the US. Aims: To examine the comparative effectiveness of IRd following initial V-based induction (3 cycles; US MM-6 pts; ‘IRd’ cohort) vs continued V-based therapy (INSIGHT MM pts; ‘V-based’ cohort) in NDMM pts. Methods: A secondary analysis of non-transplant eligible US NDMM pts with ≥stable disease after 3 cycles of V-based induction and baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2 from the US MM-6 (Manda CLML 2020) and INSIGHT MM (Costello Future Onc 2019) studies was performed. Study outcomes included first-line duration of treatment (DOT), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and reasons for treatment discontinuation. All analyses were weighted using the inverse probability of treatment weighting (IPTW) approach to reduce the imbalance of potential confounding factors between the two cohorts (adjusted analyses). Kaplan–Meier methods were used to examine DOT, PFS, OS, and associated 95% confidence intervals (CIs); the log-rank test was used to compare distribution of time to events. The Clopper-Pearson method was applied to estimate 95% CIs for ORR. Statistical significance was evaluated at alpha=0.05. Results: 100 pts from the IRd cohort (MM-6) and 111 pts from the V-based cohort (INSIGHT) were included. After IPTW, in the IRd vs V-based cohorts: median age was 75.0 vs 74.8 yrs; 56.7 vs 51.3% of pts were male; 37.4 vs 29.1% had an ECOG PS of ≥2; 48.8 vs 41.4% had International Staging System stage III at initial diagnosis, and 79.5/17.7/2.8 vs 77.3/19.5/3.1% pts had received VRd/ V-cyclophosphamide-d (VCd)/ VRCd as initial induction therapy. Adjusted ORRs in the IRd vs V-based cohorts were 74.1 (95% CI 66.0–82.2) vs 57.5% (95% CI 47.9–67.1; p<0.0001). After a median follow-up of 20.3 and 15.8 months in the IRd and V-based cohorts, respectively, DOT was 10.8 (95% CI 6.5–24.4) vs 5.3 months (95% CI 4.3–7.0; p<0.0001) (see Figure). Median PFS was not estimable (NE) in either cohort; 24-month PFS rates were 85.7 (95% CI 68.1–94.0; IRd cohort) vs 76.5% (95% CI 62.6–85.8; V-based cohort). Median OS was NE in either cohort; 24-month OS rates were 94.0 (95% CI 77.7–98.5; IRd cohort) vs 84.9% (95% CI 70.6–92.6; V-based cohort). In the IRd and V-based cohorts, 16.8 and 16.9% of pts discontinued IRd and V, respectively, due to an adverse event. Image:Summary/Conclusion: US MM-6 NDMM pts who transitioned to IRd after 3 initial cycles of V-based induction had a significantly higher ORR and longer DOT compared with pts who received continued V-based therapy in INSIGHT MM. The results suggest that iCT from continued V-based therapy to all-oral IRd may improve outcomes in pts treated at community oncology clinics.

Efficacy of Ipilimumab vs FOLFOX in Combination With Nivolumab and Trastuzumab in Patients With Previously Untreated ERBB2-Positive Esophagogastric Adenocarcinoma

In metastatic esophagogastric adenocarcinoma (EGA), the addition of programmed cell death 1 (PD-1) inhibitors to chemotherapy has improved outcomes in selected patient populations. To investigate the efficacy of trastuzumab and PD-1 inhibitors with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors or FOLFOX in first-line treatment of advanced ERBB2-positive EGA. This phase 2 multicenter, outpatient, randomized clinical trial with 2 experimental arms compared with historical control individually was conducted between March 2018 and May 2020 across 21 German sites. The reported results are based on a median follow-up of 14.3 months. Patients with previously untreated, metastatic ERBB2-positive (local immunohistochemistry score of 3+ or 2+/in situ hybridization amplification positive) EGA, adequate organ function, and eligibility for immunotherapy were included. Data analysis was performed from June to September 2021. Patients were randomized to trastuzumab and nivolumab (1 mg/kg × 4/240 mg for up to 12 months) in combination with mFOLFOX6 (FOLFOX arm) or ipilimumab (3 mg/kg × 4 for up to 12 weeks) (ipilimumab arm). The primary end point was survival improvement with a targeted increase of the 12-month overall survival rate from 55% (trastuzumab/chemotherapy-ToGA regimen) to 70% in each arm. A total of 97 patients were enrolled, and 88 were randomized (18 women, 70 men; median [range] age, 61 [41-80] years). Baseline Eastern Cooperative Oncology Group performance status was 0 in 54 patients (61%) and 1 in 34 patients (39%); 66 patients (75%) had EGA localized in the esophagogastric junction and 22 in the stomach (25%). Central post hoc biomarker analysis (84 patients) showed PD-1 ligand 1 (PD-L1) combined positive score of 1 or greater in 59 patients (72%) and 5 or greater in 46 patients (56%) and confirmed ERBB2 positivity in 76 patients. The observed overall survival rate at 12 months was 70% (95% CI, 54%-81%) with FOLFOX and 57% (95% CI, 41%-71%) with ipilimumab. Treatment-related grade 3 or greater adverse events (AEs) and serious AEs occurred in 29 and 15 patients in the FOLFOX arm and in 20 and 17 patients in the ipilimumab arm, respectively, with a higher incidence of autoimmune-related AEs in the ipilimumab arm and neuropathy in the FOLFOX arm. Liquid biopsy analyses showed strong correlation of early cell-free DNA increase with shorter progression-free and overall survival and emergence of truncating and epitope-loss ERBB2 resistance sequence variations with trastuzumab treatment. In this randomized clinical trial, trastuzumab, nivolumab, and FOLFOX showed favorable efficacy compared with historical data and trastuzumab, nivolumab, and ipilimumab in ERBB2-positive EGA. The ipilimumab arm yielded similar OS compared with the ToGA regimen. ClinicalTrials.gov Identifier: NCT03409848.

P529: FIRST EUROPEAN REAL-WORLD EVIDENCE PROSPECTIVE REGISTRY OF FIRST-LINE ADULT PATIENTS WITH BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM TREATED WITH FIRST-IN-CLASS CD123-TARGETED THERAPY TAGRAXOFUSP

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy derived from plasmacytoid dendritic cells that overexpress interleukin-3 (IL-3) receptor alpha (CD123). It is a highly aggressive disease characterized by skin and bone marrow involvement and is associated with a poor prognosis (median overall survival 8–14 months). Tagraxofusp (TAG, SL-401) is a first-in-class CD123-targeted therapy comprising human IL-3 fused to a truncated diphtheria toxin payload. It is currently the only approved first-line (1L) treatment for adult patients (pts) with BPDCN in Europe. As of July 2021, 65 pts with BPDCN have received TAG in a clinical setting outside the US as part of an expanded access program. Collecting real-world clinical data from TAG is important to increase understanding of clinical outcomes, especially in pts commonly underrepresented in clinical trials. We describe the first real-world evidence prospective registry in pts with BPDCN receiving TAG. It has been designed to meet requirements outlined in the marketing authorization of the European Commission for further evaluation of the efficacy and safety of TAG in pts with 1L or relapsed/refractory BPDCN. Aims: To investigate effectiveness and safety of TAG in pts with 1L BPDCN. Methods: This is a noninterventional, single-arm, post-authorization study (EudraCT: 2021-001684-24) in adult pts with BPDCN prescribed TAG under real-world routine clinical practice conditions (12 mcg/kg intravenously [IV] once daily on days 1–5 of a 21-day cycle, per the summary of product characteristics recommendation). A minimum of 80 pts will be included in approximately 40–55 sites in Europe, estimated over 4 years. Eligible pts have a diagnosis of BPDCN and are to be treated (or have recently started treatment) with TAG monotherapy as 1L treatment, per physician’s decision. Primary endpoints are rate of complete response (CR), defined as CR + clinical CR (CR with residual skin abnormality not indicative of active disease) after 3 months of treatment, and safety of TAG including the incidence and severity of capillary leak syndrome (CLS). Secondary endpoints include number of pts bridging to SCT, progression-free survival, overall survival, best overall response, duration of response, TAG dose interruptions/administration of IV albumin supplementation in pts with CLS or CLS symptoms, as well as safety and incidence and severity of adverse events of special interest (which include CLS and hepatic, renal, and cardiac events). Quarterly data collection is anticipated, as well as collection at screening, enrollment, early discontinuation, and study end (Figure). Safety data collection will end 18 months after the last enrolled pt’s first visit (LPFV). Interim analyses will be performed annually; an effectiveness interim analysis is scheduled at 20 months post-LPFV. Analyses will be performed using descriptive statistics. Survival data will be summarized using the Kaplan-Meier method. Subgroup analyses for effectiveness and safety may be performed, on the basis of gender, age, or baseline Eastern Cooperative Oncology Group performance status. Enrollment is planned to start by June 2022. Taking the registry as the basis, upon study finalization a complementary comparative analysis of effectiveness and safety data from the TAG registry with a retrospective clinical cohort will be undertaken using appropriate methodology, such as propensity score matching or inverse probability treatment weighting. Results: This is a TiP and there are no results at this time. Image:Summary/Conclusion: This is a TiP and there are no results at this time.