Tx Duration Research Articles

Long-term pooled safety analysis of tislelizumab as monotherapy or in combination with chemotherapy in patients with advanced cancers.

e14617 Background: The PD-1 inhibitor tislelizumab (TIS) has demonstrated efficacy and tolerability in patients (pts) with advanced cancers. To evaluate long-term safety of TIS as monotherapy (mono) or in combination (combo) with chemotherapy in pts with advanced gastrointestinal (GI) and lung cancers, data were pooled from 8 pivotal phase III studies conducted between 2017 and 2023. Methods: 2636 adult pts with GI (n=1415) or lung (n=1221) cancers and an ECOG PS of 0-1, who received ≥1 dose of study drug, were included. Endpoints included immune-mediated adverse events (imAEs) by tumor type, treatment (Tx) duration, and race. Early and delayed imAEs, defined as occurring within 1 year (yr) and >1 yr after starting TIS, respectively, were also evaluated. Results: Median (range) Tx duration in the GI and lung cancer studies was 4.9 (0.1-50.4) and 6.2 (0.2-44.9) months, respectively, with 20.9% and 29.6% of pts, respectively, having ≥1 yr exposure. Most pts were Asian (GI mono: 76.4%; GI combo: 74.9%; lung mono: 79.2%; lung combo: 100%). ImAEs occurred in 32.5% of pts in the GI mono and combo studies (Table); most were low grade, with grade ≥3 imAEs reported in 6.2% (mono) and 8.2% (combo) of pts. Incidence of imAEs in the mono and combo lung studies, respectively, was 34.3% and 43.7% (grade ≥3: 6.4% and 9.6%). ImAE incidence was comparable between Asian and White race subgroups, respectively, in the GI mono (33.6% vs 29.5%), GI combo (34.9% vs 23.9%), and lung mono (35.5% vs 32.3%) studies. Most imAEs occurred within 1 yr of starting TIS in the GI (mono: 32.0%; combo: 32.4%) and lung (mono: 34.1%; combo: 42.2%) studies. Delayed imAEs occurred less often than early imAEs; of pts still on Tx or in study follow-up 1 yr after initial Tx, 54/757 (7.1%) in GI studies and 86/804 (10.7%) in lung studies experienced a delayed imAE. Frequently reported imAEs were consistent, regardless of time of onset (early vs delayed). Conclusions: This long-term, retrospective, pooled analysis supports TIS as a tolerable Tx for pts with advanced GI and lung cancers. Delayed imAEs were relatively infrequent and were consistent with the established safety profile of TIS. Clinical trial information: NCT03412773 ; NCT03430843 ; NCT03358875 ; NCT03663205 ; NCT03777657 ; NCT03783442 ; NCT03594747 ; NCT04005716 . [Table: see text]

Costs associated with novel first-line (1L) treatments in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) from a United States (US) Medicare and commercial payer perspective.

e16552 Background: Recent drug approvals in the 1L treatment (tx) setting have expanded options for pts with la/mUC. It is important to understand the economic burden of these novel therapies within the current tx landscape. This study estimated first-year cost of care in the US from a Medicare and commercial payer perspective for pts with la/mUC treated with the following 1L tx: enfortumab vedotin (EV) + pembrolizumab (PEM) in platinum-eligible pts, nivolumab (NIV) + platinum-based chemotherapy (PBC) in cisplatin-eligible pts, and 1L PBC with or without avelumab (AVE) 1L maintenance (1LM). Methods: A cost of care model was developed to estimate direct medical care costs in the first year of tx with EV + PEM, NIV + PBC, and PBC with and without AVE 1LM in pts with la/mUC who are eligible for 1L PBC; pts treated with NIV + PBC were eligible for cisplatin. The latest available costs (2023 USD)—including drug acquisition and administration, disease management, adverse event (AE) management, and subsequent therapy (second-line or later line) costs—were calculated based on tx duration, progression-free survival, overall survival, and AE incidence with various therapies. Efficacy and safety data were sourced from key published trials (EV-302, CheckMate-901, JAVELIN Bladder 100) and product prescribing information. Results: Estimated first-year costs per treated pt are shown in the Table. Cost per treated pt was estimated to range between $56,952 to $438,660 and $90,918 to $457,390 for Medicare and commercial payers, respectively, with the highest cost for EV+PEM and the lowest for PBC only. Drug acquisition costs in the 1L represented the majority of the costs except PBC, for which subsequent tx and administration costs represented the largest cost component. Conclusions: Costs per treated pt were lower for PBC with AVE 1LM than for EV+PEM and NIV+PBC. As value-based oncology care is becoming increasingly important in the US, comprehensive understanding of costs across different tx options and sequences can facilitate informed tx choice. [Table: see text]

Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ).

7500 Background: The first line of treatment (tx) is important for patients (pts) with newly diagnosed multiple myeloma (NDMM) as pts may not have a chance for subsequent therapy. VRd is currently a standard of care (SOC) in NDMM. Isa is an approved anti-CD38 monoclonal antibody (mAb) inducing myeloma cell death through multiple mechanisms. In the Phase 3 IMROZ study (NCT03319667), we investigate the efficacy and safety of Isa-VRd vs VRd in transplant-ineligible NDMM pts. Methods: IMROZ is a global, prospective, randomized, open-label study done at 102 study sites in 21 countries. Included pts had active, measurable NDMM not considered for transplant due to elderly age or comorbidities. Pts aged ≥80 were excluded. Pts were randomized 3:2 and stratified by age, R-ISS stage and China vs non-China, to receive Isa-VRd or VRd. Isa-VRd arm pts received Isa (10 mg/kg IV); both arms received V (1.3 mg/m2 SC), R (25 mg PO) and d (20 mg IV/PO). The primary endpoint was progression-free survival (PFS). Key secondary endpoints were complete response (CR), minimal residual disease negativity (MRD-) (10-5 by NGS) in pts with CR, very good partial response or better and overall survival. Adverse events (AEs) and laboratory parameters were graded with NCI CTCAE v4.03. Results: 446 pts (265 Isa-VRd, 181 VRd) were randomized; pt characteristics were well balanced. At data cutoff (26 Sep 2023), 125 (47.2%) and 44 (24.3%) pts in Isa-VRd and VRd arms were still on tx, respectively. Median (mdn) tx duration was 53.2 (Isa-VRd) vs 31.3 (VRd) mo; addition of Isa did not significantly affect relative dose intensity of VRd. At mdn follow-up of 59.7 mo, mdn PFS was not reached (Isa-VRd) vs 54.3 mo (VRd); HR 0.596 (98.5% CI 0.406–0.876), log-rank p=0.0005. From the current trend, projected Isa-VRd mdn PFS will reach ~90 mo. PFS benefit was consistent across subgroups and maintained through subsequent line of therapy (PFS2 HR 0.697; 95% CI: 0.51-0.952). Isa-VRd led to deep and sustained responses and was well-tolerated (Table). Exposure-adjusted Grade 5 TEAE rate was 0.03 (Isa-VRd) vs 0.02 (VRd). Conclusions: IMROZ is the first Phase 3 study of an anti-CD38 mAb with SOC VRd in this pt population to show a significantly reduced risk of progression or death by 40.4% vs VRd while providing deep and sustained responses. The safety profile was consistent with addition of Isa to VRd. Numerical differences in TEAEs are largely explained by longer exposure in the Isa-VRd arm. These results support Isa-VRd as a potential new SOC in pts not intended for transplant. Clinical trial information: NCT03319667 . [Table: see text]

Abstract PO2-04-10: Effect of Alpelisib Dose Modification for AE Management on Progression-Free Survival and Treatment Duration in SOLAR-1 and BYLieve Clinical Trials

Abstract Background: Alpelisib (ALP) is an α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor and degrader approved with fulvestrant (FUL) for patients (pts) with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) following progression on/after endocrine therapy-based treatment (tx). Toxicity limited ALP exposure in some pts in the SOLAR-1 and BYLieve studies. On-target effects of PI3K inhibitors, including hyperglycemia, rash, and diarrhea, are among the most common adverse events (AEs) associated with ALP. During SOLAR-1, median onset times were 15 and 13 days for grade ≥3 hyperglycemia and rash and 46 days for grade 2/3 diarrhea. ALP dose modification can help manage AEs. We report efficacy of ALP + FUL as second-line (2L) tx in pts who underwent ALP dose reduction (DR). Methods: Pts with PIK3CA mutations from SOLAR-1 and BYLieve, treated with ALP + FUL in 2L, were included. Landmark (LM) analyses were performed at 1, 2, 3, 4, 5, and 6 mo after tx initiation to evaluate the association between DR status (yes, no) with progression-free survival (PFS) and duration of tx (DoT), respectively. Pts with PFS or exposure time less than each LM time point were excluded from each LM analysis; pts were then grouped by DR (yes, no) before each LM time point. Median PFS and DoT were obtained using a modified Kaplan-Meier method. Alternatively, Cox regression analysis was used to assess the effect of DR on PFS and DoT, where 2 time-dependent variables were included separately in the model as a covariate: 1) DR status, and 2) DR groups (300 to 250 mg [1 DR] vs no DR, 300 to 250 to 200 mg [2 DR] vs no DR). Association between AEs and DR was evaluated descriptively. A matched analysis of AEs will be presented. Results: In all, the analysis included 212 pts in 2L: 77 from SOLAR-1, and 95 and 40 from BYLieve Cohorts A and C, respectively. Of these pts, 92 (43.4%) had no DR and 120 (56.6%) had DRs: 70 (58.3%) had 1 DR, 43 (35.8%) had 2, and 7 (5.8%) had other types of DR. 25 of 92 pts (27.2%) with no DR and 40 of 120 pts (33.3%) with DR had ≥12-mo exposure to ALP. Hazard ratios (HRs) for PFS and DoT in DR status for the LM analysis are shown (Table). HRs (95% CI) for PFS from the time-dependent covariate analyses were 1.28 (0.94-1.74) with DR status as the covariate, and 1.24 (0.88-1.76) and 1.21 (0.79-1.84) with DR group (1 DR vs no DR, 2 DR vs no DR) as the covariate, respectively; for DoT, these were 1.34 (1.00-1.79) for DR status, and 1.30 (0.93-1.80) and 1.30 (0.87-1.93) for DR group, respectively. During the treatment period, the incidence rate for grade ≥3 AEs was the highest for pts with 2 DR and lowest for those with no DR. Similarly, incidence of AEs leading to DR or tx discontinuation was higher in pts with 2 DR than 1 DR. The post-DR incidence rate for grade ≥3 AE was similar for pts with 2 DR or 1 DR. A matched analysis will assess the relationship between DR group and AE. Conclusions: In this pooled analysis, regardless of if/when DR occurred, PFS was similar and DoT may be sustained with ALP + FUL. ALP DR can potentially reduce AEs, which may allow pts to remain on tx. Using DR as an AE management strategy may enable pts with PIK3CA-mutated, HR+, HER2− ABC to optimize tx duration and clinical benefit of ALP in the 2L. Landmark Analyses of PFS and Tx Duration by DR Group (Yes vs No; Pooled FAS) Citation Format: Hope Rugo, Alessandra Gennari, Stephen Chia, Dejan Juric, Neil Vasan, Sherko Küemmel, Patrick Neven, Florence Lerebours, Manuel Ruíz - Borrego, Pedram Razavi, Jyotika Singh, Yogesh Chattar, Murat Akdere, Eva Ciruelos. Effect of Alpelisib Dose Modification for AE Management on Progression-Free Survival and Treatment Duration in SOLAR-1 and BYLieve Clinical Trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-10.

Abstract PO2-01-09: Patient preferences for CDK4/6 inhibitor treatments in HR+/HER2− early breast cancer: a discrete choice survey study

Abstract Background: Patients (pts) with stage II/III HR+/HER2− early breast cancer (EBC) are at risk of recurrence that persists over years. The addition of a CDK4/6 inhibitor (CDK4/6i) to adjuvant endocrine therapy (ET) was investigated in monarchE, evaluating abemaciclib (ABE) in lymph node (LN)+ high-risk pts, and NATALEE, using ribociclib (RIB) in stage II/III disease, including pts with N0 disease. ABE was FDA approved in this indication in 2021, while NATALEE recently reported statistically significant iDFS results. Both efficacy and tolerability are relevant for pts treated in a curative setting. This prospective study evaluated the extent pts with EBC value different treatment (tx) attributes and how these may translate into preferences between the two CDK4/6i in the US. Methods: A web-based discrete choice experiment survey was conducted among pts with EBC between Jan and May 2023 before NATALEE results were available. Eligible pts were adult women in a US clinical practice setting with self-reported stage II/III HR+/HER2− EBC +/- prior chemotherapy receiving only adjuvant ET at the time of survey, who completed curative surgery 1-3 years ago. Pts selected the scenario that best reflected their preferences from a series of choice cards, each displaying a pair of hypothetical tx profiles. A total of 8 attributes related to efficacy (5-year iDFS), adverse events (AEs), monitoring requirements, tx duration, and schedule were included (Table 1). Attributes were included based on an initial pilot qualitative assessment that selected efficacy and safety attributes most relevant to pts, clinical input, and differentiating features between CDK4/6i. A conditional logit regression model was used to estimate preference weights and relative importance (RI) of each attribute. Utility scores, summarizing overall preference for CDK4/6i tx profiles, were estimated from the model, and various scenarios were tested. Subgroup analyses by menopausal status and BC stage will be presented. Results: 409 pts participated in the survey (median age, 53 years; White/Black/other race, 59%/23%/18%; BC stage II/III, 48%/52%; employed, 38%). Pt preferences for attributes that significantly impacted tx decision, in order of high to low RI, were higher efficacy (iDFS), lower risk of diarrhea, lower risk of fatigue, shorter tx duration, and lower risk of venous thromboembolic events. Attributes based on monitoring or schedule, including number of blood tests, number of EKGs, and tx schedule, did not affect tx choice (Table 2). Overall utility scores were consistently higher for reconstructed tx profiles that resembled RIB features, including under conservative scenarios where efficacy of RIB was assumed to be equivalent or lower than that of ABE. Conclusions: This study showed that, driven by strong preference for lower risk of AEs, pts with HR+/HER2− EBC prefer tx profiles that more closely resemble the clinical experience of receiving RIB. These pt preferences are important for shared decision making when discussing the addition of a CDK4/6i to adjuvant tx for eligible pts with HR+/HER2− EBC. Discrete Choice Experiment Attributes and Levels Estimated Preference Weight and Relative Importance Citation Format: Erica Mayer, Mary Lou Smith, Annie Guerin, Dominick Latremouille-Viau, Nisha C. Hazra, Yan Meng, Wendi Qu, Remi Bellefleur, Vaidyanathan Ganapathy, Liz Santarsiero, Robert Morlock, Maryam Lustberg. Patient preferences for CDK4/6 inhibitor treatments in HR+/HER2− early breast cancer: a discrete choice survey study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-09.

First-in-human phase 1 study of CC-94676, a first-in-class androgen receptor (AR) ligand-directed degrader (LDD), in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

134 Background: Androgen receptor (AR) signaling is the principal driver of PC at all stages. CC-94676 (BMS-986365) is a heterobifunctional, first-in-class, orally bioavailable AR LDD designed to induce rapid, sustained, and highly selective AR degradation in pts who progressed on standard of care therapies. We report initial results from an open-label, multicenter study, NCT04428788, evaluating CC-94676 in pts with progressive mCRPC. Methods: Pts with mCRPC who progressed on androgen deprivation therapy, ≥ 1 second generation hormonal therapy (eg, enzalutamide [enza], abiraterone [abi], darolutamide, and apalutamide) and taxane chemotherapy (chemo) (unless refused or not indicated) were enrolled to evaluate the safety, tolerability, PK/PD, and preliminary efficacy of CC-94676. Escalation doses evaluated were 100–1200 mg QD and 600–900 mg BID; expansion doses were 600 mg QD and 400–900 mg BID. Results: As of Aug 21, 2023, 95 pts received CC-94676 (median age 71 yrs) with a median of 5 (range 2–12) prior therapies, including enza (80%), abi (72%), both enza & abi (56%), and chemo (56%) (docetaxel 55%; cabazitaxel 20%). There were no ≥ Grade (G) 4 treatment-related adverse events (TRAEs) or discontinuations due to TRAEs. Of 27 pts treated in escalation, treatment (Tx) was well tolerated; 2 pts had non-serious G3 TRAEs at doses ≥ 800 mg QD, which were manageable with dose modifications. One dose-limiting toxicity of asymptomatic QTc prolongation was observed at 900 mg BID and resolved with dose interruption. The maximum tolerated dose was not reached. Of 68 pts treated in expansion, the most common TRAEs were dose-dependent: QTc prolongation (asymptomatic) (43%; G3: 9%), bradycardia (31%; ≥G3: none), and fatigue (24%; ≥G3: none). G3 TRAEs were manageable with dose modifications. The rate of pts with confirmed PSA reductions ≥ 30% (PSA30) increased dose-dependently from 400 to 900 mg BID. 23/68 (34%) pts across all dose levels achieved ≥ PSA30. At 900 mg BID, 11/20 (55%) pts showed PSA30; 7/20 (35%) and 2/20 (10%) had confirmed PSA declines of ≥50% and ≥90%, respectively. PSA responses and radiographic tumor shrinkage occurred across all dose levels, including in pts with AR wildtype (WT) , amplifications, and mutations (by cfDNA), and in heavily pretreated pts who progressed on abi, enza, and chemo. At 900 mg BID, the median duration of Tx was 182 days (range 21-448) and 9/20 (45%) pts remained free of radiographic progression with treatment ongoing at 6 months. Conclusions: CC-94676 is well tolerated with a manageable safety profile. CC-94676 shows promising and prolonged clinical activity in heavily pretreated mCRPC pts who progressed on abi, enza, and chemo with activity seen in pts with tumors expressing WT and mutant ARs. Selection of the recommended phase 2 dose is ongoing. Clinical trial information: NCT04428788 .

Single Center Experience With Sodium-Glucose Co-Transporter-2 Inhibitors (SGLT2i) in Kidney Transplant Recipients With Diabetes.

Sodium-glucose co-tranporter-2 inhibitors have been shown to be safe and effective in patients with type 2 diabetes for improving glycemia. Furthermore large, randomized control trials have shown cardiovascular and renal benefits. However, limited safety and efficacy data is available in kidney transplant patients with diabetes. To investigate the safety and efficacy of SGLT2i use on stability of renal function in adult kidney transplant recipients (KTR) with type 2 diabetes mellitus (DM2) or New Onset Diabetes After Transplantation (NODAT). We performed a single center, retrospective cohort study pre- and post-SGLT2i exposure. Adults with DM2 or NODAT who received a living or deceased kidney transplant (Tx) and started on an SGLT2i post-Tx were reviewed. Patients who had type 1 diabetes were excluded. The baseline was the SGLT2i start date. We reviewed available data from 24 months (M) before and after SGLT2i initiation. The primary endpoints were the effects of SGLT2i use on stability of renal function using serum creatinine and eGFR, change in urine albumin excretion(uACR), and glycosylated hemoglobin (A1C). Secondary endpoints compared blood pressure, body mass index and adverse reactions at baseline and quarterly after SGLT2i initiation. 125 KTRs were included in cohort: NODAT (52, 42%), DM2 (73, 58%); female (33, 27%); mean age at Tx 55 years (25-75); LD (56, 45%), DD (69, 55%); mean duration of Tx (6.8 years, 0.1-42.5); study follow-up (1.8 years, 0.3-4.9).The mean eGFR remained stable pre-SGLT2i at 64.6 mL/min/1.73m2, vs post at 64.3 mL/min/1.73m2. There was no difference in mean A1C after SGLT2i initiation. The slope of uACR using natural log transformation pre-SGLT2i compared with post-SGLT2i slope reduced from +0.7 (0.03, 0.11) to -0.04 (-0.01, -0.35) mg/mmol/3mths (P = .002). The risk of developing new genital mycotic infections among all patients was 4% (95% CI 1.3%-9.1%) While there was no significant difference in UTI before (13.6%) and after (12%) SGLT2i use (P = .68), there was a higher risk of UTI seen in patients with a previous history of UTI (23.5%) vs no previous history (10.2%) post initiation. There was no significant increase in AKI pre 8%, post 10.4%, P = .51. There was a single DKA event pre- and post-SGLT2. The limitations of this study include its retrospective nonrandomized nature. In this retrospective analysis, SGLT2i use in KTR appears to be safe and efficacious with stable renal function and glycemic control, alongside improvements in uACR. There was a low risk of new genital yeast infections after SGLT2i start. UTI occurrence was higher in patients with a previous history of UTI compared with those with no previous history.

Abstract LB_A16: DareonTM-5: An open-label Phase II trial of BI 764532, a DLL3-targeting T cell engager, in patients with relapsed/refractory small cell lung cancer or other neuroendocrine carcinomas

Abstract Background: Small cell lung cancer (SCLC), extra-pulmonary neuroendocrine carcinomas (epNECs) and large cell NECs (LCNECs) of the lung are difficult-to-treat, aggressive tumors with limited treatment (Tx) options. Standard of care for metastatic disease is platinum-based chemotherapy ± immunotherapy. However, nearly all patients (pts) relapse, and outcomes are poor. Hence, alternative therapies are needed. Delta-like ligand 3 (DLL3), a Notch ligand, is highly expressed on the cell surface of SCLCs, epNECs and LCNECs. BI 764532, a humanized IgG-like T cell engager, binds to DLL3-positive tumor cells and CD3 on T-cells and promotes T cell-mediated cytotoxicity. In an ongoing first-in-human trial, BI 764532 exhibited promising efficacy and manageable tolerability in pts with DLL3-positive SCLC, epNEC and LCNEC of the lung (NCT04429087). Here we describe a planned Phase II dose optimization trial to assess safety/efficacy of two different doses of BI 764532 monotherapy in pts with progressive/recurrent SCLC, epNEC or LCNEC of the lung (NCT05882058). Methods: The trial will recruit adult pts (n = ~120; ~70 sites; ~15 countries) with histologically/cytologically confirmed relapsed/refractory SCLC, epNEC or LCNEC of the lung who have received ≥2 (SCLC) or ≥1 (epNEC/LCNEC) prior lines of therapy, including ≥1 platinum-based regimen. Pts with mixed tumor histology are permitted if the SCLC/NEC component is predominant (≥50% of tumor tissue). Pts will be randomized 1:1 to receive one of two dose levels of intravenous BI 764532 (3-week cycles) stratified by tumor type (n ~ 60/arm). Tx will continue until disease progression, undue toxicity, withdrawal of consent or any other documented criteria for stopping Tx (maximum Tx duration: 36 months). Interim analyses for dose selection are planned after 30 pts have been followed for ≥6 and ≥12 weeks or have stopped Tx. A third interim efficacy analysis will be conducted when 60 pts per dose have been followed for ≥12 weeks or have stopped Tx. Key exclusion criteria: ECOG PS ≥2; untreated/symptomatic brain metastases or leptomeningeal disease; active/previous history of interstitial lung disease/pneumonitis; previous Tx with DLL3-targeting therapies; Tx with other anti-cancer drug <4 weeks prior to first administration of BI 764532; unresolved toxicity from prior anti-tumor Tx; diagnosis of immunodeficiency, or intake of immunosuppressive therapy ≤7 days prior to first administration of BI 764532. Primary endpoints: objective response (RECIST v1.1; investigator assessment); occurrence of Tx-emergent adverse events (TEAEs) during the on-Tx period. Secondary endpoints: duration of objective response; progression-free survival; disease control; overall survival; pt-reported outcomes; TEAEs leading to discontinuation during the on-Tx period. Further endpoints: pharmacokinetics (PK); prespecified and exploratory biomarker analysis (archival tumor tissue is required). The comparison of the two target doses in this trial will be based on the totality of data, including safety, efficacy, PK and biomarker data. Citation Format: Valentina Gambardella, Alastair Greystoke, Martin Reck, Meiruo Liu, Martha Mueller, Ulrich Duenzinger, Emily B Bergsland, Taofeek Owonikoko. DareonTM-5: An open-label Phase II trial of BI 764532, a DLL3-targeting T cell engager, in patients with relapsed/refractory small cell lung cancer or other neuroendocrine carcinomas [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A16.

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

Luspatercept for the Treatment of Anemia in Non-Transfusion-Dependent β-Thalassemia: Final Safety and Efficacy Data from the BEYOND Trial

Background: Suboptimal anemia management in patients (pts) with non-transfusion-dependent (NTD) β-thalassemia may lead to serious clinical complications. Improvements in hemoglobin (Hb) levels were shown to significantly decrease the risk of developing morbidities (Musallam KM, et al. Ann Hematol 2022;101:203-204; Musallam KM, et al. Ann Hematol 2021;100:1903-1905). There is a need for therapies that increase Hb levels besides red blood cell transfusions (RBCT), which lead to secondary iron overload. Primary and longer-term data from the BEYOND study showed that luspatercept led to significant increases in Hb levels and had a manageable safety profile in pts with NTD β-thalassemia (Taher AT, et al. Lancet Haematol 2022;9:e733-e744; Taher AT, et al. Blood 2022;140[suppl 1];8210-8212). Here we report the final data (up to last patient last visit [LPLV] date Nov 28, 2022), of the phase 2, randomized, double-blind, placebo-controlled BEYOND trial (NCT03342404). Methods: Eligible pts (N = 145) had NTD (defined as receiving ≤ 5 RBC units in the 24 wk before randomization) β-thalassemia or HbE/β-thalassemia, Hb levels ≤ 10 g/dL. Pts were randomized to luspatercept (N = 96; 1.0-1.25 mg/kg) or placebo (N = 49) subcutaneously Q3W for ≥ 48 wk. Pts continued to receive best supportive care when required. Pts who crossed over from placebo to luspatercept were not included in this analysis. Mean Hb increase ≥ 1.0 g/dL (any 12-/24-wk interval) and ≥ 1.5 g/dL from baseline (any 12-wk interval), duration of mean Hb increase ≥ 1.0 g/dL and ≥ 1.5 g/dL from baseline, iron parameters, RBCT, and safety were evaluated up to the LPLV date. Results: As of Nov 28, 2022, 93/134 (69.4%) pts on luspatercept transitioned to the long-term follow-up study (NCT04064060): 66/96 (68.8%) pts in the luspatercept arm and 27/38 (71.1%) pts who crossed over from placebo to luspatercept after study unblinding. A total of 76/96 (79.2%) pts in the luspatercept arm completed 144 wk of treatment (tx), with 55/96 (57.3%) completing 192 wk of tx; 28/96 (29.2%) pts on luspatercept discontinued tx. The median (range) luspatercept tx duration was 202.8 (15.0-242.3) wk (Table) and 61.1 (3.0-138.0) wk with placebo. Pts had a durable increase in Hb ≥ 1.0 g/dL from baseline (by 12-wk interval) through wk 240 of luspatercept tx (Figure). In the luspatercept arm, 91/96 (94.8%) pts had a mean Hb increase ≥ 1.0 g/dL from baseline during any 12-wk interval (Table). The mean (standard deviation [SD]) total duration of mean Hb increase ≥ 1.0 g/dL from baseline (any 12-wk interval) with luspatercept was 1136.0 (491.9) days. The proportion of pts achieving a mean Hb increase ≥ 1.5 g/dL during any 12-wk interval over the entire tx period was 80/96 (83.3%) and 4/49 (8.2%) in the luspatercept and placebo arms, respectively. At baseline, 83/96 and 42/49 pts in the luspatercept and placebo arms, respectively, were RBCT-free. The proportion of pts who remained RBCT-free was 78.1% (75/96) and 57.1% (28/49) in the luspatercept and placebo arms, respectively. For pts who received RBCT, the mean time to first RBCT was 482.0 days with luspatercept and 202.6 days with placebo. The mean change from baseline in serum ferritin (SF) level at wk 96 was +76.45 µg/L with luspatercept (n = 90) and +211.51 µg/L with placebo (n = 35). The mean change from baseline in SF level stabilized with longer luspatercept tx (wk 192: 49.14 µg/L [n = 71]; wk 240: 52.19 µg/L [n = 51]). The mean change from baseline in liver iron content in the luspatercept arm was −1.23 mg/g dry weight (dw) at wk 96 (n = 8) and −0.79 mg/g dw at wk 144 (n = 54). The 10 most frequently reported adverse events (AEs; ≥ 5% of pts) with luspatercept were headache, back pain, bone pain, COVID-19, arthralgia, pyrexia, pain in extremity, fatigue, diarrhea, and hypertension. Rates of serious and grade 3-4 AEs in the luspatercept arm were 24.0% [23/96] and 34.4% [33/96]), respectively. In the luspatercept arm, thromboembolic events were reported in 2/96 pts, extramedullary hemopoietic masses in 10/96 pts (all grade 1-2), and there were no malignancies. Few AEs led to tx discontinuation in the luspatercept arm (5/96 [5.2%]); no new safety signals were identified. Summary: The final results from the BEYOND study show that pts with NTD β-thalassemia treated with luspatercept maintained clinically meaningful and durable erythroid responses. The safety profile of luspatercept was manageable, and extended luspatercept exposure did not raise new safety concerns.

144. Impact of Rapid Identification and Resistance Gene Detection using an Algorithm-Based Approach in Gram-Negative Bacteremia

Abstract Background Time to appropriate antimicrobial therapy is the most important predictor of survival among patients with sepsis due to Gram-negative bacteria (GNB). Infections due to multidrug-resistant (MDR) pathogens often result in inappropriate empiric treatment (tx). The GenMark ePlex identifies organisms and resistance markers within 1.5 hours from blood culture positivity compared to 48-72 hours by conventional methods. Methods We are conducting a single-center study to assess outcomes before and after ePlex implementation. The pre-intervention period included patients with GN bacteremia from January to June 2021. Patients were excluded if they received comfort-only care within 48 hours, had polymicrobial GN bacteremia, or were infected by an organism not on the ePlex panel. Primary outcome is time to in-vitro active therapy from blood culture collection. Results 208 patients were identified during the pre-intervention period; 154 met inclusion criteria. Median age was 64 years, 49% were male, and 28% were immunocompromised. Median (IQR) Charlson Comorbidity index and Pitt Bacteremia scores were 6 (4-8) and 2 (1-8), respectively (Table 1). 16% of patients were infected by MDR GNB and 21% received inactive empiric tx. Overall median (IQR) time to in-vitro active tx was 3.9 (1–19) hours, but was 39.5 (13.6-71.9) hours among those who received inactive empiric tx. Median (IQR) time to first antibiotic modification was 2.7 (1.0-3.4) days. 38% of patients were transitioned to oral antibiotics at a median (IQR) of 4.2 (3.1-6.1) days. The median (IQR) duration of tx was 15 (10-17) days; 4.5% of patients were treated with ≤ 7 days. Median (IQR) length of hospitalization was 15.5 (7-36) days. 7.8% were re-admitted within 30 days (Table 2). In-hospital and 30-day mortality rates were numerically higher among patients who received inactive empiric therapy (27% and 21%, respectively) when compared to patients who received active empiric therapy (16.5% and 12%, respectively) (Figure 1). Results Table 1: Patient demographics, underlying conditions and infection and treatment characteristics in the pre-intervention group Results Table 2 Results Figure 1 Conclusion Our pre-intervention data highlight opportunities to improve the management of GN bacteremia. Implementation of ePlex is likely to decrease the proportion of patients treated with inactive therapy, shorten time to optimal tx and reduce lengths of stay. Disclosures Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support

Asciminib (ASC) in Combination with Imatinib (IMA), Nilotinib (NIL), or Dasatinib (DAS) May be a Potential Treatment (Tx) Option in Patients (Pts) with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase or Accelerated Phase (Ph+ CML-CP/AP): Final Results from the Asciminib Phase 1 Study

Asciminib (ASC) in Combination with Imatinib (IMA), Nilotinib (NIL), or Dasatinib (DAS) May be a Potential Treatment (Tx) Option in Patients (Pts) with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase or Accelerated Phase (Ph+ CML-CP/AP): Final Results from the Asciminib Phase 1 Study

Efficacy and Safety of Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent (ESA)-Naive Patients (Pts) with Transfusion-Dependent (TD) Lower-Risk Myelodysplastic Syndromes (LR-MDS): Full Analysis of the COMMANDS Trial

Introduction: ESAs are an established treatment (tx) for pts with TD LR-MDS and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L; however, eligible pts often do not respond, or the response duration is limited. Luspatercept is approved in the US and EU to treat anemia due to LR-MDS after ESA failure. The preplanned interim analysis of the phase 3 COMMANDS trial (NCT03682536), comparing luspatercept with epoetin alfa in ESA-naive TD pts with anemia due to LR-MDS (with or without ring sideroblasts [RS]) showed for the first time the superiority of another therapy over ESAs in improving red blood cell transfusion independence (RBC-TI) rates (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736[23]00874-7). Here we report the full efficacy and safety analysis of the COMMANDS trial. Methods: Eligible pts were ≥ 18 y of age, had Revised International Prognostic Scoring System-defined LR-MDS with < 5% bone marrow blasts, sEPO < 500 U/L, and were TD (received 2-6 RBC U/8 wk for ≥ 8 wk before randomization). Pts were randomized 1:1 to luspatercept (1.0-1.75 mg/kg) subcutaneously (SC) Q3W, or epoetin alfa (450-1050 IU/kg) SC Q1W for ≥ 24 wk and stratified by baseline RBC transfusion burden (< 4 vs ≥ 4 RBC U/8 wk), RS status (RS+ vs RS−), and sEPO (≤ 200 vs > 200 U/L). The primary endpoint was the achievement of RBC-TI ≥ 12 wk with a concurrent mean hemoglobin (Hb) increase ≥ 1.5 g/dL (wk 1-24). Key secondary endpoints (wk 1-24) included achievement of RBC-TI ≥ 12 and for 24 wk and hematologic improvement-erythroid (HI-E) ≥ 8 wk. Other endpoints included duration of RBC-TI ≥ 12 wk, progression to acute myeloid leukemia (AML), and safety. Results: As of Mar 31, 2023, 182 pts were randomized to luspatercept and 181 to epoetin alfa, with a median (range) tx duration of 51.3 (3-196) and 37.0 (1-202) wk and median (range) follow-up of 17.2 (1-46) and 16.9 (0-46) months, respectively. The primary endpoint was achieved by110 (60.4%) pts in the luspatercept arm versus 63 (34.8%) in the epoetin alfa arm ( P < 0.0001). Subgroup analysis of the primary endpoint response showed that response rates achieved with luspatercept versus epoetin alfa, respectively, were greater for SF3B1-mutated and non-mutated pts (Table), greater for pts with baseline sEPO ≤ 200 U/L and with baseline sEPO > 200 to < 500 U/L (Table), and greater for RS+ pts (Table). The response rates were comparable between tx arms for RS− pts (Table). RBC-TI ≥ 12 wk was achieved by 124 (68.1%) and 88 (48.6%) pts in the luspatercept and epoetin alfa arms, respectively, RBC-TI for 24 wk by 87 (47.8%) and 56 (30.9%) pts, and HI-E ≥ 8 wk by 135 (74.2%) and 96 (53.0%) pts. The median (95% CI) duration of RBC-TI ≥ 12 wk was longer with luspatercept versus epoetin alfa (128.1 wk [108.3-not estimable (NE)] versus 89.7 wk [5.9-157.3]; HR, 0.534; Figure), and longer for clinically relevant subgroups, including RS+ and RS−. The median duration of tx was longer in the luspatercept arm compared with the epoetin alfa arm (51.3 versus 37.0 wk). Five (2.7%) and 6 (3.3%) pts in the luspatercept and epoetin alfa arms, respectively, progressed to AML. Overall, 178 (97.8%) and 165 (92.2%) pts receiving luspatercept and epoetin alfa reported tx-emergent adverse events (TEAEs) of any grade; 107 (58.8%) and 88 (49.2%) pts reported grade 3/4 TEAEs, respectively. The most common any-grade TEAEs in either arm (≥ 10% of pts) were diarrhea (17.6% luspatercept vs 14.0% epoetin alfa), COVID-19 (14.8% vs 15.6%), asthenia (13.7% vs 16.2%), and anemia (12.1% vs 10.6%). TEAEs of interest were reported by 105 (57.7%) and 81 (45.3%) pts receiving luspatercept and epoetin alfa, respectively, with asthenia including fatigue, malaise, and lethargy (30.8% vs 24.6%), hypertension (15.9% vs 9.5%), malignancies and premalignant disorders (14.3% vs 12.8%), kidney toxicity (8.8% vs 6.7%), and injection site reactions (6.6% vs 2.2%), occurring in > 5% pts. In both tx arms, rates of on-tx deaths (8.2% for luspatercept and 7.2% for epoetin alfa) and post-tx deaths (13.2% and 13.4%) were similar. Conclusions: Results of this full analysis confirm the findings from the interim analysis; RBC-TI duration and erythroid responses achieved with luspatercept are superior compared with epoetin alfa. Luspatercept safety results were consistent with previous MDS studies. These data show that luspatercept could represent a new standard of care for pts with TD LR-MDS.

Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial.

LBA500 Background: RIB + ET has demonstrated significant survival benefits in pre- and postmenopausal pts with HR+/HER2− metastatic BC. To investigate whether RIB + ET also improves outcomes in early BC (EBC), the Phase III NATALEE trial (NCT03701334) evaluated adjuvant RIB + ET in a broad population of pts with stage II or III HR+/HER2− EBC at risk for recurrence, including pts with no nodal involvement (N0). As extended duration of tx is crucial to prolong cell cycle arrest and drive more tumor cells into senescence or death, a 3-y duration of RIB tx at a dose of 400 mg was chosen to improve tolerability while maintaining efficacy. Results from a prespecified interim analysis of invasive disease–free survival (iDFS; primary endpoint) are presented. Methods: Men and pre- or postmenopausal women were randomized 1:1 to RIB (400 mg/day; 3 wk on/1 wk off for 3 y) + ET (letrozole 2.5 mg/day or anastrozole 1 mg/day, for ≥ 5 y) or ET alone. Men and premenopausal women also received goserelin. Eligible pts had an ECOG PS of 0-1 and BC anatomic stage IIA (either N0 with additional risk factors or 1-3 axillary lymph nodes [N1]), stage IIB, or stage III per AJCC (8th ed); prior (neo)adjuvant ET was allowed if initiated ≤ 12 mo before randomization. Stratification factors were menopausal status, disease stage, prior (neo)adjuvant chemotherapy, and geographic region. This prespecified interim analysis of iDFS, defined per STEEP criteria, was planned after ≈ 425 iDFS events (≈ 85% of planned total events). iDFS was evaluated by Kaplan-Meier methods, and statistical comparison was made by a stratified log-rank test, with a protocol-defined Lan-DeMets (O'Brien-Flemming) stopping boundary of a 1-sided P < .0128 for superior efficacy. Results: From 10 Jan 2019 to 20 April 2021, 5101 pts were randomized (RIB+ET, n = 2549; ET alone, n = 2552). As of the data cutoff (11 Jan 2023), median follow-up was 34 mo (min, 21 mo). 3- and 2-y RIB tx was completed by 515 pts (20.2%) and 1449 pts (56.8%), respectively; 3810 (74.7%) remained on study tx (RIB+ET, n = 1984; ET alone, n = 1826). iDFS was evaluated after 426 events (RIB + ET, n = 189; ET alone, n = 237). RIB + ET demonstrated significantly longer iDFS than ET alone (HR, 0.748; 95% CI, 0.618-0.906; P = .0014); 3-y iDFS rates were 90.4% vs 87.1%. iDFS benefit was generally consistent across stratification factors and other subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease–free survival consistently favored RIB. RIB at 400 mg had a favorable safety profile with no new signals. Conclusions: Ribociclib added to standard-of-care ET demonstrated a statistically significant, clinically meaningful improvement in iDFS with a well-tolerated safety profile. The NATALEE results support ribociclib + ET as the treatment of choice in a broad population of pts with stage II or III HR+/HER2− EBC, including pts with N0 disease. Clinical trial information: NCT03701334 .

REAL‐WORLD DURATION OF VENETOCLAX TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA AND SMALL LYMPHOCYTIC LYMPHOMA

Introduction: Venetoclax (V) is an approved fixed-duration treatment (tx) for chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL), as a 12-cycle regimen (∼12 mos) with obinutuzumab (O) in the first-line (1L) setting or as a 24-cycle regimen (∼24 mos) with rituximab (R) in the relapsed/refractory (R/R) setting. We analyzed real-world tx patterns of V+O in 1L and V+R in R/R settings in patients (pts) with CLL/SLL in the United States. Methods: A retrospective cohort analysis was conducted using the IQVIA PharMetrics® Plus database to identify pts ≥18 y treated with V+O (1L cohort; May 2019 to September 2021) or V+R (R/R cohort; June 2018 to September 2021). Start of tx regimen was defined as the index date. All pts were required to have ≥1 diagnosis code for CLL/SLL and continuous enrollment 12 mos prior to and ≥3 mos after index date. Duration of tx (DoT) was defined as time from index date to earliest of either tx discontinuation (i.e., ≥60-d gap in V prescription refills) or censoring (i.e., end of follow-up). Fixed-duration tx cycle was defined as 12- or 24-cycle dosing (days 336−364 for 1L setting and days 707−735 for R/R setting, based on the dosing schedule plus 28 days). Kaplan-Meier analysis was used to estimate the probability of remaining on tx for the 1L and R/R cohorts. Results: A total of 116 pts in 1L setting (mean age, 62.3 y) and 145 pts in R/R setting (mean age, 64.2 y) were identified; 48.3% of R/R pts had prior targeted therapy. Median (95% CI) DoT in V+O pts (n = 115) was 12.4 (11.5, 13.4) mos over a median follow-up of 11.4 mos; probability of remaining on tx at 12, 18, and 24 mos was 56.4%, 20.2%, and 5.1%. Median (95% CI) DoT in V+R pts (n = 133) was 24.5 (13.4, 25.2) mos over a median follow-up of 15.5 mos; probability of remaining on tx at 24, 30, and 36 mos was 53.8%, 19.0%, and 19.0%. Among V+O pts, 47.8% (55/115) had ≥12 mos follow-up, of whom 9.1% had fixed cycles and 38.2% discontinued early (median DoT: 4.6 mos). Among V+R pts, 29.3% (39/133) had ≥24 mos follow-up, of whom 5.1% had fixed cycles and 46.2% discontinued early (median DoT: 7.1 mos). The remaining pts in each cohort had DoT >12 or 24 cycles (Table). Conclusions: While median DoT was approximately 12 mos for V+O-treated pts (1L setting) and 24 mos for V+R-treated pts (R/R setting), a high number of pts did not maintain the fixed-dosing schedule. This study provides evidence that a V-based approach may not be suitable for all pts with CLL/SLL. Encore Abstract—previously submitted to regional or national meetings (up to <1’000 attendees), EHA 2023 The research was funded by: AstraZeneca Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract A. Teschemaker Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca S. Hakre Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Tse Research funding: AstraZeneca Pharmaceuticals. IQVIA received research funding from AstraZeneca to conduct this study. N. F. Shaikh Research funding: AstraZeneca Pharmaceuticals. IQVIA received research funding from AstraZeneca to conduct this study. Y. Gu Research funding: AstraZeneca Pharmaceuticals. IQVIA received research funding from AstraZeneca to conduct this study. A. Near Research funding: AstraZeneca Pharmaceuticals. IQVIA received research funding from AstraZeneca to conduct this study.

Ixazomib and daratumumab without dexamethasone (I-Dara) in elderly frail patients with RRMM: Results of the multicenter phase 2 study (IFM 2018-02) of the Intergroupe Francophone du Myélome (IFM).

8054 Background: Frailty is associated with inferior outcome in older myeloma patients, especially in the relapse setting.1,2 This adverse prognosis is mainly related to a high discontinuation rate for treatment (Tx) related adverse events (AE). Dexamethasone is responsible of a high rate of infections and metabolic AE. We present here the updated results from the phase 2 study I-Dara evaluating efficacy and tolerability of Ixazomib-Daratumumab without Dexamethasone in elderly frail patients with relapsed myeloma (RRMM) (NCT03757221). Methods: Ixa-Dara naïve RRMM patients received oral Ixazomib (4 mg: days 1, 8, 15), IV Daratumumab (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Daratumumab (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled after 1 or 2 prior therapy if their frailty score was ≥ 2 by IMWG score. The primary endpoint was ≥ very good partial response rate (VGPR) at one year. Secondary endpoints included ORR, PFS, OS &amp; toxicity according to NCI-CTCAE version 5. Results: Sixty-three patients were screened and 55 enrolled between 03/2018 and 09/2021. Patient were at first (n = 36) or second relapse (n = 19). Thirty-five patients (64%) were previously exposed to bortezomib, 37 (67%) were previously exposed to lenalidomide (Len) and 23 (42 %) were refractory to Len. Median age was 82 (72-93). All patients had a frailty score ≥2 and 13 (24 %) had a 3 or 4 frailty score. In 41 patients ISS at diagnosis was stage I (n = 11), II (n = 18) or III (n = 12). Seventeen (36%) patients harbored high-risk (HR) cytogenetic, including t(4;14) (n = 8) or del17p (n = 10). The median duration of Tx (DOT) in 14 pts with ongoing Tx was 22 mos [min-max: 16-40] at data cutoff (January, 19)]. The median DOT in 41 pts who stopped Tx was 10 mos [min-max: 0-31]: 28 had progressive disease (PD). Fourteen patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2), sepsis (n = 3), pneumonia (n = 2), PD (n = 7). Regarding toxicity, 31 pts had a ≥grade 3 AE (55%). The most common grade 3-4 AE were thrombocytopenia (n = 10), other cytopenias (n = 5), anemia (n = 3), infection (n = 6), gastrointestinal disorders (n = 5) and hypertension (n = 3). The ≥VGPR rate is 32 % @ 1 year (34 % overall) with an ORR of 70% @ 1 year (74 % overall). In Len refractory patients the ≥VGPR rate is 40% @ 1 y and the ORR 70 %, in HR patients the ≥VGPR rate is 60 % and ORR 80%. With a median follow-up of 23.0 mos median PFS is 18.5 mos and median OS NR (75% OS estimated at 27.9 mos). Conclusions: In this elderly frail population Ixa-Dara is a feasible combination with favorable efficacy profile even in Len refractory and HR cytogenetic patients. Early toxicity remains a concern in this population eventhough more manageable with Dara SC. Late benefit is consistent with one third of patients still on treatment. Clinical trial information: NCT03757221 .

First-in-human dose-escalation trial of BI 764532, a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager in patients (pts) with DLL3-positive (DLL3+) small-cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC).

8502 Background: The inhibitory Notch ligand, DLL3, is highly expressed on the cell surface of SCLC and NEC tumors and is a promising drug target. BI 764532 is a DLL3/CD3 T cell engaging bispecific antibody that has shown potent preclinical anti-tumor activity in DLL3+ cells and xenograft models. NCT04429087 is an ongoing phase I first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, NEC or small cell carcinoma of any other origin (grouped as NEC), or large cell NEC (LCNEC). Methods: BI 764532 was administered intravenously using three different regimens: Regimen (R) A (fixed iv dose q3w); RB1 (fixed iv dose qw); RB2 (step-in doses followed by a fixed dose). Treatment (Tx) continued until progressive disease (PD), unacceptable toxicity, other withdrawal criteria, or maximum Tx duration (36 mos). The main objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion of BI 764532, based on dose-limiting toxicities (DLTs) during the MTD evaluation period. Further objectives were safety, tolerability, PK/PD and preliminary efficacy based on investigator review (RECIST v1.1). Results: As of 28th Dec 2022, 90 pts received ≥1 dose of BI 764532 (RA: n = 24, 8 dose levels; RB1: n = 10, 3 dose levels; RB2: n = 56, 6 dose levels; starting dose: 0.03 µg/kg). Median age: 60 years (32–78); ECOG PS 0/1: 24/74%; prior PD1/PD-L1 Tx: 40%; ≥2 prior lines of Tx: 69%. SCLC/NEC/LCNEC: 52/41/4%. Median Tx duration: 43 days (range 1–443); 25 pts are ongoing. DLTs were seen in 1 pt on RA (Grade 3 confusion) and 4 pts on RB2 (Grade 4 cytokine release syndrome [CRS]; Grade 3 CRS, Grade 3 nervous system disorder, Grade 2 infusion-related reaction). MTD has not been reached and dose escalation is ongoing. Overall, the most common treatment-related AEs were (any/Grade 3+): CRS (58/2%); pyrexia (19/0%); decreased lymphocytes (18/14%); asthenia (17/1%); dysgeusia (14/0%). CRS was managed with supportive care, corticosteroids, and/or anti-IL-6R antibodies. With RB2, most CRS and neurological events occurred early, and were reversable. Tumor response data were available for 70 pts (RA/RB1/RB2: n = 19/8/43). In pts with SCLC (n = 24) or NEC (n = 23) who received ≥ target dose of BI 764532, ORR was 33% and 22% across all regimens, respectively. One pt with LCNEC was also evaluable for response and achieved PR. Conclusions: BI 764532 showed clinically manageable tolerability and MTD has not been reached at the doses administered to date. Promising efficacy has been observed, not only in SCLC but also in difficult to treat entities such as NEC and LCNEC. The study is ongoing; updated data will be presented. Clinical trial information: NCT04429087 .

Real-world (RW) treatment (tx) patterns of patients (pts) with higher-risk myelodysplastic syndrome (MDS) in a US RWE database (COTA).

e19077 Background: Pts with higher-risk MDS have poor outcomes. To understand current tx patterns/identify unmet needs, the COTA database, using pt-level curated electronic health record (EHR) data from centers across the US, was analyzed. Methods: This was a retrospective, descriptive analysis of deidentified secondary data from the COTA MDS RWE database. Data were abstracted from EHRs using these criteria: inclusion of adults with IPSS-R intermediate (I)/high (H)/very high-risk (vHR) MDS on/after 1/1/2012, exclusion of pts with no diagnosis date/clinician notes or pts with concurrent malignancies. Follow-up was until the last recorded event (last visit/other cancer/death; data cutoff 06/2022). Results: Data from 640 pts were included in this analysis. See Table for baseline demographic data. Most pts with IR- (225/281, 80%) and HR-MDS (162/239, 68%) were treated at community centers; pts with vHR-MDS were equally treated at academic (59/120, 49%) and community centers (61/120, 51%). Genetic/molecular data were limited; among pts with data available, the most common genetic mutation was TP53 (75/215, 35%). Of 640 pts, 108 (17%) did not receive tx and 110 (17%) received allogeneic stem cell transplant (alloSCT). Of those given systemic tx, hypomethylating agents (HMAs) were the most common first-line tx (444/532, 83%). Venetoclax was given to 35/640 pts (5%; as first line: 10/532, 2%; as second line: 20/170, 12%; as third line: 4/66, 6%). Median time to start tx from diagnosis was 2.2, 1.1, and 0.9 mo for IR-, HR-, and vHR-MDS, respectively. Of 512 pts assessed for first-line tx with duration data, tx duration was 7.4, 5.4, and 4.2 mo for IR-, HR-, and vHR-MDS, respectively. In 340 pts—including pts who underwent alloSCT—with response data, pts with IR-, HR-, and vHR-MDS had RW response rates (any response) of 73%, 72%, and 58%, respectively. Median OS (mOS) from start of tx was 29.0, 20.3, and 11.9 mo for IR-, HR-, and vHR-MDS, respectively. mOS (from tx start) according to tx: alloSCT 31.4 mo, chemotherapy 19.1 mo, HMAs 23.1 mo, investigational 22.1 mo, venetoclax 10.1 mo, and others 23.8 mo. About 20% of pts transformed into acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, or chronic lymphocytic leukemia. Conclusions: This RW study showed that available tx for pts with higher-risk MDS in the US is limited and remains a high unmet need. [Table: see text]

A real-world evaluation of treatment (Tx) patterns and outcomes of acute myeloid leukemia (AML) induction therapies in the community setting.

e19006 Background: AML is an aggressive hematologic malignancy of older adults (median age at diagnosis: 68 y); median overall survival (mOS) is low, even with Tx. The VIALE-A study changed the standard of care by combining venetoclax (VEN) with a hypomethylating agent (HMA), extending mOS from 9 to 14 mo. With the evolving Tx landscape and growing availability of less-intensive induction chemotherapy (IC), it is important to understand the impact of these Tx in the real world. This study evaluated Tx patterns and clinical outcomes for patients (pts) with AML who received intensive IC, VEN-based Tx (eg, VEN + azacitidine), or non-VEN-based low-intensity (NVB-LI) Tx (eg, a single HMA) in the first-line (1L) setting. Methods: A retrospective, observational, US-based, cohort study was conducted utilizing electronic health record data from adults with AML who initiated 1L IC between 01/01/2016 and 12/31/2019, or 1L VEN-based Tx or 1L NVB-LI Tx between 01/01/2019 and 12/31/2020. Eligible pts had ≥6 mo of follow-up after 1L initiation (or &lt;6 mo due to death). Pts who received AML Tx as part of clinical trials were excluded. Remission was defined as a physician-reported best response of complete remission (CR), CR with incomplete hematologic improvement, or CR with no measurable residual disease. Time-to-event outcomes were assessed using the Kaplan–Meier method; all other data were summarized using descriptive statistics. Results: A total of 451 pts were included; 54% were male, 70% were White. Median follow-up was 17 mos. Mean age at 1L initiation was 52, 73, and 76 y in the IC, VEN, and NVB-LI cohorts, respectively. Among the 207 pts in the IC cohort, 99% discontinued Tx during follow-up, 85% of whom discontinued due to completion of Tx. Among the 152 pts in the VEN cohort and 92 in the NVB-LI cohort, 72% and 75% discontinued Tx, respectively, primarily due to disease progression (59% and 68% of discontinuing pts, respectively). Median duration of 1L Tx was 2, 11, and 7 mo in the IC, VEN and NVB-LI cohorts, respectively. In the IC, VEN, and NVB-LI cohorts, 80%, 45%, and 20% of pts achieved remission during 1L Tx; median time to remission was 1, 3, and 3 mo, respectively. Median relapse-free survival was not reached during follow-up in any of the cohorts. In the IC cohort mOS was not reached; mOS was 17 mo in the VEN cohort, and 9 mo in the NVB-LI cohort. Conclusions: Pts receiving 1L IC had the highest rate of remission, the shortest time to remission, and the most favorable mOS among all Tx cohorts, supporting continued intensive chemotherapeutic approaches with curative intent in eligible pts. mOS favored combination VEN-based Tx over NVB-LI, suggesting that VEN-based therapies may provide more benefit for pts ineligible for IC. Further research is warranted to determine the most appropriate Tx approach for pts with AML based on Tx effectiveness, pt medical history, and IC eligibility.

Hematologic and transfusion outcomes in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) receiving luspatercept: Real-world assessment in the community practice setting.

7057 Background: Erythropoiesis-stimulating agents (ESAs) are used as first-line (1L) treatment (tx) for the management of symptomatic anemia in LR-MDS. Luspatercept is approved for pts with LR-MDS with ring sideroblasts (RS) who experience ESA failure and are transfusion dependent. We assessed clinical outcomes of pts with LR-MDS with RS, or MDS/myeloproliferative neoplasms with RS and thrombocytosis, treated with luspatercept in US community practices. Methods: This retrospective, observational cohort study used physician-abstracted chart data from community oncology clinics and included adults diagnosed with LR-MDS (including Very low- to Intermediate-risk IPSS-R status) on/after Jan 1, 2015 who received luspatercept for ≥ 3 months (mos) with ≥ 3 mos of follow-up. Transfusion burden (TB) was defined by number of sessions (ses) received in the 8 weeks (wks) prior to luspatercept tx (baseline) and the lowest number for any consecutive period ≥ 8 wks during wks 1–24 of tx: transfusion independent (TI); low TB (LTB), 1–3 ses; and moderate TB (MTB), 4–5 ses. Results: Of 253 pts, 219 (87%) had 1 tx prior to luspatercept tx and 31 (12%) received ≥ 2. ESAs were used as 1L tx in 210 pts (83%). Median follow-up was 5.7 mos. The most common reason for discontinuing initial MDS tx among patients who received ≥ 1 tx prior to luspatercept was lack of anemia improvement (133/250). At baseline, 21 (8%) pts were TI, 208 (82%) had LTB, and 24 (10%) MTB. Median duration of luspatercept tx was 10.8 mos. During wks 1–24, 20/21 (95%) pts remained TI and 201/232 (87%) pts with LTB/MTB at baseline achieved TI for ≥ 8 wks. The Table shows changes in median hemoglobin (Hb), absolute neutrophil count (ANC), and platelet (plt) count. Conclusions: Most pts with LR-MDS received 1L ESAs and over half discontinued the first tx prior to luspatercept due to lack of anemia improvement, highlighting the need for alternative options to improve clinical outcomes. Consistent with data from the MEDALIST trial, 87% of pts with LTB/MTB who received luspatercept achieved TI for ≥ 8 wks, supporting its clinical benefit in routine clinical practice. [Table: see text]