PURPOSE:The role of the natriuretic peptides in radiation heart injury (RHI) has not been thoroughly examined. Pharmacologic modulation of the natriuretic peptide system with sacubitril/valsartan (sac/val) has led to improvements in heart failure therapy, and preliminary data suggest that RHI is associated with decreased atrial natriuretic peptide (ANP). In this study, we assessed sac/val as a radioprotector in a partial-heart irradiation mouse model and explored preliminary trends in patients receiving thoracic irradiation. METHODS AND MATERIALS:Female 8-10-week-old C57BL/6J mice were randomly assigned to receive sham irradiation, with or without sac/val, or irradiation with or without sac/val. The superior two-thirds of the heart was exposed to 20 Gy of x-rays using a small animal radiation research platform. Cardiac function was assessed at 10-week intervals over 30 weeks by transthoracic echocardiography and electrocardiography. Plasma levels of ANP were analyzed at 30 weeks. Small retrospective clinical series were undertaken in patients undergoing thoracic radiation therapy, to assess ANP dynamics and sac/val safety. RESULTS:At 30 weeks, irradiated mice that received sac/val exhibited a marked improvement in structural remodeling, systolic longitudinal strain, diastolic function, and electrophysiological parameters, compared with irradiated animals that did not receive sac/val. Functional sparing with sac/val was detectable as early as 10 weeks postirradiation by global longitudinal strain. Animals and patients tolerated the combination of sac/val with radiation without additional adverse effects. NT-proANP levels generally decreased among patients during thoracic radiation therapy and posttreatment NT-proANP changes were dose dependent. There was no effect on tolerability or efficacy of (chemo)radiation for patients on sac/val concurrently for heart failure. CONCLUSIONS:Sac/val attenuated structural and functional aspects of RHI and was well tolerated in animals when given with radiation. Clinical data suggest that ANP changes dynamically during radiation therapy and that sac/val is safe to take concurrently. Further investigation of sac/val as a cardiac radioprotector is warranted.

BACKGROUND:Standard of care for inoperable and/or unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy followed by 12 months of adjuvant durvalumab. Many patients are ineligible due to poor fitness, comorbidity or concerns around their ability to tolerate concurrent therapy or immunotherapy. As a result, these patients experience inferior outcomes. CASE STUDIES:This article summarises four case studies initially presented at a UK-based academic webinar in August 2025. The focus of the webinar was the radiotherapy-based management of complex patients with stage III NSCLC. This included tumour factors (i.e. vascular invasion and bulky disease) and patient factors (i.e. interstitial lung disease, multiple comorbidities and frailty). Strategies to navigate these challenges and improve outcomes are highlighted. DISCUSSION:Patients ineligible for standard-of-care treatment are under-represented in practice-defining trials. As a result, there is limited evidence to guide their management. Broader eligibility criteria and inclusive trials are needed to generate safety and efficacy data for this population. Enhanced phenotyping with biomarkers, adoption of advanced radiotherapy techniques, risk-adapted dose guidance and novel drug-radiotherapy combinations offer potential to expand access to curative-intent treatment and improve outcomes.

TPS648 Background: Pts with relapsed/refractory epNEC have poor outcomes with currently available therapies. DLL3 is expressed on the surface of many epNEC cells, offering a promising therapeutic target. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that binds simultaneously to CD3 on T-cells and DLL3 on tumor cells, resulting in immune-mediated tumor cell lysis. In an ongoing first-in-human Phase I trial (NCT04429087), obrixtamig monotherapy had promising efficacy in pts with DLL3+ SCLC, epNEC or large-cell NEC of the lung (LCNEC-L) and a manageable toxicity profile, justifying further clinical investigation. The Phase II DAREON-5 trial (NCT05882058) is a dose selection and expansion trial of obrixtamig monotherapy in pts with histologically confirmed relapsed/refractory SCLC, epNEC or LCNEC-L after prior standard of care. The completed dose selection part evaluated the safety and efficacy of two obrixtamig doses. We describe the design of the expansion part of the study that is currently enrolling. Methods: The expansion part of DAREON-5 is assessing obrixtamig antitumor activity at the selected dose for expansion in pts with centrally assessed DLL3-high expressing epNEC; defined as ≥50% of evaluable tumor cells with moderate to strong membrane and/or cytoplasmic DLL3 staining using the VENTANA DLL3 (SP347) assay. Eligible pts have relapsed/refractory, advanced/metastatic, histologically confirmed epNEC after prior platinum-based chemotherapy (≥1 lines of therapy). Pts will receive IV obrixtamig infusions as step-up doses followed by the target dose. Primary endpoint is objective response per RECIST v1.1, assessed by blinded independent central review. Secondary endpoints include duration of objective response, PFS, disease control, overall survival, treatment-emergent AEs, and patient-reported outcomes. The planned enrollment for the expansion cohort is ~50 pts recruited from the following countries: Belgium, China, Germany, Japan, Portugal, South Korea, Spain, UK and USA. Previously presented at ESMO, FPN (Final publication Number): 1731TiP, Pavel et al. Reused with permission. Clinical trial information: NCT05882058 .

BACKGROUND:Sociodemographic inequalities impact patients with non-small cell lung cancer (NSCLC). Advances in novel therapeutics have increased treatment options; however, for advanced disease, prognosis remains poor and inequalities in care are recognised to exist, requiring further characterisation. This population-based study aimed to describe the associations between markers of sociodemographic characteristics and novel anticancer therapy utilisation for a stage IV NSCLC population in a publicly funded healthcare system. METHODS:A retrospective cohort of 73 640 patients with histologically confirmed stage IV NSCLC between 1 January 2017 and 31 December 2021 was identified from the English national cancer registry and linked to the Systemic Anti-Cancer Therapy database. Multivariable logistic regression evaluated likelihood of novel therapy utilisation across sociodemographic characteristics and for pre-COVID-19 and peri-COVID-19 time periods. RESULTS:Patients resident in the most deprived quintile had the lowest likelihood of novel therapy receipt. Patients ≥70 years old had reduced likelihood of receipt (OR: 0.79, CI 0.73 to 0.86), as did patients recorded as ethnicity 'unknown' (OR: 0.85, CI 0.75 to 0.97). Likelihood of utilisation increased from 2017 to 2019 and decreased in 2020 and 2021. Pre-COVID-19 and peri-COVID-19 analysis identified reduced sociodemographic inequalities from 2020, but variation across therapy subgroups. CONCLUSION:Even in the National Health Service (NHS) in England, where cancer medication access is free, inequalities in NSCLC novel therapies utilisation persisted in 2017-2021, despite more treatment options and greater clinician familiarity. There is evidence of decreasing utilisation during this study period. These findings are important to ensure equitable access to novel therapies and require further study of future trends and impact on real-world survival.

BACKGROUND/OBJECTIVES:Simple frailty assessments, such as the clinical frailty scale (CFS), are prognostic for worse outcomes in older adults with cancer and could support treatment decision-making. This interview study aims to explore clinicians' experiences of using simple frailty assessments in oncology, including the impacts on patient care and barriers and facilitators to successful implementation. METHODS:Semi-structured individual interviews were conducted with clinicians at three UK sites that had implemented CFS screening in lung cancer clinics as part of a national pilot, to explore how frailty assessments are applied and are impacting care. Purposive sampling targeted a range of professionals involved in assessing frailty and making treatment decisions. Recordings were transcribed verbatim and analysed thematically. RESULTS:Ten clinicians participated, and four main themes were identified. 'Assessing fitness and frailty' explores the central role of performance status (PS), as well as its limitations, and what frailty assessments add. 'Scoring and interpreting CFS' describes the ease and relative yield of CFS use, particularly for patients with 'borderline' PS scores (e.g., PS 1-2 or 2-3), and the importance of contextual interpretation. 'Role of frailty and impacts of assessment' highlights how frailty assessments can enhance patient-centered care and support, and clinical and shared decision-making, with potential for streamlined care and system-level benefits. 'Barriers and facilitators to implementation' are described, including time, culture, guidance, and training, with recommendations provided. CONCLUSIONS:Assessing frailty has wide-ranging potential benefits for patients, oncology teams, and the wider system, but barriers must be overcome. Specific recommendations are provided to support the routine implementation of frailty assessments, which is a key step towards the benefits of frailty-informed care being realised at scale.

Abstract Background: Patients with relapsed/refractory extrapulmonary neuroendocrine carcinoma (epNEC) have poor outcomes with currently available therapies. Delta-like ligand 3 (DLL3) is expressed on the surface of many epNEC cells, offering a promising therapeutic target. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that binds simultaneously to CD3 on T-cells and DLL3 on tumor cells, resulting in immune-mediated tumor cell lysis. In an ongoing first-in-human Phase I trial, obrixtamig monotherapy had promising efficacy in patients with DLL3+ small cell lung cancer (SCLC), epNEC, or large cell NEC of the lung (LCNEC-L) and a manageable toxicity profile, justifying further clinical investigation. The Phase II DAREON-5 trial is a dose-selection and -expansion trial of obrixtamig monotherapy in patients with histologically confirmed relapsed/refractory SCLC, epNEC, or LCNEC-L after prior standard of care therapy. The completed dose-selection part evaluated the safety and efficacy of 2 obrixtamig doses. We describe the design of the expansion part of the study that is currently enrolling. Methods: The expansion part of DAREON-5 is assessing obrixtamig antitumor activity at the selected dose for expansion in patients with centrally assessed DLL3 high-expressing epNEC (NCT05882058); defined as ≥50% of evaluable tumor cells with moderate to strong membrane and/or cytoplasmic DLL3 staining using the VENTANA DLL3 (SP347) assay. Eligible patients have relapsed/refractory, advanced/metastatic, histologically confirmed epNEC after prior platinum-based chemotherapy (≥1 line of therapy). Patients will receive intravenous obrixtamig infusions as step-up doses followed by the target dose. Primary endpoint is objective response per Response Evaluation Criteria in Solid Tumors version 1.1, assessed by blinded independent central review. Secondary endpoints include duration of objective response, progression-free survival, disease control, overall survival, treatment-emergent adverse events, and patient-reported outcomes. The planned enrollment for the expansion cohort is ∼50 patients recruited from the following countries: Belgium, China, Germany, Japan, Portugal, South Korea, Spain, UK, and USA. Citation Format: Marianne Pavel, Chris Verslype, Pedro Rocha, Alastair Greystoke, Aman Chauhan, Julia Koevi, Martha Mueller, Eric Song, Valeria Lifke, Andrea Standring, Emily Bergsland. Obrixtamig (BI 764532) in patients with relapsed/refractory delta-like ligand 3 (DLL3) high-expressing extrapulmonary neuroendocrine carcinoma (epNEC): trial in progress of the dose expansion part of the Phase II DAREON-5 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT222.

Background The management of stage III non-small cell lung cancer (NSCLC) has become increasingly complex, driven by advances in neoadjuvant and perioperative chemo-immunotherapy as well as targeted therapies. These evolving treatment paradigms have introduced new challenges for multidisciplinary teams (MDTs), regarding patient selection, treatment sequencing, surgical planning and definitions of operability and resectability. Case presentation We present a case of a 69-year-old male with cT3N2aM0 (single-station N2) adenocarcinoma NSCLC with a programmed death-ligand 1 (PD-L1) tumour proportion score of 100%. Following discussion in MDT, he received 3 cycles of neoadjuvant carboplatin, paclitaxel, and nivolumab. The initial surgical plan was for a pneumonectomy due to tumour proximity to the right main bronchus, a procedure associated with perioperative risk and long-term functional compromise. Restaging computed tomography (CT) scan demonstrated a partial response, with a 60% reduction in axial tumour dimensions. This downstaging facilitated a change in surgical plan from pneumonectomy to the less extensive right upper lobectomy, resulting in a pathological complete response (ypT0ypN0). Discussion The case was discussed during an academic webinar in August 2025. Expert faculty from respiratory medicine, thoracic surgery and medical and radiation/clinical oncology highlighted key discussion points and challenges. This included: 1) evolving definitions of operability and resectability, 2) perioperative systemic therapy selection, 3) the risk of not proceeding to surgery, and 4) the role of postoperative radiotherapy (PORT) and salvage therapy in case of progression. Conclusion The case underscores current controversies in the management of stage III NSCLC and the critical role of the MDT. While neoadjuvant and perioperative chemo-immunotherapy offers an opportunity for less extensive surgical resection and improved oncological outcomes, this strategy is not without risks and validated biomarkers to guide decision making are lacking. Concurrent chemoradiotherapy (cCRT) followed by durvalumab remains the standard for fit patients with unresectable or inoperable stage III disease. Future progress depends on clinical trials, biomarker development, and real-world data collection and national audits.

Abstract Background: BT5528 is a BDC® comprising a bicyclic peptide targeting EphA2 linked to MMAE via a cleavable linker. EphA2 is overexpressed in various solid tumors and is correlated with poor clinical outcomes. Earlier EphA2-targeted therapies were associated with significant toxicity which limited efficacy analysis. BDCs have potential to limit toxicity by reducing non-tumor exposure due to low molecular weight and high selectivity. Favorable dose escalation (DE) safety data for BT5528 monotherapy supported initiating the BT5528 + nivolumab (nivo) DE part (A-2) of the safety and efficacy study of BT5528 in pts with advanced solid tumors (NCT04180371). Methods: Eligible adults had recurrent metastatic solid tumors with tissue available for EphA2 expression testing and had exhausted all appropriate treatment options. Pts received BT5528 IV (2.2 or 4.4 mg/m2 once weekly, or 6.5 mg/m2 once every 2 weeks (wks) + nivo IV (480 mg once every 4 wks). Primary objectives: safety/tolerability. Secondary objectives: preliminary anti-tumor activity/pharmacokinetic (PK) parameters. EphA2 immunohistochemistry was retrospective using Tumor Proportion Score >1 to determine positivity. Results: As of November 10, 2025, 21 pts were treated. Median age was 65 years; 57% had ECOG PS 1; median prior lines of therapy was 2 (range 1-7); 11/18 (61%) tumor samples were EphA2+. All 14 pts in the 6.5 mg/m2 cohort had metastatic urothelial carcinoma (mUC) and had previously progressed on a checkpoint inhibitor and 10 while on enfortumab vedotin. Median BT5528 treatment duration was 58.0 days in all pts; 81.5 days in the 6.5 mg/m2 cohort; 5 pts remain on treatment. The most common BT5528-related adverse events (TRAEs) were fatigue (29%), nausea (24%), diarrhea (19%), and vomiting (14%). Grade ≥3 TRAEs were fatigue (10%) and ALT/AST increase (5% each). TRAEs of clinical interest were skin reactions (24%) and peripheral neuropathy (10%), all Grade 1/2. No TRAEs of hemorrhage occurred. There was one dose-limiting toxicity of fatigue in the 6.5 mg/m2 cohort. The objective response rate in all pts was 14%. In the 6.5 mg/m2 cohort, 3/10 pts who had EphA2+ mUC achieved a confirmed partial response (cPR); of 3 pts who were EphA2+ and MMAE-naïve, 2 achieved a cPR. The clinical benefit rate (complete response + PR + stable disease ≥4 months) for all pts was 24% and 100% for the 3 EphA2+ MMAE-naïve pts in the 6.5 mg/m2 cohort. PK of BT5528 and MMAE are similar +/- nivo, indicating no apparent PK interaction. Conclusions: BT5528 + nivo demonstrated a generally well-tolerated safety profile across doses, with no new safety signals, in contrast to prior attempts to target EphA2, with no PK drug-drug interactions. Preliminary anti-tumor activity was demonstrated in pts with mUC at a dose of BT5528 6.5 mg/m2 once every 2 wks + nivo 480 mg once every 4 wks, especially in MMAE-naive pts with EphA2+ tumors. Citation Format: Babar Bashir, Juan Martin-Liberal, Judy S. Wang, Raid Aljumaily, Bernard Doger de Spéville, Elena Garralda, Meredith McKean, Elisa Fontana, Hans Prenen, Daniel A. Peterson, Vienna Reichert, Xuemin Gu, Mengyao Li, Assunta De Rienzo, Alastair Greystoke. An EphA2-targeting Bicycle Drug Conjugate (BDC), BT5528, in combination with nivolumab in patients (pts) with advanced solid tumors: Results from a Phase 1/2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT063.

INTRODUCTION:Somatic mutation testing in solid tumours represents a rapidly advancing field which increases opportunities for access to molecularly targeted therapeutics and clinical trials. This systematic review determined whether socio-demographic inequalities affect utilisation of novel somatic mutation testing. METHODS:Following PRISMA 2020 guidance, MEDLINE, EMBASE, Scopus, CINAHL, Web of Science, PubMed and PsycINFO were searched for peer-reviewed studies (January 2018-March 2025). Data was extracted reporting utilisation of novel somatic mutation testing panels, including Oncotype DX, for solid tumours by socio-demographic measures. A modified International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist assessed study quality. Unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated where needed and narrative synthesis undertaken. Data was stratified by receipt of Oncotype DX testing and next-generation sequencing (NGS) panels. RESULTS:The 27,749 citations screened identified 24 studies meeting the inclusion criteria. These reported on two modalities of testing (Oncotype DX and other NGS sequencing panels) across five cancers. Twenty-three studies were from US populations. These highlighted disparities in utility of testing across socio-demographic measures and particularly decreased utilisation with increased age, non-white ethnicity, lower socio-economic status, and non-private insurance. The mean study quality score by a modified ISPOR checklist was 8.3/10. CONCLUSION:These results provide a contemporary update on evidence of disparities in access to novel genomic testing. As an expanding field, this requires further investigation to prevent accentuations in inequitable implementation of precision oncology and differences in outcomes between different socio-demographic groups.

PURPOSE:The development of effective radiation therapy (RT)-drug combinations has been slow, largely because early-phase trial designs have mirrored systemic drug development paradigms based on the maximum tolerated dose (MTD). The U.S. Food and Drug Administration's Project Optimus advocates replacing the MTD approach with the identification of an optimum biologically effective dose, integrating both efficacy and tolerability. Applying these principles to RT-drug development could accelerate the establishment of safe and effective combinations. METHODS AND MATERIALS:An international panel of experts examined how Project Optimus principles could be adapted to RT-drug development. We discuss: (1) the legacy of the MTD in RT-drug development; (2) adapting Project Optimus principles to RT-drug trials; (3) key considerations for safety and efficacy assessment; (4) trial design innovations; and (5) future directions for implementation. RESULTS:The panel identified key limitations of the traditional MTD approach, including inadequate capture of delayed and cumulative adverse events and a lack of biological relevance for radiosensitization or immune modulation. The proposed RT-Optimus framework redefines dose-finding objectives to identify the Optimum Radiation Therapy Combination Regimen-the combination of drug dose, schedule, and RT parameters that optimizes tumor control while minimizing normal tissue side effects. Implementation of this approach requires extended windows to assess side effects, incorporation of patient-reported outcomes, intermediate efficacy endpoints (eg, circulating tumor DNA clearance, radiomics), and use of adaptive, model-informed trial designs to efficiently evaluate multiple agents and schedules. CONCLUSIONS:An RT-Optimus framework offers a biologically and ethically grounded pathway to modernize early-phase RT-drug trials. By focusing on the Optimum Radiation Therapy Combination Regimen rather than MTD, and embedding mechanistic, biomarker-informed, and patient-centered endpoints, this approach could improve the efficiency, reproducibility, and clinical relevance of RT-drug development, helping to avoid failures seen in previous RT-drug combinations and ultimately accelerating progress toward safer and more effective multimodality cancer treatments.

There are no current stratified medicine options for STK11-deficient NSCLC. STK11 loss mediates mTORC activation, GLUT1 up-regulation and increased glycolysis. This metabolic reprogramming might represent a therapeutic vulnerability targetable with mTORC1/2 inhibition. In arm B2 of the National Lung Matrix Trial 54 patients with NSCLC received vistusertib, of which 49 were STK11-deficient (30 with KRAS mutation (B2D), 19 without (B2S)). Objective response (OR) and durable clinical benefit (DCB) rates with 95% credible intervals (CrI) were estimated from posterior probability distributions generated using Bayesian beta-binomial conjugate analysis. In B2D, 2 per-protocol patients obtained OR (estimated true OR rate (95%CrI) 9.8% (2.4–24.3). Estimates of true DCB rate (95%CrI): B2D 24.4% (11.1–42.3), B2S 14.6% (3.6–34.7). Overall, vistusertib cannot be recommended in this context. Longitudinal ctDNA analysis demonstrates enrichment of SMARCA4 mutations post-treatment. In vitro studies show adaptive resistance to mTORC1/2 inhibition via AKT reactivation. (NCT02664935, ISRCTN38344105, EudraCT 2014-000814-73, 10 June 2015)

Develop an instrument to assess unmet needs in cancer patients using immuno-, biological and precision (IBP) therapies. Development followed COSMIN guidance. Instruments to assess unmet needs of advanced cancer patients were identified, and quality and content were evaluated in a systematic review (Phase 1). Semi-structured interviews with patients utilising IBP therapies (n = 31) and healthcare professionals (n = 22) explored supportive care needs (Phase 2). Phase 3 selected a base instrument to adapt, generated new items and iteratively refined these through six meetings involving professionals (n = 8) and public and patient involvement representatives (n = 9) and patient cognitive interviews (n = 16). Phase 4 piloted the new instrument (n = 50 patients). Twenty-four instruments were identified; none was developed for patients utilising IBP therapies (Phase 1). Ten domains of unmet needs were identified from the interview data (Phase 2). SCNS-SF34 was selected as the base instrument. Informed by interview data, an “add-on module” (SCNS-TARGET) was developed for patients utilising IBP therapies comprising 25 questions (psychological domain, 7 items; information, 6; healthcare, 5; economic, 3; role, 2; physical, 1; social, 1; Phase 3). Levels of missingness were low; reliability varied across questions, and, on average, patients reported 7.40 (standard deviation = 8.43) unmet needs on SCNS-TARGET (Phase 4). SCNS-TARGET is designed for use alongside SCNS-SF34 to assess unmet needs in those using IBP therapies. Content and face validity have been established. SCNS-TARGET can help researchers and healthcare professionals determine unmet needs and inform requirements for new services and interventions, among patients using IBP therapies.

Breast cancer is the most commonly diagnosed cancer worldwide, with early detection and advanced treatments contributing to declining mortality rates. However, managing comorbid conditions, particularly mental illness, presents significant challenges for cancer treatment. This study systematically reviews and meta-analyses the impact of having a pre-existing mental illness on breast cancer treatment utilisation, focusing on specific treatments and comparing different mental illnesses. MEDLINE, EMBASE, CINAHL, and APA PsycInfo databases were searched. After screening, fifteen studies were identified as meeting the inclusion criteria. The included studies were predominantly from high-income countries, and compared breast cancer treatment in patients with and without pre-existing mental illnesses including anxiety, mood disorders, schizophrenia and psychotic disorders, and neurodevelopmental disorders. Meta-analysis revealed that patients with mental illnesses were significantly less likely to receive guideline-recommended treatments (OR = 0.78, 95% CI 0.72-0.83, N = 5), chemotherapy (OR = 0.56, 95% CI 0.34-0.78, N = 6), or radiotherapy (OR = 0.79, 95% CI 0.66-0.93, N = 5). They were also significantly more likely to undergo mastectomy instead of breast-conserving surgery (OR = 1.38, 95% CI 1.24-1.52, N = 4). Findings were consistent across different mental illnesses. This review highlights the need for targeted interventions to improve healthcare access and address provider biases, promoting better integration of mental health and oncology care.

PURPOSE:This early-phase study evaluated safety/tolerability, pharmacokinetics, and preliminary efficacy of dendrimer-nanoparticle delivery platform (DEP)-SN38, a polylysine-based nanoparticle conjugate of the irinotecan active metabolite, SN38. METHODS:Adults with advanced solid tumors received DEP-SN38 intravenously once every 3 weeks (Q3W) or once every 2 weeks (Q2W) monotherapy, or Q2W combined with fluorouracil/leucovorin (FU/LV) to identify a recommended dose for each regimen. Primary end points were safety/tolerability. Secondary end points included efficacy (RECIST-v1.1) and pharmacokinetics. RESULTS:Heavily pretreated patients (N = 114; median 4 previous therapies) received DEP-SN38 (8-15-mg/m2 SN38), with 12.5 mg/m2 recommended for all regimens. Most DEP-SN38-attributed treatment-related adverse events (TRAEs) were mild/moderate (89.7%), with neutropenia the key dose-limiting toxicity and the most common grade 3/4 TRAE (48% of grade 3/4 events). Severe GI TRAEs were rare (grade 3 diarrhea and vomiting [0.9% of patients each]; nausea [1.8%]). Cholinergic symptoms were not observed. Efficacy signals were observed across several tumor types, particularly Q2W regimens and in patients with platinum-resistant ovarian cancer (PROC) and colorectal cancer (CRC). Among evaluable patients, objective response rates for Q3W or Q2W monotherapy and Q2W DEP-SN38/FU/LV were 1.8%, 21.4% (PROC 42.9%), and 12.5% (CRC 14.3%), respectively; disease control rates were 56.4%, 71.4%, and 81.3%, respectively. Median progression-free survival (PFS, all treated) was 2.1, 6.0, and 4.2 months for Q3W, Q2W, and Q2W DEP-SN38/FU/LV, respectively. Patients achieving PFS for at least 6 months included seven PROC (Q2W monotherapy, n = 5; > 12 months, n = 3), 12 CRC (DEP-SN38/FU/LV, n = 6, including four patients for >12 months), one pancreatic (10.2 months), one non-small cell lung (8.4 months), and two with breast cancer (16.6 months, 6 months). CONCLUSION:DEP-SN38 was clinically well tolerated with minimal severe GI TRAEs. Preliminary antitumor activity in heavily pretreated patients with cancer demonstrates the potential clinical utility of DEP-SN38 monotherapy and combination regimens.