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A multicenter, randomized phase Ib trial to evaluate neoadjuvant immunotherapy combination of nivolumab alone or plus ipilimumab with the IL-2 superkine MDNA11 alone or with tocilizumab in patients with high-risk, surgically resectable melanoma: The NEO-CYT trial.
TPS9612 Background: Neoadjuvant immunotherapy, administered upfront of surgery in patients with resectable stage III melanoma, has shown superior efficacy in recent trials compared to post-surgical adjuvant treatment, due to enhanced anti-tumor immunity when the tumor microenvironment is intact. A pre-operative regimen of 2 cycles of ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy (as per NADINA trial) results in substantially improved event-free survival. However, even with this regimen 41% of patients did not achieve a Major Pathologic Response (MPR), with 8% having a partial pathological response and 26.4% showing pathological non-response. Previous analyses have shown a ‘cold’ CD4-IL-2 signature being associated with no-response, which could be overcome by the addition of IL-2. MDNA11 is a long-acting engineered interleukin (IL)-2 albumin fusion protein, with enhanced affinity for IL-2 receptor β (IL-2Rβ/CD122) and no binding to IL-2Rα (CD25). This design enhances the stimulation of IL-2Rβ-expressing CD8+ T cells and NK cells whilst diminishing the activation of Tregs constitutively expressing the heterotrimeric receptor containing IL-2Rα. Thus, we hypothesize that MDNA11 combination with nivolumab +/- ipilimumab may further enhance clinical outcomes of neoadjuvant standard therapy. Methods: This is a phase Ib, prospective, open-label, randomised study where a 6- week neoadjuvant phase is followed by a 7-week surgery/post-surgery phase and a 49-week adjuvant phase as per clinical practice. The study population will include adult patients of either sex aged ≥ 18 years with surgically resectable stage IIIB/C/D cutaneous melanoma. Twenty patients will be enrolled in each arm for a total of up to 80 patients. The ARM A is the control one with Ipilimumab 80 mg plus Nivolumab 240 mg administered every 3 weeks for 2 cycles as for NADINA trial; the ARM B includes Nivolumab 240 mg every 3 weeks for 2 cycles plus MDNA11 at 30 μg/kg on week 0 followed by MDNA11 at 60 μg/kg on week 2 and week 4; the ARM C includes Ipilimumab 80 mg plus Nivolumab 240 mg administered every 3 weeks for 2 cycles plus MDNA11 at 30 μg/kg on week 0 followed by MDNA11 at 60 μg/kg on week 2 and week 4; the ARM D adds tocilizumab 4 mg/Kg on week 0 at the same schedule of the ARM C. The study’s primary endpoint is the Major Pathologic Response (MPR) rate at surgery, defined as ≤10% viable tumor in the treated tumor bed. Co-primary endpoints include the incidence, severity, and duration of treatment-related adverse events, particularly immune-related, as per CTCAE v5.0. Health-related quality of life will be analyzed using longitudinal models. Exploratory analyses will investigate biomarker associations with outcomes to generate hypotheses. Clinical trial information: 2024-519010-31-00.
Clinicopathologic and imaging predictors of pathologic complete response after neoadjuvant chemoimmunotherapy in resectable NSCLC: A systematic review and meta-analysis.
e20068 Background: Neoadjuvant chemoimmunotherapy (CIT) improves pathologic complete response (pCR) rates in resectable non–small cell lung cancer (NSCLC), yet substantial variability persists across studies. Robust predictors of pCR are not well defined, limiting patient selection and translational application. We conducted a systematic review and meta-analysis to identify clinicopathologic and biologic factors associated with pCR and to assess gaps in current predictive approaches. Methods: MEDLINE, Embase, Web of Science, and Cochrane Library were searched for prospective trials and observational cohorts (2015–2025) reporting surgical resection after neoadjuvant CIT for resectable NSCLC and evaluating predictors of pCR. Candidate predictors included PD-L1 expression, clinical stage and nodal status, radiologic response (RECIST), metabolic response on FDG-PET, systemic inflammatory markers, circulating tumor DNA dynamics, tumor mutational burden, and radiomics features. Random-effects meta-analyses estimated pooled odds ratios (ORs) with 95% confidence intervals (CIs) for associations with pCR when ≥2 studies reported comparable data. Studies proposing multivariable prediction models were evaluated qualitatively using TRIPOD and PROBAST criteria. Results: A total of 14 studies including 1,842 patients were eligible (6 prospective trials, 8 observational cohorts). Higher PD-L1 expression was associated with increased odds of pCR (per 10% increase in TPS: OR 1.28, 95% CI 1.10–1.49, I²=58%). FDG-PET metabolic response (ΔSUVmax ≥50%) showed a strong association with pCR (OR 2.41, 95% CI 1.62–3.58, I²=42%) and outperformed size-based radiologic response. Absence of mediastinal nodal disease (cN0–1 vs cN2) was associated with higher pCR rates (OR 1.76, 95% CI 1.22–2.54, I²=36%). Data on tumor mutational burden, circulating tumor DNA clearance, systemic inflammatory markers, and radiomics were sparse and heterogeneous, precluding quantitative synthesis. Only a minority of studies reported multivariable analyses, and none included external validation, calibration assessment, or evaluation of clinical utility; no study met PROBAST criteria for low risk of bias. Conclusions: PD-L1 expression, metabolic response on FDG-PET, and baseline nodal status are the most reproducible factors associated with pCR after neoadjuvant CIT in resectable NSCLC. However, current evidence highlights a significant translational gap, with insufficient data and methodological rigor to support generalizable predictive models. Prospective studies integrating imaging and biologic variables with external validation are urgently needed to enable clinically actionable pCR prediction.
Racial and ethnic disparities in breast cancer care: Barriers associated with treatment delays.
e12706 Background: Breast cancer is one of the most common cancers among women. Yet, disparities in access to a timely diagnosis and treatment persist for racial and ethnic minority groups. These disparities may be explained by socioeconomic factors such as poverty, limited education, or lack of insurance. Current national breast cancer guidelines suggest diagnosis should happen within 60 days of an abnormal screening. Treatment delays longer than 90 days are linked to lower survival rates. Previous research has shown that Black and Hispanic women face longer time to treatment, regardless of their cancer stage or insurance coverage. For this reason, uncovering factors that may lead to treatment delays is crucial to create equitable care. This study aims to identify which factors contribute to treatment delays in women with breast cancer at an urban academic center. Methods: Participants completed a survey to assess unmet needs and perceived barriers during their treatment journey. Retrospective review of medical charts quantified number of days at 3 time points: abnormal mammogram to biopsy, from biopsy to first oncology or surgery visit, and from biopsy to start of first treatment received. Data collected from medical charts included race or ethnicity, primary language, insurance status, tumor stage, and type of treatment received. Results: A total of 53 surveys were analyzed, 34.0% were Latina (n = 18), 39.6% White (n = 21), 22.6% Black (n = 12), and 3.8% Asian (n = 2). Average time from mammogram to biopsy for Latinas was 46.7 days (95% CI 30.8-62.7), White 41.7 days (95% CI 16.9-66.5), Black (55.9 days (95% CI 24.1-87.7). Average time from biopsy to first mammogram appointment for everyone was 17 days (95% CI 12.8-22.7). Average time from biopsy to first treatment received for Latinas was 59.7 days (95% CI 43-76.5), White was 46 days (95% CI 39.9-52.1), Black 49.2 days (95% CI 38.5-59.8). Latino patients were more likely to receive chemotherapy compared to white individuals. Average time to treatment for chemotherapy was at 78 days compared to 26 days for White patients. A composite barrier index demonstrated that 66.7% of Latina participants reported at least 1 barrier, compared with 22.9% of non-Latina participants. This included feeling depressed, anxiety, and fear of an unfavorable outcome. Income demonstrated an association with treatment delay (Spearman ρ = –0.20, p = 0.16). Conclusions: Treatment delays start before the first visit in scheduling diagnostic mammograms and initial biopsy. Latina women showed greater treatment delay at time of starting first treatment. Moreover, they report higher levels of anxiety, depression, and fear of an unfavorable outcome along with increased financial concerns. Treatment delay barriers persist despite no problem understanding their treatment, highlighting the role of structural, socioeconomic, and psychological stressors as a possible cause of treatment delays.
Prognostic impact of estrogen and progesterone receptor expression disparity in early-stage HR+/HER2- breast cancer.
e12534 Background: In hormone receptor-positive, HER2-negative early-stage breast cancer (HR+/HER2- EBC), the biological characteristics and therapeutic response to endocrine treatment are fundamentally shaped by the synergistic interplay between estrogen receptor (ER) and progesterone receptor (PR). Nevertheless, the role of discordant expression levels between ER and PR—termed ΔER-PR—remains poorly studied, and its effect on patient outcomes is unclear. Methods: This large-scale, multicenter retrospective study analyzed data from 3521 patients with HR+/HER2- EBC, treated across four institutions between January 2013 and June 2019. The continuous variable ΔER-PR was calculated, and its optimal cut-off value was determined using X-tile software, with subsequent validation via the survminer package in R. Based on this threshold, patients were categorized into two groups for comparative analysis. To ensure balanced baseline characteristics and minimize selection bias, propensity score matching (PSM) was employed to adjust for potential confounders. The primary endpoint, disease-free survival (DFS), was evaluated using Kaplan-Meier (KM) survival curves, and both univariate and multivariate Cox proportional hazards regression analyses were conducted to identify independent prognostic factors. Results: The optimal cut-off for ΔER-PR was identified as 25%. This stratified patients into a “Discordant Expression Group” (ΔER-PR > 25%) and a “Concordant Expression Group” (ΔER-PR ≤ 25%). Before PSM, the cohorts consisted of 1417 and 2104 patients, respectively. After PSM, 2236 patients were equally matched (1118 per group). KM survival analysis consistently demonstrated significantly inferior DFS in the Discordant Expression Group compared to the Concordant Group, both before and after matching (all P < 0.001). Multivariate Cox regression analyses confirmed that belonging to the Discordant Expression Group was an independent adverse prognostic factor for DFS (pre-PSM: HR 1.52, 95% CI 1.27–1.81, P < 0.001; post-PSM: HR 1.47, 95% CI 1.21–1.79, P < 0.001). Subgroup analyses across various patient strata further corroborated the consistent negative prognostic impact of significant ER/PR expression disparity. Conclusions: This study demonstrates that a disparity in ER and PR expression (ΔER-PR > 25%) is associated with inferior prognosis in HR+/HER2- EBC, underscoring that imbalance between these receptors may substantially influence the effectiveness of endocrine therapy.
Impact of remote symptom monitoring program on payor-specific healthcare costs.
1632 Background: Remote symptom monitoring (RSM) programs are currently being implemented across oncology practices nationwide; however, the impact of RSM on costs by payor has been understudied. Methods: This is a secondary analysis of a hybrid implementation-effectiveness trial of electronic, patient reported outcome-based RSM for patients with cancer initiating systemic therapy (May 2021-May 2024). Differences in costs for healthcare services for RSM-enrolled patients were compared to historical controls. Outcomes included overall, monthly, payor-, and service-specific costs of care received at 3 and 6 months after RSM-enrollment date or initiation of systemic therapy for controls. Adjusted generalized linear models estimated predicted mean costs, mean cost ratios (MR) and 95% confidence intervals (CIs) for RSM-enrolled patients versus controls. Results: Patients receiving RSM (n=968) were 25% Black, 44% privately insured, and 27% living in a highly disadvantaged neighborhood. Historical controls (n=3,488) were demographically similar. Though non-statistically significant, RSM enrolled patients had 5% lower mean costs 3 months post-index date compared to historical controls (MR 0.95, 95% CI 0.78-1.16), translating to an estimated cost savings of $1,347 per patient (95% CI -$3,596, $6,290). Medicare Fee-for-Service (FFS) beneficiaries showed the greatest, though non-statistically significant, cost reductions, with RSM FFS beneficiaries having 10% lower costs than FFS controls (MR 0.90, 95% CI 0.67-1.19) at 3 months post-index date. Though non-statically significant, RSM-enrolled patients had 23% lower costs for radiation, 14% lower inpatient costs, 9% lower costs for labs, scans, or tests, and 2% lower outpatient costs compared to controls at 3 months post-index date. At one-month post-index date, RSM enrolled patients had statistically significantly lower payor costs compared to controls ($11,849 [95% CI $9,364-$14,335] vs. $15,706 [$14,291-$17,121]; p=.004). Costs for RSM enrolled patients and controls were similar two to six-months post-index date. Conclusions: We observed payor cost savings of $1,347 in the 3 months of RSM enrollment compared to controls. As the largest payor cost differences were seen for Medicare FFS beneficiaries, our results suggest RSM may address a gap in the provision of care coordination to patients not offered these services through their insurer. Cost savings were most prominent within the first month of treatment initiation; thus, RSM may aid in reducing acute care needs and optimizing resource utilization for patients with cancer. Our results support future research in potential risk-stratification methods to improve RSM engagement and delivery to reduce costs and improve outcomes for patients with cancer.
Real-world treatment patterns and survival outcomes in splenic marginal zone lymphoma: A SEER analysis (2000-2022).
e19096 Background: Splenic marginal zone lymphoma (SMZL) is a rare, indolent B-cell non-Hodgkin lymphoma with heterogeneous clinical behavior and evolving treatment paradigms. Population-level data on management patterns and long-term outcomes remain limited. We analyzed trends in treatment utilization and survival outcomes for patients with SMZL using a large, nationally representative cohort. Methods: Patients diagnosed with SMZL between 2000-2022 were identified from the SEER database. Demographic, clinical, and treatment variables, including age, sex, race/ethnicity, grade, Ann Arbor stage, splenectomy, chemotherapy, and survival outcomes were extracted. Treatment eras were categorized as 2000-2007, 2008-2015, and 2016-2022. Kaplan–Meier methods estimated overall survival (OS) and cancer-specific survival (CSS). Cox proportional hazards models evaluated prognostic factors. Results: A total of 2,641 patients were included (median age 67 years; 45% male; 89% white; 91% non-Hispanic). Advanced-stage disease (III–IV) was present in 42.8%. Observation was the most common treatment strategy (48.3%), followed by chemotherapy (21.3%), splenectomy (17.9%), and combined therapy (4.5%). Treatment patterns varied significantly across eras (p < 0.001), with declining splenectomy use and increased adoption of systemic therapy. Median OS was 134 months. OS rates at 1, 5, and 10 years were 91.4%, 74.0%, and 54.6%, respectively. The 10-year CSS was 76.3%, with a lymphoma-specific mortality rate of 18.7%. In multivariable analysis, age ≥75 years was strongly associated with inferior OS (HR 11.01, p <0.001), as were male sex (HR 1.18; p <0.05) and stage III disease (HR 1.76; p<0.05). Diagnosis in the 2008-2015 era was associated with improved survival compared with 2000–2007 (HR 0.76, p < 0.001). Combined splenectomy + chemotherapy was associated with increased mortality risk (HR 1.63, p < 0.001). Splenectomy showed a modest unadjusted OS benefit (p = 0.011), but this was not significant after adjustment (p = 0.788). Conclusions: In our study, SMZL demonstrated excellent long-term disease-specific survival but substantial age-related mortality. Treatment patterns evolved significantly over two decades, with decreasing reliance on splenectomy. Advanced age, male sex, and higher stage were independent predictors of worse outcomes. Combined splenectomy + chemotherapy was associated with inferior survival, underscoring the need for careful treatment selection.
Comparative effectiveness of pembrolizumab and nivolumab as first-line treatment for advanced/unresectable or metastatic melanoma: A propensity-score adjusted analysis from a US national health system.
e21513 Background: Therapies targeting programmed cell death protein 1 (PD1) are mainstays of modern cancer therapy. Pembrolizumab and nivolumab outcomes have not been established in a prospective randomized trial. Comparative analyses in indications where both are used identically may support interchangeability. Retrospective analyses suggest similar outcomes but have not been evaluated in a national US health system. We therefore compared effectiveness and safety outcomes for pembrolizumab versus nivolumab in advanced/unresectable or metastatic melanoma using data from the national Veterans Affairs (VA) health system. Methods: We extracted all pembrolizumab and nivolumab administrations for advanced/unresectable or metastatic melanoma using ICD-9/10 codes and natural language processing (NLP) from January 1, 2015 to July 1, 2025 from the VA’s Corporate Data Warehouse. Patients with known BRAF mutations at immunotherapy initiation and those treated with ipilimumab/nivolumab were excluded. Baseline covariates influencing anti-PD1 prescribing were balanced using propensity score adjustment, with missing data addressed via multiple imputation. The primary outcome was time-to-next treatment (TTNT); secondary outcomes were overall survival (OS) and prolonged, high-dose corticosteroids (a proxy for clinically significant immune-related adverse events [irAEs]). Propensity-weighted Cox models and Kaplan-Meier estimates were pooled using Rubin’s rules. The VA Ann Arbor Institutional Review Board approved the study. Results: Among 742 patients, 413 (55.7%) received pembrolizumab and 329 (44.3%) nivolumab. Pembrolizumab recipients were older and more likely to have initiated therapy in recent years. Median follow-up was 68 months and 66 months, respectively, with excellent covariate balance after adjustment (standardized difference <0.05). Median TTNT was 14.6 months for pembrolizumab and 13.2 months for nivolumab (adjusted hazard ratio [aHR] 0.93, 95% CI 0.78, 1.11; p=0.43). Median OS was 27.9 months for pembrolizumab and 25.3 months for nivolumab (aHR 0.97, 95% CI 0.80, 1.17; p=0.73). Two-year cumulative event rates of prolonged corticosteroid use were 22.1% and 23.5%, respectively (aHR 1.02, 95% CI 0.71, 1.47; p=0.93). Conclusions: In this national cohort, pembrolizumab and nivolumab demonstrated equivalent effectiveness as first-line therapies for advanced/unresectable or metastatic melanoma, consistent with an anti-PD1 class effect. Limitations include reliance on ICD coding, lack of randomization, and corticosteroid use as a proxy for irAEs. Given real-world data from different health systems in multiple countries demonstrating near-equivalent outcomes, these findings support pembrolizumab and nivolumab interchangeability.
Longitudinal changes in pulmonary function following multiple courses of thoracic radiotherapy.
e20103 Background: Pulmonary function decline following thoracic radiotherapy (RT), particularly DLCO, is well documented after single courses of RT in lung and esophageal cancer cohorts. However, in current practice patients increasingly undergo multiple distinct thoracic RT courses. Re-irradiation analyses to date focus on feasibility, toxicity, and dosimetry rather than functional longitudinal PFT endpoints linked to prior RT exposure at the time of testing. We investigated DLCO changes following multiple courses of thoracic RT. Methods: We performed a retrospective chart review of patients at our institution who received ≥2 distinct courses of thoracic RT, and we abstracted baseline and follow-up PFTs. Among 167 patients who underwent thoracic re-irradiation, 35 patients had paired pre- and post-treatment PFT data and formed our sample population (25 with 2 thoracic RT courses; 10 with 3 thoracic RT courses). Thoracic RT courses in this cohort were delivered between 2007 and 2024. Individual patient changes were assessed using paired tests (paired t-test or Wilcoxon signed-rank, as appropriate). We evaluated predictors of DLCO change using multivariable linear regression while adjusting for baseline DLCO %pred, age at baseline PFT, and sex. We also evaluated clinically meaningful DLCO decline, defined as DLCO ≥10 %-pred point decline or ≥15% relative decline, using binary endpoints. Results: Baseline PFTs preceded first RT completion by a median of 91 days (IQR 134), and follow-up PFTs were obtained a median of 620 days (IQR 966) after the most recent RT course preceding the post-RT PFT. Given variable follow-up timing, analyses were stratified by RT courses completed before the post-RT PFT. Patients with paired pre- and post-RT PFTs showed declines in DLCO (−9.8±18.8 %pred; n = 28; p = 0.010), FEV1 (−12.3±18.6 %pred; n = 35; p = 0.0004), and FVC (−8.2±17.0 %pred; n = 35; p = 0.0074) from baseline to their most recent follow-up. Unadjusted declines in DLCO were greater when PFTs were obtained following ≥2 RT courses versus 1 RT course (DLCO: −14.2±19.7 vs −2.8±15.6 %pred). In multivariable linear regression adjusting for baseline DLCO, age at baseline PFT, and sex, undergoing ≥2 thoracic RT courses was associated with a trend towards greater DLCO decline (β = −11.0 %pred points; 95% CI −22.6 to 0.5; p = 0.061). Clinically meaningful DLCO decline was also more frequent after ≥2 courses at the time of follow-up testing (DLCO ≥10 %-pred point decline: 58.8% vs 36.4%; DLCO ≥15% relative decline: 52.9% vs 27.3%). Conclusions: Greater longitudinal DLCO decline was observed with successive courses of thoracic radiotherapy. This study adds novel patient-level longitudinal pulmonary function data to the thoracic re-irradiation literature. Furthermore, these findings underscore the importance of pulmonary function surveillance strategies and can guide risk stratification with PFT thresholds for repeat thoracic RT.
Improving resident education in ambulatory oncology: A novel flipped-classroom curriculum for internal medicine residents.
e21009 Background: There is a paucity of oncology curricula for internal medicine (IM) residents, particularly related to ambulatory practice. Adequate knowledge of oncology is crucial for internists as guideline-driven cancer screening and prompt diagnosis of new malignancy can improve patient outcomes. A targeted needs assessment of IM residents at Johns Hopkins Bayview (JHBMC) demonstrated that the majority of residents felt dissatisfied with current oncology curricula and did not feel confident in their knowledge of core topics in ambulatory oncology. Based on this data, an innovative educational curriculum in ambulatory oncology was developed for IM residents utilizing a flipped-classroom format. Methods: Using the results of a previously reported targeted needs assessment, a flipped-classroom curricular approach was administered to PGY-1 IM residents at JHBMC, consisting of 2 asynchronous videos followed by a synchronous session applying learned concepts in case-based scenarios. Videos were created to focus on high-yield oncology topics for internists using results of the needs assessment, ABIM Blueprint and ACP MKSAP. Topics included lung, breast and colon cancer screening, diagnostic work-up of suspected malignancy, and performance status evaluation. Knowledge assessment surveys consisting of validated questions from ACP MKSAP were administered pre- and post-curriculum. Residents were asked to rate their satisfaction with the curriculum and confidence in curricular areas after the session. Results: The curriculum was delivered to 22 IM residents. 68% (15/22) completed the pre- and post-curricular surveys. Knowledge improved from 61% to 73% ( p = 0.012) after delivery of the curriculum. Areas demonstrating the weakest baseline knowledge were lung cancer screening and diagnostic evaluation of lung and colon cancer in the primary care setting. 95% of residents felt “extremely satisfied” with topics covered and 90% felt “extremely satisfied” with the format. 71% felt “significantly more confident” in initiating a diagnostic work up of cancer in the ambulatory setting and 95% felt “slightly” or “significantly more confident” in the use of performance status evaluations in clinical practice. Conclusions: Our flipped classroom curriculum supports the use of asynchronous videos followed by a case-based discussion to teach ambulatory oncology topics to IM residents. This offers a novel opportunity to address the knowledge gap among IM residency curricula regarding the management of patients with solid tumor malignancies and improve confidence in the care of these patients.
Assessing the performance of ChatGPT in addressing ethical dilemmas in oncology.
e23292 Background: Large language models such as ChatGPT have been shown to demonstrate accuracy in diagnostic reasoning and treatment plan generation.1,2 However, its utility in navigating ethically complex medical scenarios is less well explored.3 Herein, we evaluated the performance of GPT-5 in addressing commonly encountered ethical cases in oncology. Methods: We conducted a descriptive, cross-sectional approach to assess GPT-5 performance in response to eight ethically complex medical vignettes. A panel of eight board-certified oncologists independently assessed the LLM-generated responses. Vignettes and evaluation dimensions were reviewed by a professor of bioethics who serves as both a clinical ethicist and an institutional board (IRB) member to establish content validity prior to clinician assessment. Outcomes included ethical relevance, reasoning, accuracy, practicability, comprehensibility, and completeness. Oncologists rated each dimension on a 5-point Likert-type scale (1 = strongly disagree to 5 = strongly agree). Interrater reliability was assessed using intraclass correlation coefficient. Results: Of the six outcomes used to evaluate GPT-5 response, the mean score was 4.31/5. GPT-5 responses were rated highest in comprehensibility, defined as the response being clearly written and easy to understand (4.55/5). It was rated lowest in completeness, defined as the response fully addressing all ethical considerations of the case (3.97/5). An intraclass coefficient (ICC) of 0.83 indicates good interrater reliability. GPT-5 response for each clinical vignette was also assessed. Responses were rated highest for the ethical dilemma concerning informed consent, which assessed whether a patient with previously alert, articulated wishes who had developed recent altered mental status had capacity to consent for GBM chemotherapy (4.58/5). Responses were rated lowest for the ethical dilemma of non-disclosure of diagnosis, which assessed approaches to a family hesitant about a clinician sharing a cancer diagnosis with a patient (3.98/5). No significant difference in GPT-5 performance across dimensions or clinical vignettes was found. Conclusions: GPT-5 can provide comprehensible, mostly accurate, and mostly practical responses to help clinicians navigate common ethical dilemmas, although it may not fully capture all ethical considerations. Further research is needed to understand how LLMs can be effectively applied to support ethical decision-making in clinical practice.
Clinical outcomes of gabapentinoids for oncologic pruritus: A retrospective cohort study.
12066 Background: Pruritus is a debilitating symptom in oncologic patients, sometimes leading to interruption of cancer therapy. Gabapentinoids such as gabapentin and pregabalin are effective for the treatment of uremic and neuropathic pruritus. We report on the safety and efficacy of gabapentinoids for oncologic pruritus defined as any pruritus originating from malignancy, oncologic therapies, or other cancer-associated toxicities, such as cutaneous graft-versus-host disease (GVHD). Methods: In this single-center retrospective cohort study conducted at the Memorial Sloan Kettering Cancer Center between 4/1/2019 and 8/1/2024, 224 patients who were prescribed gabapentinoids for oncologic pruritus were included. Patients taking gabapentinoids for indications other than pruritus were excluded. The primary efficacy endpoint was ≥ 1-grade improvement for pruritus severity on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale. Results: The cohort was predominantly male (54%) and White (67%), with Black (14.3%) and Asian (12.5%) patients also represented; the mean age was 63.2 ± 15 years. Gabapentinoids were most prescribed for drug-induced causes (58.9%) and malignancy-related pruritus (14.3%). Of the drug-induced causes, immune checkpoint inhibitors (40.2%), monoclonal antibodies (12.9%; including mogamulizumab, brentuximab vedotin, and enfortumab vedotin), and tyrosine kinase inhibitors (11.4%) were the most common triggers. Pregabalin was more commonly prescribed compared to gabapentin (80.8% vs. 19.2%). Ninety percent of patients (n=202) experienced a ≥1-CTCAE grade improvement at a median total daily dosage of 50 mg (IQR, 25 mg) for pregabalin and 300 mg (IQR, 50 mg) for gabapentin. Median time for patient-reported improvement was 18.5 days and there was no significant difference in gabapentin response between pruritus etiologies. The most common adverse event was sedation (8.5%), with 3 patients discontinuing gabapentinoids due to fatigue. Conclusions: This study is the first to report that gabapentinoids are a safe and effective way to treat oncologic pruritus stemming from malignancy, cancer therapies, or cutaneous GVHD. Prospective trials would further establish gabapentinoids’ safety and efficacy profile in the oncologic population. Outcomes & adverse events of patients on gabapentinoids. Variable Category/Statistic N (%) CTCAE Grade Change Did Not Improve (0 Grade) 22 (9.8%) Improved 1 Grade 132 (58.9%) Improved ≥ 2 Grade 70 (31.3%) Antineoplastic Therapy Interrupted Due to Oncologic Pruritus Yes 26 (11.7%) No 157 (70.4%) Not Applicable 40 (17.9%) Adverse Events* Sedation 19 (8.5%) Leg Swelling 2 (0.9%) Other 9 (4.0%) *The remaining 194 (86.6%) patients did not report any adverse events related to the gabapentinoids.
Escalating site burden and cost: What’s driving the surge in oncology investigator grants over the past decade.
e23149 Background: Publicly accessible data and industry analyses strongly confirm that site costs, including investigator grants, have risen steadily from 2015–2025, especially in oncology, which remains the most complex and expensive therapeutic area in clinical research. Leveraging proprietary data, Premier Research analyzed historical investigator grant pricing to identify the key cost drivers contributing to rising investigator fees. Methods: Based on the review of more than 170 site budgets, per-patient investigator grant costs increased approximately 133%-175% from 2015-2025. In 2015, average per-patient investigator grant costs on a Phase I oncology study were $30,000-$40,000; by 2025, costs for comparable studies have more than doubled to $70,000–$110,000 per patient. The Trial Cost Estimates model shows a consistent rise in clinical trial costs from 2015–2025, driven by trial complexity, regulatory uncertainty, and data-intensive protocols. This added complexity increases Principal Investigator (PI) and Sub-Investigator oversight effort, data entry, monitoring visit coordination, and study visit assessments, directly impacting site budgets and personnel workload, given their time- and procedure-based structure. Further, 81.5% of oncology clinical trials undergo at least one protocol amendment, which can have significant impact on trial budgets. Results: Premier’s data revealed that personnel costs were one of the largest drivers of rising investigator grant fees from 2015-2025. Post-COVID, beginning in fiscal year 2021, the industry experienced widespread and significant salary inflation among key personnel at academic sites. Based on publicly available data across multiple academic medical centers, it was discovered that oncology PI salaries increased by an average of 24% from 2021-2025, while clinical research coordinator salaries rose by approximately 33% over the same period. Apart from increased trial complexity and salary inflation, other notable drivers contributing to rising investigator grant costs include site start-up fees (increasing by > 46%), IRB fees (increasing by > 56%), and pharmacy handling fees (increasing by > 53%). Site indirect or overhead (OH) costs also increased. While variable by institution, data from 20 US-based oncology academic centers shows an average OH fee increase of approximately 10-15%, rising from 30-35% in 2015 to 40-50% in 2025. Conclusions: In summary, oncology site investigator grants have surged over the past decade with rising protocol complexity, amendment frequency, expanding data and operational burdens, escalating PI/CRC staffing costs, and steadily increasing institutional overhead and site fees. These factors have collectively driven a substantial and sustained increase in site-level trial expenses.
Palliative care utilization and acute care outcomes in metastatic prostate cancer in a safety-net health system.
e24064 Background: Patients with metastatic prostate cancer (MPCa) experience high symptom burden and frequent emergency department (ED) visits and hospitalizations. Early integration of palliative care (PC) is recommended, yet PC utilization and timing remain variable. We evaluated patterns of PC referral and associated acute care outcomes in a safety-net cohort. Methods: We conducted a single-institution retrospective study of patients with MPCa treated at the University of Illinois Hospital between 2016 and 2025. Patients were identified through the institutional electronic medical record using diagnosis codes and chart review. Patients were categorized by receipt of a documented PC consult (PC vs no PC). Primary outcomes included ED visits, hospitalizations, and ICU admissions after metastatic diagnosis. Early PC was defined as consult within ≤60 days of metastatic diagnosis. Outcomes were summarized using descriptive statistics and compared between groups. Results: Among 184 patients with MPCa, the cohort was predominantly Black (70.3%) and non-Hispanic (82.3%). Insurance coverage was primarily Medicare (51.4%) and Medicaid (26.3%), with 5.1% uninsured. Overall, 74/184 (40.2%) received a documented PC consult. Within the PC cohort, 21/74 (28.4%) received early PC (≤60 days) while 45/74 (60.8%) received late PC (>60 days). The most common indications for PC referral included symptom control (51.4%), pain management (43.1%), and goals-of-care discussions (33.3%). PC was delivered in outpatient and inpatient settings (55.6% and 50.0%, respectively). Acute care utilization was higher among patients receiving PC. PC patients had higher mean ED visits after metastatic diagnosis (1.70 vs 0.92), higher ED utilization (≥1 ED visit: 59.5% vs 37.3%), and higher frequent ED use (≥2 ED visits: 39.2% vs 23.6%). The PC cohort also demonstrated higher mean hospitalizations (1.91 vs 1.14) and a higher proportion experiencing ≥1 hospitalization (67.6% vs 52.7%). ICU utilization was increased among PC patients (≥1 ICU admission: 23.0% vs 10.0%). In a timing analysis among PC patients, late PC referral was associated with higher ED utilization compared with early PC (mean ED visits: 1.91 vs 1.43; ED ≥2 visits: 46.7% vs 28.6%). Additional analyses will be available at presentation if accepted. Conclusions: In this diverse safety-net cohort, patients receiving palliative care demonstrated higher acute care utilization, consistent with referral patterns among higher-acuity and more clinically complex patients. Among PC recipients, late referral was associated with increased ED utilization compared with early PC, highlighting an opportunity for earlier integration of PC and supportive oncology services in MPCa.
Personalized neoantigen vaccine as adjuvant therapy in high-risk postoperative esophageal carcinoma.
2511 Background: Effective adjuvant strategies for patients with esophageal carcinoma (EC) with residual pathological disease (non-pCR) following neoadjuvant chemoimmunotherapy and radical surgery are urgently needed to reduce the high risk of recurrence. This investigator-initiated, single-arm clinical trial (NCT05307835) evaluated the safety, efficacy, and immunogenicity of iNeo-Vac-P01, a personalized neoantigen peptide vaccine, administered as adjuvant therapy in this high-risk setting. To our knowledge, this study represents the first and largest global cohort of a personalized neoantigen vaccine for postoperative EC, with the longest follow-up duration to date. Methods: Eligible stage IIA-IIIB EC patients with non-pCR were enrolled. For each patient, somatic mutations were identified, and up to 20 individualized long peptides (15-30 amino acids), encompassing predicted HLA-I and II neoantigens, were designed and synthesized using a proprietary bioinformatics platform. The vaccine (300μg per peptide) was administered subcutaneously in conjunction with GM-CSF (40μg) on a multi-dose schedule (Days 1, 4, 8, 15±3, 22±3, 52±7, and 82±7). The primary endpoints were safety and 1-year recurrence-free survival (RFS). Secondary endpoints included RFS, overall survival (OS), and antigen-specific T-cell responses assessed by ELISpot and TCR sequencing. Results: As of November 15, 2025, 26 patients were enrolled, with 23 patients constituting the efficacy-evaluable population. Treatment-related adverse events were primarily Grade 1-2 (fatigue: 39.1%; fever: 30.4%; injection site reactions: 21.7%), with one Grade III acute hypersensitivity event. All 23 patients completed the initial 7-vaccination course. With a median follow-up of 25.3 months from surgery, the 1-year, 2-year, and 3-year RFS rates were 91.3%, 85.6%, and 78.5%, respectively. The corresponding 1-year, 2-year, and 3-year OS rates were 100%, 95%, and 83.1%. These survival outcomes compare favorably with historical controls, notably exceeding the 3-year RFS of 43% reported in the landmark CheckMate 577 trial (adjuvant nivolumab). Immunological analyses confirmed robust vaccine-induced immunogenicity. ELISpot assays detected neoantigen-specific T-cell responses in 100% (23/23) of evaluated patients, with 79.5% (233/296) of the administered vaccine peptides eliciting de novo T-cell activation. TCR sequencing further demonstrated the durable expansion of neoantigen-reactive T-cell clones, which were detectable during treatment and persisted for at least six months following the final vaccination. Conclusions: These results demonstrates that adjuvant therapy with a personalized neoantigen peptide vaccine confers a substantial and durable survival benefit in high-risk EC patients following surgery, coupled with a favorable safety profile. Clinical trial information: NCT05307835 .
Exploring LEGO as a constructivist teaching tool in undergraduate and patient education of cancer survivorship topics.
e13787 Background: Cancer survivorship is a multidimensional, chronic condition requiring effective communication, interprofessional collaboration, and patient-centered care. Educational strategies that enable medical students and patients to visualize and articulate complex survivorship challenges remain limited. LEGO(R) bricks have been used for over two decades as facilitation tools to enhance creative thinking and communication; however, their application in medical education and survivorship care is underexplored. Methods: A LEGO(R)-based constructivist methodology was implemented in two contexts. First, the OncoBRICKS(R) program in Portugal delivered LEGO(R) Serious Play(R) workshops to pediatric and adolescent/young adult (AYA) cancer patients and caregivers, eliciting representations of lived survivorship experiences, including emotional, cognitive, and relational dimensions. Second, US medical students (n = 14), participated in a 15-week ASCO-themed survivorship elective engaging with survivors, caregivers, and interdisciplinary team members. At six time points, they constructed LEGO(R) models addressing key survivorship domains: survivor challenges, caregiver needs, social determinants of health, end-of-life issues, and a health system design of a new cancer survivorship center. Student-submitted models, photos and reflective narratives generated six, topic-specific qualitative datasets. Results: LEGO(R) models created by patients and caregivers revealed unmet psychosocial needs, future uncertainty, treatment-related cognitive and emotional burden, disrupted social connectedness, and challenges navigating survivorship pathways, alongside a preference for home-based, technology-enabled, family-centered care. LEGO(R) models created by medical students upon reflecting on real-life encounters with survivors or caregivers improved communication skills and helped coin new communication metaphors. This LEGO(R)-based methodology was very helpful as a new visual thinking strategy tool describing cancer situations and did not feel at all as a burdensome cognitive load. Analysis of photos/reflective narratives suggests Y2 students are highly capable of recognizing survivorship challenges and proposing accurate solutions. Increased creativity, thinking in a different way, collaborative active learning offering new perspectives and visualizing the human experience emerged as common themes of benefit. Conclusions: LEGO(R)-based constructivist learning was feasible, acceptable, and effective for enhancing survivorship communication among patients, caregivers, and undergraduate medical learners. It supported patient-centered perspectives, interprofessional awareness, and holistic understanding of survivorship, representing an innovative strategy aligned with ASCO survivorship competencies.
Does treatment delay matter?: Impact of time to immunotherapy on survival in extensive-stage small cell lung cancer.
8115 Background: Immune checkpoint inhibitors (ICI) combined with platinum-etoposide chemotherapy are the standard first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN and IMpower133 trials. Given the aggressive nature of ES-SCLC, timely initiation of systemic therapy is critical; however, delays in treatment initiation are common in real-world practice. The impact of time to immunotherapy initiation (TTI) on survival has not been well characterized. Methods: Adult patients diagnosed with EO-SCLC (2019-2021) who received immunotherapy as part of first-line systemic therapy were identified from NCDB. TTI was defined as the time from diagnosis to first immunotherapy and categorized as ≤30, 31–60, or > 60 days. Association between TTI and OS was analysed using multivariable Cox proportional hazards models adjusting for patient and facility-level factors. A 90-day landmark analysis were performed to mitigate immortal time bias. Multivariable logistic regression was used to identify predictors of delayed initiation (> 30 days). Results: A total of 18,630 patients were identified. 2,652 (14.24%) died during follow-up. Median TTI was 29 days (IQR 18–45), with median follow-up of 9.36 months. In multivariable Cox models, TTI was not independently associated with OS (31–60 vs ≤30 days: HR 0.92 [0.84–1.00]; > 60 vs ≤30 days: HR 1.00 [0.89–1.11]). Results were consistent in a 90-day landmark analysis. Increasing age was associated with higher mortality (HR 1.01 per year, p = 0.003). Treatment at academic/research programs was associated with better OS (HR 0.71 [0.61–0.82]), while Medicaid insurance was associated with worse OS (HR 1.31 [1.15–1.49]). Black patients were more likely to receive delayed treatment (OR 1.31 [1.16–1.48]) while Asian patients were less likely (OR 0.74 [0.55–0.98]), when compared with Non-Hispanic White patients. Medicaid (OR 1.36 [1.20–1.53]) and Medicare insurance (OR 1.10 [1.01–1.21]) were associated with increased odds of delay versus private insurance. Higher comorbidity burden (Charlson–Deyo score ≥2 vs 0: OR 1.10 [1.02–1.19]) and treatment at academic centers (OR 1.33 [1.17–1.51]) were also associated with delay. Higher neighborhood income was protective (highest vs lowest quartile: OR 0.86 [0.77–0.95]). Conclusions: In a large national cohort of ES-SCLC patients receiving immunotherapy, modest delays in treatment initiation were not associated with OS. However, significant disparities exist in timely access, highlighting opportunities for system-level interventions to improve equity in cancer care delivery.
Clinical outcomes of <i>TP53</i> -mutated myeloid neoplasms after allogeneic hematopoietic cell transplantation: A Canadian multicenter propensity score–matched analysis.
6553 Background: TP53 mutations define a biologically aggressive subset of myeloid malignancies with poor outcomes. We evaluated clinical, disease-related, and transplant-associated variables influencing post-allogeneic hematopoietic cell transplant (HCT) outcomes in this high-risk group. Methods: We conducted a retrospective multicenter study across 10 Canadian transplant centers, including 153 individuals with TP53 -mutated and 2,207 patients with TP53 wild-type acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) from the Cell Therapy and Transplant Canada (CTTC) registry. Propensity score matching was performed to account for baseline differences. The primary outcomes were relapse and overall survival (OS) after HCT. Results: Presence of TP53 mutation was associated with increased risk of relapse compared with TP53 wild-type (HR 2.21; 95% CI: 1.5–3.1; p<0.01). Among TP53 -mutated patients (n=153), with a median follow-up of 35.8 months (Q1-Q3: 29-48), the 2-year cumulative incidence of relapse was 53.2% (95% CI: 44.4-61.2), and OS 40.1% (95% CI: 31.6-48.4). In multivariable analysis, multi-hit TP53 mutations (HR 2.17, 95% CI: 1.3-3.7; p<0.01), and graft-vs-host disease (GVHD) prophylaxis regimens containing anti-thymocyte globulin (ATG) with (HR 3.53, 95% CI: 1.5-8.1; p<0.01) or without (HR 2.59, 95% CI: 1.2-5.6; p=0.01) post-transplant cyclophosphamide were associated with higher relapse risk. Conditioning regimen intensity, and chronic GVHD, modelled as a time-dependent covariable, did not significantly impact relapse, while chronic GVHD was associated with improved OS (HR 0.46; 95% CI: 0.2-0.9, p=0.03). Conclusions: In patients with myeloid malignancies, TP53 mutations are associated with a high risk of relapse and poor survival after HCT, while chronic GVHD appears to be protective, underscoring the importance of careful selection of GVHD prophylaxis and the need for effective post-transplant strategies in this high-risk population. Multivariable analysis. Variable Hazard Ratio 95% CI p value Relapse TP53 mutation status Single hit Multi hit Ref2.17 Ref1.27-3.71 Ref0.005 Disease risk index Intermediate High/very high Ref1.53 Ref0.77-3.03 Ref0.220 GVHD prophylaxis CNI-MTX ATG-CNI-MTX ATG-PTCY-CNI PTCY-CNI-MMF Ref2.593.531.66 Ref1.21-5.561.52-8.170.58-4.74 Ref0.0140.0030.350 Chronic GVHD (time dependent) 1.25 0.63–2.45 0.526 Overall survival TP53 mutation status Single hit Multi hit Ref2.26 Ref1.30-3.90 Ref0.003 Disease risk index Intermediate High/very high Ref0.93 Ref0.49-1.77 Ref0.823 GVHD prophylaxis CNI-MTX ATG-CNI-MTX ATG-PTCY-CNI PTCY-CNI-MMF Ref2.181.621.04 Ref1.12-4.240.73-3.610.36-2.99 Ref0.0210.2360.949 Chronic GVHD (time dependent) 0.46 0.23-0.93 0.030
Pathological outcomes of neoadjuvant osimertinib-based therapies versus chemotherapy in resectable EGFR-mutant NSCLC: A component network meta-analysis.
e20067 Background: Neoadjuvent chemotherapy is the current standard for resectable non–small cell lung cancer (NSCLC) yielding modest pathological outcomes. Emerging data demonstrates better outcomes with neoadjuvant use of osimertinib. We performed a component network meta-analysis (CNMA) comparing neoadjuvant osimertinib-based regimens versus chemotherapy alone using direct and indirect evidence. Methods: Phase II–III trials through January 2026 were included. Two treatment components—osimertinib monotherapy and osimertinib plus chemotherapy—were each evaluated independently relative to chemotherapy alone using a frequentist random-effects CNMA. Odds ratios (ORs) were estimated for pathological complete response (pCR), major pathological response (MPR), Nodal downstaging (DS), R0 resection rate, and grade ≥3 adverse events (AEs). Results: Three studies (n = 481) formed a connected network comparing osimertinib-based strategies with chemotherapy alone. Osimertinib monotherapy significantly improved MPR (OR 22.71, 95% CI 4.99–103.28) and pCR (OR 14.94, 95% CI 1.91–117.05). Osimertinib plus chemotherapy also improved MPR (OR 16.66, 95% CI 3.54–78.52) but did not significantly improve pCR (OR 6.12, 95% CI 0.69–54.27). Nodal DS was improved with both osimertinib monotherapy (OR, 2.51; 95% CI, 1.19–5.30) and the combination regimen (OR, 3.27; 95% CI, 1.53–6.98). R0 resection rates did not differ significantly across groups. Osimertinib was associated with fewer grade ≥3 adverse events (OR, 0.29; 95% CI, 0.15–0.57), whereas combination therapy increased severe toxicity (OR, 4.13; 95% CI, 1.53–11.19). Heterogeneity was low to moderate (I² ≈ 0–60%). Conclusions: Neoadjuvant osimertinib-based therapy improved pathological response and nodal downstaging with a more favorable safety profile observed with monotherapy, while R0 resection rates did not differ significantly. These findings support neoadjuvent osimertinib monotherapy as a promising strategy in resectable EGFR-mutant NSCLC. Pathological outcomes vs chemotherapy alone. Outcome Treatment Odds Ratio (95% CI) P-value MPR OSI 22.71 (4.99-103.28) <0.0001 MPR OSI + CT 16.66 (3.54-78.52) <0.0001 pCR OSI 14.94 (1.91-117.05) 0.01 pCR OSI + CT 6.12 (0.69-54.27) 0.104 Nodal DS OSI 2.51 (1.19-5.3) 0.016 Nodal DS OSI + CT 3.27 (1.53-6.98) 0.002 R0 rate OSI 1.40 (0.50-3.92) 0.518 R0 rate OSI + CT 1.47 (0.45-4.83) 0.527 ≥G3 AEs OSI 0.29 (0.15-0.57) <0.001 ≥G3 AEs OSI + CT 1.10 (0.65-1.88) 0.719 Abbreviations: OSI, osimertinib; CT, chemotherapy; MPR, major pathological response; pCR, pathological complete response; DS, nodal downstaging; R0, microscopically margin-negative resection; AEs, adverse events.
Multimodal intraoperative diagnosis and grading system integrating macroscopic images, CT imaging, and textual reports for adenocarcinoma (MaCTex) in early-stage LUAD: A multicentric diagnostic study.
8023 Background: Intraoperative frozen section (IFS) analysis is pivotal for guiding surgical strategies in stage IA lung adenocarcinoma (LUAD), specifically the extent of resection and lymph node dissection. However, IFS is constrained by sampling errors and prolonged turnaround times, which can compromise diagnostic precision and surgical efficiency. To address these unmet needs, we developed and validated a multimodal artificial intelligence framework. By integrating preoperative chest CT imaging, unstructured radiology text reports, and intraoperative macroscopic images of resected specimens, this system aims to deliver rapid, precise intraoperative predictions, thereby mitigating reliance on traditional IFS and optimizing surgical decision-making. Methods: This retrospective, multicenter study enrolled patients with stage IA LUAD who underwent complete resection between June 2020 and September 2023 across three institutions (Guangdong Provincial People's Hospital, Affiliated Hospital of Guangdong Medical University, and Meizhou People's Hospital). We collected preoperative thin-slice chest CT scans and unstructured text reports within three months prior to surgery. Intraoperative macroscopic images of resected specimens were captured via smartphone under natural lighting. We developed MaCTex, a multimodal AI model, to predict the IASLC grading system (PIL, MIA, IAC G1, G2, G3). Performance was evaluated against the gold standard of postoperative paraffin pathology. The study is registered with the Chinese Clinical Trial Registry (ChiCTR2500111776). Results: The cohort included 1,516 patients (yielding 1,638 pulmonary nodules) with matched preoperative CT imagings/reports and 2,344 intraoperative macroscopic images. We developed four distinct models for evaluation: a CT-only model, a CT-Text model, a Gross Image model, and the comprehensive MaCTex framework. The CT-Text model achieved a diagnostic AUC of 0.857, outperforming the unimodal CT model with an AUC of 0.837. The Gross Image model achieved a performance of 0.82 in five-class prediction. Notably, the integration of unstructured CT text reports significantly enhanced model efficacy, underscoring the critical value of radiologist expertise in refining intraoperative diagnostics. Conclusions: We established a robust multimodal AI framework integrating radiographic data, clinical text, and macroscopic pathology that enables efficient and accurate intraoperative prediction of IASLC grading in lung adenocarcinoma. By circumventing the sampling limitations of traditional methods, MaCTex serves as a promising alternative or adjunct to intraoperative frozen sections, providing thoracic surgeons with real-time, precise decision support to optimize surgical management.
Volrustomig, a novel bispecific PD-1/CTLA-4 monoclonal antibody, as single-agent first-line therapy for unresectable pleural mesothelioma: Substudy 5 of the eVOLVE-02 phase 2 study.
TPS8126 Background: Standard first-line treatment for unresectable pleural mesothelioma has evolved recently to include anti-PD-1 ± anti-CTLA-4 immunotherapy-based options. Nivolumab + ipilimumab and pembrolizumab + pemetrexed + platinum chemotherapy showed improved survival vs chemotherapy alone, with greater benefit in non-epithelioid compared to epithelioid pleural mesothelioma. However, there is still significant unmet need given the ongoing poor prognosis; further study is needed to optimize dual checkpoint approaches across histologic subtypes and refine regimen selection. Volrustomig is a monovalent, bispecific, humanized IgG1 monoclonal antibody engineered to specifically inhibit PD-1 and CTLA-4, with increased CTLA-4 blockade on PD-1-positive activated T cells compared to PD-1-negative resting peripheral T cells. Volrustomig + chemotherapy is being evaluated as first-line treatment in unresectable pleural mesothelioma in the phase 3 eVOLVE-Meso trial. Volrustomig monotherapy has shown encouraging results in a Phase 1 study of patients with solid tumors; this new eVOLVE-02 (NCT06535607) substudy will evaluate its efficacy and safety as monotherapy in unresectable pleural mesothelioma. Methods: ~75 patients with unresectable pleural mesothelioma (epithelioid or non-epithelioid histology) will receive intravenous volrustomig until disease progression, unacceptable toxicity, consent withdrawal, or maximum treatment duration is reached. Eligibility criteria include age ≥18 years, Eastern Cooperative Oncology Group performance status 0/1, histologically confirmed pleural mesothelioma with known histology, advanced unresectable disease, measurable disease per mRECIST (modified Response Evaluation Criteria in Solid Tumors) v1.1 (pleural lesions) and/or RECIST v1.1 (metastatic non-pleural lesions), no prior systemic therapy for pleural mesothelioma, and no prior exposure to immune-mediated therapy. The primary endpoint is objective response rate. Secondary endpoints include disease control rate, time to response, duration of response, progression-free survival, and overall survival. eVOLVE-02 is recruiting patients; 3 substudies are ongoing in cervical cancer and head and neck squamous cell carcinoma. Substudy 5 enrollment is planned at sites in 8 countries/regions: Australia, Canada, China, Germany, Italy, Taiwan, UK, and USA. Clinical trial information: NCT06535607 .