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Integrating BTK inhibition into R-da-EPOCH for HIV-related DLBCL.
7001 Background: Human immunodeficiency virus (HIV)-related diffuse large B-cell lymphomas (DLBCL) are heterogeneous in nature, clinically, & molecularly. R-da-EPOCH is accepted as a standard of care in HIV+DLBCL. Classifying tumors with respect to immunophenotype & genomic features may facilitate personalized therapy to improve outcomes in this diverse disease. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (ibr), also inhibits inducible T cell kinase (ITK). As HIV hijacks host ITK during replication, ibr may have additional clinical benefits in HIV+DLBCL. This trial added ibr to R-da-EPOCH in HIV+DLBCL, with an attempt to enrich for non-germinal center B-cell (non-GCB) subtype, to evaluate safety, feasibility & activity, impact on T cells, & correlate lymphoma cell of origin (COO) with response. Methods: This multi-center study included a 3+3 dose de-escalation cohort followed by dose-expansion at recommended phase 2 dose (RP2D). Participants (pts) age 18-64 years (y) with stage II-IV HIV-DLBCL were untreated or received 1 cycle (cy) R-da-EPOCH/CHOP off-study. CD4 <100 & asymptomatic leptomeningeal disease were allowed. Ibr was dosed daily days 1-21 & R-da-EPOCH administered as previously published (PMID 32430507) for 6 total cy. Moderate/strong CYP3A4 inhibitors were excluded, due to effects on ibr and chemotherapy. Results: 43 pts were evaluable for toxicity & 37 evaluable for response. 41/43 (95%) pts tolerated ≥2 cy; median cy of study therapy (tx) received = 5. At baseline median age was 52y (24-64) & CD4 count 204 (21-757); 9 pts had CD4 <100. 81% were male, 42% White & 49% Black. 86% were stage III/IV, 40% non-GCB, & 88% had ECOG 0-1. Ibr RP2D was 560mg daily. Noting PET was optional, overall response rate was 100% with 57% (21/37) complete (CR) & 43% (16/37) partial responses (PR). Relapse/progression occurred in 16% (6/37; 1CR, 5PR) during a median follow-up of 4.2y (95%CI = 2.3 to 4.87); median duration of response = 2.8y. 3y event-free (EFS) & overall survival (OS) were 83 & 81% respectively (GCB: 88 & 87%, non-GCB: 76 & 63%). Among 679 treatment-related adverse events (TRAE), the most frequent were (total, % grade (gr) 3+) anemia (105, 50%), thrombocytopenia (81, 41%), neutropenia (60, 88%) & lymphopenia (60, 68%). Non-hematologic AEs (total TRAE, # max gr) included diarrhea (22, 2 gr3), nausea (21, 1 g3), hypokalemia (20, 4 gr3), fatigue (17, 17 gr1), & sepsis (1 gr4). Reasons for tx discontinuation: 1 progression, 4 withdrawal, 4 TRAE, 1 lost to follow up. Conclusions: Incorporating ibrutinib 560mg daily with R-da-EPOCH in HIV-related DLBCL treatment resulted in manageable toxicities typical of R-da-EPOCH. Although lower confirmed CR, 3y EFS & OS are comparable or higher than prior studies of HIV+DLBCL R-da-EPOCH. Ongoing studies to be updated at the meeting include impact on T cell subsets, & correlations of response & survival with circulating tumor DNA & lymphoma features (EBV, MYC, BCL2, BCL6 & genomic determinations of COO). Clinical trial information: NCI-2017-01240 .
Prevalence and trends in rural patient enrollment in SWOG cancer clinical trials, 1992-2022.
11068 Background: A recent ASCO report highlighted improving patient access to cancer clinical trials as a fundamental priority. Although prior research found that 19% of participants in NCI-sponsored trials reside in rural areas, there is substantial heterogeneity in the classification of rurality. In addition, sociodemographic characteristics across different levels of rurality are unknown. In this analysis, we evaluated the prevalence and trends over time in trial enrollment by categories of rurality. Methods: We analyzed pooled data from phase II, II/III, and III trials conducted by the SWOG Cancer Research Network from 1992-2022. Rurality was defined by linking patient zip code to the Rural-Urban Continuum Codes, and categorized into four groups (large urban, small urban, rural, frontier). Baseline and patient demographic data were obtained from trial registration forms. Neighborhood deprivation, based on the Area Deprivation Index, was derived from patient zip code. The associations between rurality and patient characteristics were evaluated using multivariate logistic regression with covariate adjustments. Rurality enrollment was compared to corresponding overall US rurality estimates during the same period. Results: In total, N = 39,729 patients enrolled in 69 trials in brain, breast, GI, GU, gynecological, head and neck, lung, sarcoma, melanoma, and hematologic cancers were examined. Across the geographic groups, 52.2% lived in large urban, 30.9% lived in small urban, 11.6% lived in rural, and 5.4% lived in frontier areas, compared to corresponding US population estimates of 56.0% large urban, 28.6% small urban, 10.3% rural, and 5.0% frontier. Patients residing in frontier areas were nearly 80 times as likely to live in the highest versus lowest deprivation areas (OR = 78.37, 95% CI, 64.71-94.92, p < .0001). Similar though less pronounced associations were found among patients from rural and small urban areas (p < .0001). Frontier patients were more likely to be on Medicare (OR = 1.96, 95% CI, 1.66-2.30, p < .0001). Over the 30-year study period, trial enrollment among patients from frontier areas has decreased over time relative to the US population, whereas trial enrollment of patients from large urban areas has increased. Conclusions: Patients from rural and frontier areas are well-represented in SWOG clinical trials, however, enrollment among patients from frontier areas has shown a declining trend. Strong representation of patients with cancer from rural areas enhances the generalizability of trial findings. Given ongoing changes to healthcare, declining representation from frontier areas is likely to continue without targeted interventions. Further research is needed to expand access to care in these vulnerable areas and guide efforts that ensure adequate socioeconomic support for all patients, regardless of their geographic locale.
A retrospective analysis of tarlatamab outcomes and safety in a global multicenter electronic health record network (TriNetX) database.
e20167 Background: Tarlatamab, a bispecific T-cell engager (BiTE) targeting Delta-like Ligand 3 (DLL3), has been approved for the treatment of relapsed Extensive-stage Small Cell Lung Cancer (ES-SCLC). However, trial populations often exclude patients with active central nervous system (CNS) metastases or poor performance status. Real-world evidence is needed to characterize outcomes and safety of Tarlatamab in a broader patient population. Methods: We conducted a retrospective, propensity score-matched cohort study using a multi-center electronic health record network including 170 health care organizations globally (TriNetX). Adult patients with ES-SCLC who received tarlatamab were included and stratified by chemotherapy-free interval (CFI): “chemotherapy-free” (≥ 90 days) or “early chemotherapy” ( < 90 days). Cohorts were matched 1:1 on baseline demographic and clinical characteristics, Outcomes included overall survival (OS), CRS, and ICANS toxicities. Risk estimates and time-to-event analyses with Kaplan-Meier methods and Cox proportional hazards models were used for analyses. Results: The total cohort in this dataset had 658 patients. Table 1 included baseline characteristics. Safety analysis of the total cohort revealed an overall CRS incidence of 27.66% (Grade 1/2: 19.45%; Grade 3-5:1.98%; unspecified: 9.52%) and an overall ICANS incidence of 16.41% (Grade 1/2: 7.75%; Grade 3-5: 1.67%; unspecified: 10.33%), with 100% of events occurring within 14 days of the first dose. Tarlatamab was utilized as 2nd-line (28.9%), 3rd-line (24.0%), or 4th-line or greater (12.5%) with (34.6%) not reported. With a median follow-up of 18 months, the median OS for the whole cohort was 15.2 months. In the propensity score-matched analysis (n = 430, 215 patients per group), the chemo-free group showed a significant survival advantage (HR 0.691; 95% CI, 0.495–0.965), while toxicity remained comparable between matched groups for Grade 1/2 CRS (OR 0.971) and Grade 1/2 ICANS (OR 1.205). Conclusions: This large real-world analysis demonstrated outcome and safety data of tarlatamab in a diverse ES-SCLC population, demonstrating a median overall survival of 15.2 months. Safety profiles were lower than reported in clinical trials, with earlier median onset CRS and ICANS possibly due to reporting bias. Subgroup analysis identified a significant survival benefit for patients initiating tarlatamab after a chemotherapy-free interval of ≥ 90 days (HR 0.691), suggesting a potential biomarker for tarlatamab efficacy. However, additional mechanistic studies are needed to elucidate the role tumor biology and immune environment in this setting. that treatment sequencing to allow for immune recovery may optimize BiTE efficacy. Patient cohort N=658 Female % 51.27 Male % 48.73 Median age 67 Geographic distributionUSOutside US 93.5%6.5% History of brain metastases 42.2%(278)
CONCEPT (combination of cetuximab plus fruquintinib treatment ± immunotherapy): A multicenter, randomized, open-label phase II trial in first-line pMMR <i>RAS/BRAF</i> wild-type unresectable metastatic colorectal cancer.
TPS3680 Background: In pMMR unresectable metastatic colorectal cancer (mCRC), first-line standards combine cytotoxic chemotherapy with targeted agents (anti-EGFR or anti-VEGF). A chemotherapy-sparing strategy may be clinically relevant for selected patients, and biologically supported by potential synergy between EGFR inhibition and VEGFR blockade, with immunotherapy potentially enhanced by vascular normalization and microenvironment modulation. CONCEPT evaluates the safety and antitumor activity of cetuximab-β plus fruquintinib, with or without immune checkpoint blockade, as a first-line option in pMMR RAS/BRAF wild-type unresectable mCRC. Methods: CONCEPT is an open-label, multicenter, randomized phase II trial. Key eligibility: age 18–85, ECOG 0–1, histologically confirmed colorectal adenocarcinoma, pMMR, KRAS/NRAS/BRAF wild-type, unresectable metastatic disease, and ≥1 measurable lesion per RECIST v1.1. Planned N=70; randomization 1:1:1 to: A) cetuximab-β 500 mg/m² IV q2w + fruquintinib 5 mg PO QD (3 weeks on/1 week off); B) regimen A + PD-1 antibody 200 mg IV q4w; C) regimen A + PD-1/CTLA-4 antibody 5 mg/kg IV q4w. The study uses a seamless two-stage selection design: initial cohort (10 patients/arm) to assess early safety/activity, followed by expansion of one or two selected arm(s) (+20 patients per selected arm). Safety assessments are performed each cycle; radiologic tumor assessment is every 2 cycles. Primary endpoints: progression-free survival (PFS) and safety. Secondary endpoints include objective response rate (ORR), disease control rate (DCR) and overall survival (OS). The study is registered with ClinicalTrials.gov (NCI 07257653). Clinical trial information: NCI 07257653 .
Real-world adoption and sequencing of CLDN18.2, PD-L1, and HER2 testing in advanced gastric and gastroesophageal junction adenocarcinoma.
4035 Background: The FDA approval of zolbetuximab for CLDN18.2-positive advanced gastric and gastroesophageal junction adenocarcinoma (GEA) in Oct 2024, based on the SPOTLIGHT and GLOW trials, represents an important advance in biomarker-driven therapy. We aimed to describe real-world adoption of CLDN18.2 testing in the US, and CLDN18.2 co-expression with other clinically relevant biomarkers. Methods: Using the US-based, electronic health record-derived deidentified Flatiron Health Research Database, we evaluated biomarker testing patterns among patients diagnosed after 2016 across three periods: pre-SPOTLIGHT publication (2016–2022), post-SPOTLIGHT/pre-FDA approval (Jan 2023–Sep 2024), and post-FDA approval (Oct 2024 onward). We assessed CLDN18.2 testing uptake and co-expression with PD-L1 and HER2. Results: In total, our study included 11,099 patients (7,515 pre-SPOTLIGHT, 2,364 pre-FDA, 1,220 post-FDA). Compared to HER2 testing, 1.1% had CLDN18.2 testing pre-SPOTLIGHT, 21.3% pre-FDA and 39.5% post-FDA. The prevalence of biomarker positivity was as follows: HER2 20.1% (2,617/13,033), PD-L1 25.6% (1,913/7,487), CLDN18.2 42.6% (473/1,109). Among patients tested for all three biomarkers with available result dates, 69.9% underwent upfront comprehensive testing (HER2, PD-L1, CLDN18.2 within one week), while 30.1% had sequential testing, with a median interval of 91 days between tests. Among 1,034 patients tested for all three biomarkers, 13.9% were dual PD-L1/CLDN18.2 positive, and 4.4% were triple-positive. Conclusions: In this real-world analysis, CLDN18.2 testing uptake increased following SPOTLIGHT but remained incomplete, and nearly one-third underwent sequential rather than upfront comprehensive biomarker testing, resulting in clinically meaningful delays. These findings highlight the need for improved education and implementation of upfront, comprehensive biomarker testing strategies to optimize treatment sequencing and preserve therapeutic options for patients with GEA.
Neoadjuvant immunotherapy combined with immunonutrition therapy for gastric cancer: A single-center, randomized clinical trial.
e16054 Background: This study aimed to explore whether immunonutrition therapy could enhance the efficacy of gastric cancer immunotherapy by reshaping the tumor immune microenvironment, providing new ideas and schemes for the neoadjuvant therapy of locally advanced gastric cancer (LAGC). Methods: This study is a pragmatic, open label, single-center randomized controlled study. Suitable LAGC patients were screened and randomly assigned in a 1:1 ratio to the control group - neoadjuvant chemotherapy (NAC) and the intervention group - neoadjuvant chemotherapy combined with immunotherapy (tislelizumab) and oral immunonutrition (oral impact, NACII). The primary endpoint is pathological complete response (pCR) after 3 cycle treatment. The following secondary endpoints will be evaluated: R0 resection rate; lymph node status after neoadjuvant therapy; The safety of the treatment plan. The accompanying changes in the immune status and tumor microenvironment is set as the exploratory endpoint. 76 LAGC at least is expected to include in this study. Results: As of January 26 2026, a total of 43 participants were included, among which 23 were in the NAC group and 20 were in the NACII group. A total of 36 subjects underwent radical gastrectomy for gastric cancer (20 in the NAC group and 16 in the NACII group). The pCR rate in the NAC group was significantly lower than that in the NACII group (0% vs 35%, p < 0.001), while there was no significant statistical difference in the R0 resection rate between the two groups. After three cycles of immunotherapy combined with oral immunonutritional supplementation treatment, it was able to significantly reduce the proportions of ypT stage (p < 0.001), intravascular tumor thrombus (p = 0.024), and nerve invasion (p = 0.023), and also reduce the proportion of postoperative complications (p = 0.001). Through multiple immunostaining, it was found that the number of infiltrating lymphocytes within the cancer nests in the NACII group was significantly higher than that in the NAC group, especially the infiltration of DC cells was more pronounced. Conclusions: Immunotherapy combined with oral immune nutritional supplementation can significantly increase the postoperative PCR rate of neoadjuvant treatment for LAGC and achieve tumor downstaging. Immunonutrition therapy can reshape the tumor immune microenvironment, so as to further enhance the immunotherapy effect of advanced gastric cancer. The specific mechanism needs to be further studied. Clinical trial information: ChiCTR2300077461.
Early therapeutic intervention versus observation in high-risk smoldering multiple myeloma: A systematic review and meta-analysis.
e19547 Background: Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma (MM) with heterogeneous risk of progression. High-risk SMM is associated with early transformation and end-organ damage. Although observation has historically been standard of care, advances in risk stratification and novel therapies have challenged the watch-and-wait paradigm. This meta-analysis evaluated the impact of early therapeutic intervention on survival outcomes in high-risk SMM. Methods: PubMed, Embase, Web of Science, Ovid MEDLINE, Scopus, and ClinicalTrials.gov were searched for studies published between 2003 and 2024. Randomized controlled trials and selected prospective studies comparing early systemic therapy with observation or placebo in intermediate- or high-risk SMM were included. Primary outcomes were progression-free survival (PFS), time to progression (TTP) to symptomatic MM, and overall survival (OS). Secondary outcomes included treatment response and toxicity. Time-to-event outcomes were pooled as hazard ratios (HRs) and dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs) using a random-effects meta-analysis (DerSimonian–Laird method). Statistical significance was assessed using the Z-test, and heterogeneity was evaluated using the I² statistic. Results: Nineteen studies involving 1,217 patients were included, comprising eight randomized controlled trials (n=885). Early therapeutic intervention significantly reduced progression to symptomatic MM compared with observation (RR=0.53; 95% CI, 0.33–0.87; P=0.01). Among high-risk SMM patients, early treatment significantly decreased disease progression (RR=0.51; 95% CI, 0.37–0.70; P=0.0001) and mortality (RR=0.53; 95% CI, 0.29–0.96; P=0.04). Lenalidomide-based regimens demonstrated consistent benefit, with hazard ratios for progression ranging from 0.18 to 0.28 and prolongation of median TTP from approximately 2.1 years with observation to up to 9.5 years with early therapy. Pooled 12-month PFS and OS rates were 94% (95% CI, 89%–98%) and 99% (95% CI, 97%–100%) in intervention groups versus 76% and 97% with observation, respectively. The overall response rate was 64% (95% CI, 50%–77%), complete response rate 12% (95% CI, 3%–25%), and minimal residual disease negativity 62% (95% CI, 42%–81%). Grade 3–4 adverse events occurred in 36% (95% CI, 30%–43%). Conclusions: Early therapeutic intervention significantly delays progression to symptomatic multiple myeloma and is associated with improved survival in patients with high-risk SMM. These findings support a risk-adapted treatment approach and reinforce the evolving role of early intervention in biologically aggressive disease.
Cladribine (CLAD) + low-dose AraC (LDAC) + venetoclax (VEN) in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome: Real-world analysis from a large community-based oncology practice.
6542 Background: A lower intensity combination cladribine (CLAD), low dose cytarabine (LDAC), and venetoclax (VEN), alternating with hypomethylating agents (HMA) + VEN has been shown to be highly effective in the treatment of older and/or unfit patients with newly diagnosed AML, producing high rates of MRD negative complete remission (CR), low early mortality, and successful transition to allogeneic stem cell transplant. While this was conducted in a large academic center in a prospective phase II study, we aimed to assess the efficacy and safety of this approach in a community practice setting, with important implications of broader applicability. Methods: This is a single-center retrospective study evaluating the efficacy and safety of using the CLAD/LDAC/VEN alternating with HMA/VEN regimen in a large oncology practice in the community setting. Dosing of CLAD/LDAC/VEN was according to published experience (Kadia, et al. JCO 2022). Patients with high risk MDS or AML treated in our institution from January 13, 2023-November 18, 2025 were included. Pts with prior treatment, including HMA for prior MDS transforming to AML (treated secondary AML, ts-AML) were also included. Results: A total of 72 patients received at least 1 cycle of CLAD/LDAC/VEN. The median age was 74 yrs (range: 43-90). Median PS was 1 (0-2), including 21 (29%) pts with ECOG PS of 2 (29%). 58 pts had AML, including 44 (78%) with untreated AML, 10 (18%) with ts-AML, and 12 (22%) with relapsed AML; 14 pts had high risk MDS, of which 5 (36%) had failed prior HMA . 37 pts (51%) had adverse risk karyotype by ELN 2022 , 16 (22%) had TP53 mutation and 29 29 (40%) had secondary AML. Twenty-nine (40%) pts had received prior therapy, including 13 pts (18%) with prior HMA. The median number of cycles received was 2 (range 1-14). Among untreated AML and MDS, the composite CR (CRc) rates were 63% and 58%, respectively. Six out of 16 pts with p53 (38%) achieved CRc and of 16 pts with prior HMA 6 (38%) achieved CRc. The median survival (OS) was 8 months (range 0.16-33m). Eleven pts (15%) went on to have allo-SCT. Five pts (7%) died within 28 days of first treatment. Three of these died of infectious complications, 1 died of an acute coronary event and 1 patient decided to go on comfort care mid-way through treatment. Conclusions: CLAD/LDAC/VEN was feasible and effective in a high-risk, older patient population including pts with prior treatment who were able to achieve meaningful disease control and used as a bridge to transplant. The regimen translated well to a community setting, with relatively low 28-day mortality and good tolerability.
Factors influencing the decision for contralateral risk-reducing mastectomy in Japanese patients with breast cancer harboring <i>BRCA1/2</i> pathogenic variants: The BRCA-Decision study.
e22661 Background: Contralateral risk-reducing mastectomy (CRRM) is an option for reducing contralateral breast cancer risk in patients with BRCA1/2 pathogenic variants (BRCA1/2 PV). However, decision-making involves complex interactions of patient values, life circumstances, and psychological factors. The specific factors influencing CRRM selection among Japanese patients remain inadequately characterized. This study aimed to elucidate differences in patient characteristics and decision-making factors between those who underwent CRRM and those who did not. Methods: A multicenter cross-sectional survey was conducted among primary breast cancer patients diagnosed with BRCA1/2 PV after April 2020 who were at least 3 months post-surgery. Factors influencing CRRM decision-making were evaluated in 160 patients who completed the web-based questionnaire. Results: Compared with the non-CRRM group, the CRRM group had significantly higher proportions of patients aged ≤50 years (60.0% vs 42.9%, P = 0.038) and full-time workers (54.4% vs 32.9%, P = 0.021), and a lower proportion of smokers (1.1% vs 8.6%, P = 0.009). In decision-making, the CRRM group demonstrated greater influence from physician opinions (84.3% vs 68.3%, P = 0.020), higher anxiety regarding new breast cancer development (88.8% vs 70.3%, P = 0.004), and greater expectations for survival improvement (88.6% vs 61.9%, P < 0.001). Conversely, the CRRM group showed lower concerns about surgical complications (38.9% vs 61.9%, P = 0.005), resistance to removing healthy breasts (47.8% vs 74.6%, P = 0.001), anxiety about physical function limitations (32.2% vs 56.2%, P = 0.003), and perceived time burden of postoperative recovery (54.4% vs 70.8%, P = 0.039). Conclusions: This represents the first large-scale study examining factors influencing CRRM decision-making in Japanese patients with breast cancer harboring BRCA1/2 PV. CRRM uptake was strongly influenced by younger age, employment status, physician opinions, and psychological factors, providing important implications for individualized decision-making support. Factors influencing the decision for contralateral risk-reducing mastectomy in japanese patients with breast cancer harboring brca1/2 pathogenic variants. Characteristic CRRM Group Non-CRRM Group P-value Age ≤50 years 60.0% 42.9% 0.038 Full-time workers 54.4% 32.9% 0.021 Current smokers 1.1% 8.6% 0.009 Influenced by physician opinion 84.3% 68.3% 0.020 Anxiety regarding new breast cancer 88.8% 70.3% 0.004 Expectation for survival improvement 88.6% 61.9% <0.001 Concerns about surgical complications 38.9% 61.9% 0.005 Resistance to removing healthy breasts 47.8% 74.6% 0.001 Anxiety about physical function limitations 32.2% 56.2% 0.003 Perceived time burden of recovery 54.4% 70.8% 0.039
Disparities in incidence and stage at presentation of hepatocellular carcinoma: A SEER-based study of disaggregated AANHPI populations.
e13734 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in the United States. The Asian American, Native Hawaiian, and Pacific Islander (AANHPI) population bears a disproportionately high burden of HCC compared to non-Hispanic White (NHW) populations, driven in part by a higher prevalence of hepatitis B infection, variable access to surveillance, and differences in liver disease etiology. AANHPI populations are frequently analyzed as an aggregated racial group despite substantial heterogeneity across subgroups. This has previously been shown to mask inequities. We examined disparities in HCC stage at presentation using disaggregated AANHPI subgroups within the Surveillance, Epidemiology, and End Results (SEER) program. Methods: We conducted a retrospective, population-based study using SEER Data from 17 registries (2000–2022). Race and ethnicity were analyzed using disaggregated categories, with NHW patients as the reference. Stage at diagnosis was modeled as an ordinal outcome (localized, regional, distant). Ordinal logistic regression estimated adjusted odds ratios (AORs) and 95% confidence intervals, adjusting for age, sex, median household income, and rural versus urban residence. Higher AORs indicated greater odds of advanced-stage disease. Due to limited population denominators, incidence rates were calculated with aggregated AANHPI populations. Results: Aggregate AANHPI populations had a higher incidence of HCC (9.4 per 100,000) than NHW patients (3.8 per 100,000). In adjusted analysis, race and ethnicity were significantly associated with stage at presentation. Compared with NHW patients, Non-Hispanic Black patients had lower odds of advanced-stage disease, while Hispanic White patients had higher odds. Among AANHPI subgroups, Chinese and Vietnamese patients had higher odds of advanced-stage presentation, while Filipino, Laotian, and Pacific Islander patients had lower odds. Conclusions: In this SEER-based analysis, race and ethnicity were independently associated with stage at presentation of HCC. Disaggregation of AANHPI populations revealed heterogeneity that would otherwise be obscured in aggregate analyses. These findings underscore the need for subgroup-specific surveillance and prevention strategies to reduce disparities and combat inequities in advanced-stage HCC diagnosis. Association between race/ethnicity and advanced stage at diagnosis. Race/Ethnicity Adjusted Odds Ratio 95% CI p-value Black 0.88 0.85–0.91 <0.001 Hispanic White 1.1 1.07–1.14 <0.001 American Indian/Alaska Native 1.11 0.99–1.23 0.067 Chinese 1.17 1.10–1.25 <0.001 Vietnamese 1.07 1.01–1.15 0.029 Filipino 0.92 0.85–0.99 0.029 Laotian 0.72 0.59–0.89 0.002 Pacific Islander 0.78 0.66–0.92 0.004 Other Asian American 1.20 1.05–1.37 0.008 *Other AANHPI subgroups without statistical significance.
CHRONO: A randomized phase II trial of the chronology of surgery after neoadjuvant chemotherapy for ovarian cancer.
5505 Background: In patients treated for advanced ovarian cancer not suitable for complete primary surgery, interval surgery after three courses of neoadjuvant chemotherapy (NAC) has been considered standard management since the EORTC randomized trial published in 2010 (NCT00003636, DOI: 10.1056/NEJMoa090880). Delaying surgery after six courses of NAC in highly chemosensitive patients amenable to complete surgery after 3 cycles remains controversial. CHRONO is a multicenter, randomized phase II trial addressing this question (NCT03579394). Methods: Patients treated for a stage IIIB-IVA high grade epithelial ovarian cancer by NAC and amenable to complete surgery after 3 cycles were randomized (1:1) to either complete surgery followed by 5 cycles of chemotherapy (control arm: C) or an additional 3 cycles of NAC followed by complete surgery then 2 cycles of chemotherapy (experimental arm: E). Maintenance treatment was administered according to standard of care. Primary endpoint was disease free survival (DFS) defined as the time from randomization until the date of disease progression or second cancer or death from any cause. The study was designed to detect an improvement in median (m) DFS from 10 months to 17 months (HR=0.59) with a 85% power and 2-sided α=0.05. Main secondary endpoints were Pathological complete response (CC0) rate, post operative morbidity and mortality, quality of life (QOL) and overall survival (OS). Results: Between 18/10/2018 and 23/04/2024, 209 patients (median age: 69 years) were randomized to arm C (n=103) or E (n=106). Median total number of cycles of NAC was 7 (5-9) and 8 (3-9) in arm C and E .CC0 rate was 83.2% vs 90%. After a median follow up of 40.4 months, mDFS was 20.2 months (95%CI: 18.2-23.6) in arm C vs 23.4 (19.0-30.4) in arm E (Log-rank test p=0.48, HR: 0.88 (95%CI: 0.63-1.24). The longitudinal analysis of QoL found no significant differences between the two arms, however, social functioning, insomnia, and sexuality showed a trend toward further improvement (≥5 points) in arm E. Major postoperative complication rates within 30 days were 5% and 11% in arm C and E, (p=0.11) , with no death within 30 days after surgery. Conclusions: CHRONO is the first randomized trial addressing the clinical impact of delayed surgery after 6 courses of NAC in first line treatment of advanced ovarian cancer. No statistically significant difference was shown between the two arms of the study considering DFS, severe morbidity, mortality or QoL. New trials are needed for a better understanding of this alternative to interval surgery in highly chemosensitive advanced ovarian cancer patients. Clinical trial information: NCT03579394 .
Treatment sequencing after adjuvant treatment failure in patients with melanoma: A retrospective cohort study.
e21540 Background: Despite risk reduction for recurrence with adjuvant immune checkpoint inhibitors (ICI) and targeted therapy (TT) in resected stage IIB–III melanoma, the optimal treatment sequence in post-adj. relapse setting is unclear. Methods: Single-center retrospective cohort of pts with AJCC IIB–III cutaneous melanoma who relapsed after starting adj. treatment. The objective was to characterize treatment patterns of post-adj. relapse and to examine how treatment sequencing affects survival. Outcomes measured were recurrence-free survival 2 (RFS2), progression-free (PFS), time to second progression/relapse after adj. treatment start (TTSP) and overall survival (OS). RFS2 was time from 1 st resectable relapse to 2 nd relapse. PFS was time from 1 st irresectable relapse after start of adj. therapy to 2 nd progression. Sequencing groups were ICI→ICI rechallenge (A), ICI→TT switch (B), TT→ICI switch (C) and TT→TT rechallenge (D). Prespecified subgroup analyses assessed relapse resectability, BRAF status and relapse ON or OFF adj. treatment. Results: 306 pts received adj. treatment, 243 pts with stage III, from which 126 BRAF mut tumors, and 63 pts stage II. 88 pts recurred, 57 ON and 31 OFF adj. treatment, and 78/88 were treated with ICIs. 43/88 pts developed resectable relapse and 41 received a second adj systemic treatment (Table). 16/41 subsequently relapsed, but neither adj. treatment-related factors (type of adj. treatment, site of relapse) nor sequencing strategy significantly affected RFS2. 45 pts with irresectable relapse received systemic therapy only, 29 in group A, 11 in group B and 5 in group C. In 5/29 pts in group A second-line was anti-PD1 mono and in 24/29 anti-PD1+anti-CTLA4. In pts with BRAF mut tumors, treatment switch from ICI to TT derived better PFS than rechallenge. Finally, pts with irresectable relapse occurring during ICI adj. treatment demonstrated prolonged TTSP when subsequent treatment was TT, but not ICI rechallenge. Median OS was not reached for the total cohort. Conclusions: Relapse ON or OFF adj. treatment, type of relapse and subsequent treatment (ICI or TT) deemed significant predictors. Treatment switch after progression under ICI may improve survival of pts with BRAF mut melanoma and adverse prognostic features, such as early and irresectable relapse, possibly informing future therapeutic decision-making. RFS2 and PFS in pts with relapse after adj. treatment start and treatment sequencing from adj. to post-relapse setting. Resectable Irresectable Pts (n) / Events (n) (%) p-value Pts (n) / Events (n) (%) p-value Total 41 / 16 45 / 29 Treatment Sequencing ICI → ICI 20* / 8 (40) 0.610 29 / 21 (72.4) 0.06 ICI → TT 16 / 5 (31.3) 11 / 4 (36.4) TT → ICI 4 / 3 (75) 5 / 4 (80) TT → TT 1 / 0 (0) - Class of subsequent treatment post-adjuvant relapse Switch 20 / 8 (40) 0.852 16 / 8 (50) 0.05 Rechallenge 21 / 8 (38.1) 29 / 21 (72.4) *19 pts subsequent anti-PD1 mono and 1 anti-CTLA4. P-value from log-rank test.
Comprehensive oncology research mapping in Morocco: Patterns, quality, and unmet needs.
e23185 Background: The Moroccan oncology research landscape is constrained by limited infrastructure, uneven capacity and poorly characterised alignment with clinical needs. To move beyond simple counts, we performed a comprehensive, reproducible bibliometric analysis of Moroccan-affiliated oncology publications to quantify temporal trends by study design and speciality, evaluate methodological quality, and map publication gaps against the national cancer burden to inform capacity building, collaboration, and research prioritisation. Methods: The study was conducted per PRISMA-S-compliant systematic search of PubMed, Scopus and WoS for oncology-only records dated 1st January 2000 - 31st December 2025. Original peer-reviewed research, editorials, letters, and conference abstracts with > 1 author affiliated to a Moroccan institution were included. Interrater reliability was quantified using Cohen’s κ. Methodological quality and risk of bias were assessed using the Newcastle-Ottawa Scale (NOS) for observational studies and RoB 2 for randomised trials. Temporal trends were evaluated with Cochran-Armitage tests and segmented regression to detect inflection points, and descriptive summaries were stratified by period, speciality, and centre. Results: 1150 peer-reviewed articles met the inclusion criteria with an interrater screening reliability of 0.86 (95% CI: 0.83–0.89) for title/abstract and 0.91 (95% CI: 0.88–0.94) for full-text; NOS of 6.2 (SD 1.4). Annual output increased from ~ 2 articles in 2000 to ~ 110 articles in 2025 (CAGR = 14%, p < 0.001), with inflection points in 2010 (National Cancer Plan) and 2020 (COVID-19), a transient decline in 2017-2019 and recovery post-2020. Case series dominate the Moroccan oncology literature 410 (33.9%), followed by retrospective studies 285 (23.6%), with relatively few clinical trials 61 (5%), translational research 54 (4.5%), and systematic reviews 38 (3.1%); with a modest but increasing proportion of clinical trials (p = 0.046) and systematic reviews (p = 0.049) in the last decade as for translational research after 2010 (p = 0.02). Research was concentrated around breast 312 (30%), followed by gastrointestinal 200 (19%), while radiation oncology represents 105 (10%). Most studies were monocentric 412 (34.1%), diagnosis- 398 (32.9%) and treatment-orientated 372 (30.8%), with relatively fewer epidemiology 87 (7.2%); concentrated in Rabat and Casablanca public academic institutions 752 (65%). External funding was reported in 21.4% of studies; 41.3% were published open access, with the mean number of authors per article 5.2. Conclusions: Moroccan research output has grown substantially, showing alignment with national rises in breast and gastrointestinal cancer incidence but remains concentrated in a few centres and dominated by single-centre, descriptive studies with limited randomised, multicentre, palliative care, and survivorship research.
Immune-related thyroid dysfunction and overall survival in metastatic colorectal cancer treated with pembrolizumab: A real-world TriNetX analysis.
e15558 Background: Immune checkpoint inhibitors (ICIs) are standard therapy for MSI-H/dMMR metastatic colorectal cancer (CRC), yet reliable on-treatment biomarkers of benefit are lacking. Thyroid dysfunction is a common immune-related adverse event (irAE) associated with ICIs and has been linked to improved outcomes in non-gastrointestinal cancers; however, it remains unclear whether this association holds in metastatic CRC. Methods: Using the TriNetX Research Network, we conducted a retrospective cohort study of adults with metastatic colorectal cancer treated with pembrolizumab from 2014–2024. Patients were divided into two groups based on whether they developed new-onset thyroid dysfunction after starting pembrolizumab. Thyroid dysfunction was defined by new thyroid ICD-10 diagnoses, thyroid medication initiation, or elevated TSH within 16 weeks of treatment initiation, excluding patients with pre-existing thyroid disease. Propensity score matching (1:1) was performed to balance baseline clinical differences between groups. Overall survival (OS) was assessed using Kaplan–Meier and Cox models. A 12-week landmark analysis was performed to reduce potential immortal time bias. Results: Among 2,477 eligible patients, 190 (7.7%) developed thyroid dysfunction after pembrolizumab initiation. After propensity score matching, 380 patients were included (190 per cohort). The matched cohort had a mean age of 64 years, was predominantly female (57%) and White (82%), with colon primaries in 67%. Baseline comorbidities were balanced between groups (Table 1). When comparing survival between patients who did versus did not develop thyroid dysfunction, those who developed thyroid dysfunction had significantly improved OS in the primary matched analysis (median OS 780 vs 513 days; 5-year OS 44% vs 29%; log-rank p = 0.017), corresponding to a lower risk of death (HR 0.71; 95% CI 0.54–0.94). In the 12-week landmark analysis, survival remained numerically higher in the thyroid dysfunction group (5-year OS 47% vs 36%), although the difference was no longer statistically significant (HR 0.87; 95% CI 0.63–1.19; p = 0.37). Conclusions: In this large real-world cohort of metastatic CRC patients treated with pembrolizumab, patients who developed immune-related thyroid dysfunction experienced longer overall survival than those who did not. These findings support thyroid irAEs as a potential on-treatment biomarker of benefit in MSI-H/dMMR CRC and warrant further validation. Baseline characteristics in matched cohort. Variable Thyroid Dysfunction (n=190) No Thyroid Dysfunction (n=190) Demographics Age, mean (SD) 64 (13) 64 (12) Female sex, % 60 57 White race, % 81 84 Primary tumor site, % Colon 69 66 Rectum/rectosigmoid 31 34 Comorbidities, % Diabetes mellitus 20 20 Chronic kidney disease 13 15 Coronary artery disease 15 15 Heart failure 7 10 COPD 10 10
Racial disparities and sex differences in the incidence of HPV-positive cancers: A SEER database study.
e22619 Background: Human papilloma virus (HPV) is a viral infection that can cause malignant changes in infected tissues and is linked with multiple cancers affecting both males and females. The incidence and outcomes of HPV-positive cancer differ by cancer type, race and sex This study evaluates differences in HPV-positive cancer incidence and mortality across racial subgroups with additional evaluation of sex-based differences. Methods: A retrospective analysis of HPV-positive cancers was conducted using the Surveillance, Epidemiology, and End Results (SEER) database from 2018 to 2022. Included cancer types were tonsil, tongue, cervical, oropharyngeal, vulvar, vaginal, anal, and penile cancers. Descriptive statistics were used to summarize patient characteristics by sex and race. Chi-square test was performed to evaluate the association of race and sex with cancer incidence and mortality. Results: Among 5,472 HPV-positive cancers, the most common sites were tonsil (35.6%), tongue (29.6%), cervical (18.8%), and oropharyngeal (10.3%). Males comprised 66% of cases. Significant sex differences were observed for tonsil (χ² = 492.7, p < 0.001) and tongue cancers (χ² = 606.7, p < 0.001), demonstrating clear male predominance. Overall incidence differed by race (χ² = 42.9, p = 0.003), with White patients representing the majority across all sites. Cervical cancer was the only cancer in site-specific analysis showing a statistically significant racial disparity (White 72.9%, Black 14.0%, API* 11.2%, AIAN* 1.9%; p = 0.004), while differences for other cancers were not significant, likely due to smaller sample sizes in racial subgroups. A total of 548 deaths occurred, most frequently from tongue and tonsil cancers, with no significant mortality differences by race (χ² = 28.48, p = 0.127). Conclusions: While overall racial differences were observed, only cervical cancer demonstrated a significant disparity in site-specific analysis, highlighting the need for targeted prevention strategies. Moreover, HPV-positive cancers showed a clear male predominance. This may be explained by lower vaccination rates and differences in exposure. These findings support the need for broad HPV vaccination programs that include all populations, along with continued prevention and education to address disparities and improve outcomes. Incidence and mortality of hpv-positive cancers by race. Cancer Type Total Cases White (%) Black (%) API (%) AIAN (%) p-value Tongue 1,618 91.9 4.9 2.5 0.7 0.774 Tonsil 1,950 91.5 5.2 2.5 0.8 0.232 Cervix Uteri 1,029 72.9 14 11.2 1.9 0.004 Oropharynx 563 91.1 5 2.3 1.6 0.567 Vulva 225 88.4 7.6 2.7 1.3 0.876 Vagina 64 84.8 7.6 7.6 0 0.864 Anus / Anal / Anorectum 17 73.7 26.3 0 0 0.153 Penis 6 50 33.3 16.7 0 0.153 Overall 5,472 — — — — 0.003 API = Asian/Pacific Islander; AIAN = American Indian/Alaska Native. P-values were calculated using chi-square tests; p < 0.05 was considered statistically significant.
Genomic landscape and patient demographics in endocervical adenocarcinoma: Insights from the AACR Project GENIE.
5531 Background: Endocervical Adenocarcinoma (EA) makes up 20-25% of cases of cervical cancer, and has an 80-90% association with HPV infection.Treatment outcomes of EA have significant disparities: cases of EA arising from HPV have a much higher survival rate than survival rate for non-HPV-related EA. While survival outcomes with modern treatments such as radical hysterectomy are positive for HPV associated cases, increasing frequency of diagnosis and treatment heterogeneity, along with variability in diagnostic timing emphasize the need to define molecular drivers for targeted therapies. Using the AACR GENIE database, this study characterizes EA's mutational landscape to identify genetic markers and therapeutic targets. Methods: The American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange database was accessed using cBioPortal (v18.0-public) on November 29, 2025 to identify all patients with EA. The most common somatic point mutations, demographic correlations, and mutual exclusivities were analyzed using a two-sided T-test and non-parametric tests, with Benjamini-Hochberg false discovery rate correction. Results: This study included 257 samples from 245 patients. The patient cohort was 61.2% non-Hispanic and 13.9% Hispanic. The cohort was 10.2% Asian, 61.2% White, 4.1% Black, and 12.2% unknown/other patients. A majority of the samples used were obtained from primary tumors (60.3%), while 80 (31.1%) were from metastatic tumors. The most common mutations were identified in PIK3CA (n=68; 26.4%), TP53 (n=51; 19.8%), KRAS (n=41; 15.9%), SMAD4 (n=37; 14.4%), ERBB2 (n=35; 13.6%), ARID1A (n=32; 12.4%), KMT2D (n=26; 10.1%), GNAS (n = 26; 10.1%), ERBB3 (n = 23; 8.9%), KMT2C (n = 21; 8.1%), STK11 (n = 20; 7.8%), MED12 (n = 18; 7.0%), and ATM (n = 17; 6.6%). Several mutations were uniquely observed in Black patients, HFE,RAD54B, ADAMTS20, ADGRB3, and BCL3, with n = 1 for each observed mutation. Among exclusively primary tumor samples, the HSD3B2 mutation was identified (n = 1). RXRA (p < 0.05), TBX3, and TET1 (p>0.05) mutations with n = 3 each were exclusively observed in the metastatic samples. Frequencies of recurrent alterations in key genes such as KRAS (15.2%) and PRKDC (7.5%), showed substantial overlap and no significant differences between the groups. No significant mutual exclusivity patterns were identified among profiled genes. Conclusions: To the best of our knowledge, this is the first GENIE database analysis of EA, addressing a significant knowledge gap regarding its genomic landscape. These findings suggest PIK3CA and TP53 as targets for targeted inhibitors or immunomodulators. Further research is warranted to validate these genomic associations and translate them into precision medicine therapeutics for patients with endocervical adenocarcinoma.
Fixed-duration subcutaneous (SC) mosunetuzumab (Mosun) in elderly/unfit patients with previously untreated diffuse large B-cell lymphoma (DLBCL): Interim analysis and patient-reported outcomes (PROs) from the phase 2 MorningSun study.
7029 Background: Mosun, a CD20xCD3 T-cell engaging bispecific antibody, is approved for relapsed/refractory follicular lymphoma after ≥2 prior lines of therapy. We report an interim analysis and PROs with Mosun SC in elderly/unfit patients with previously untreated DLBCL. Methods: MorningSun (NCT05207670) is a Phase 2, basket study of Mosun SC in patients with B-cell non-Hodgkin lymphoma. In the DLBCL cohort, eligible patients (aged ≥80 years, or 65–79 years and ineligible for chemoimmunotherapy) received outpatient Mosun SC: Day (D) 1 (5 mg), D8 (45 mg) and D15 (45 mg) of Cycle (C) 1, then 45 mg on D1 for up to 17 21-day cycles. Primary endpoint was progression-free survival (PFS) rate at 24 months. Other endpoints included overall survival (OS), objective response rate (ORR), complete response (CR) rate, change from baseline (CfB) in lymphoma symptoms as assessed by the Functional Assessment of Cancer Therapy-Lymphoma subscale (FACT-Lym LYMS; higher scores indicate improvement, a ≥3-point increase is considered clinically meaningful) and safety. Results: Forty-nine patients were enrolled, primarily from community sites (n=34). Median age was 83 years (range: 71–101). International Prognostic Index was 3–5 in 53.1% patients and 18.4% of patients had bulky disease. As of February 10, 2025, the median duration of follow-up was 12.5 months (range: 1.4–30.8). PFS and OS rates at 12 months were 71.3% (95% confidence interval [CI]: 54.8–82.7) and 74.7% (95% CI: 58.5–85.4), respectively. ORR was 73.5% and CR rate was 59.2%. Completion rates for FACT-Lym LYMS were ≥95% at baseline and remained ≥87% at each subsequent timepoint. Patients reported improvement in health-related quality of life (HRQoL) over time, demonstrated by increased mean CfB (standard deviation [SD]) in FACT-Lym LYMS scores: C4D1, 5.1 (9.8); C9D1, 5.6 (11.8); C17D1, 9.8 (11.4). Clinically meaningful improvements in lymphoma symptoms were observed in 53.1% (95% CI: 38.3–67.5) of patients. The most common any-grade adverse event (AE) was injection site reaction (53.1%; all Grade [Gr] 1/2). Gr 3/4 AEs were reported in 65.3% of patients and 8.2% experienced a Gr 5 AE (no Gr 5 AEs were Mosun related, per investigator assessment). Serious AEs occurred in 42.9% of patients. Infection AEs occurred in 49.0% of patients (Gr 1: 4.1%; Gr 2: 28.6%; Gr 3: 16.3%) and resolved in 91.7%. Cytokine release syndrome occurred in 12.2% of patients (Gr 1: 10.2%; Gr 2: 2.0%; all resolved). Updated data with around one additional year of follow-up will be presented. Conclusions: Mosun SC showed promising efficacy with manageable safety in elderly/unfit patients with previously untreated DLBCL in an outpatient setting. Clinically meaningful improvements in lymphoma symptoms suggest that Mosun SC improves aspects of HRQoL in this population. Clinical trial information: NCT05207670 .
FIRE-4 (AIO KRK-0114): Efficacy of third-line rechallenge with cetuximab versus investigator’s choice in relation to the interval between initial and third-line anti-EGFR therapy.
3575 Background: The randomized FIRE-4 study evaluated the effect of cetuximab rechallenge versus investigator’s choice in the 3 rd -line treatment of patients (pts) with RAS-wildtype (RAS-wt) metastatic colorectal cancer (mCRC). The present analysis focuses on the time between the end of initial anti-EGFR-based treatment and start of 3 rd -line therapy (TIS-3) as a potential predictor of response. Methods: In FIRE-4, all pts received induction therapy with FOLFIRI plus cetuximab. After 1 st PD, an anti-EGFR-free “window therapy” was recommended. At diagnosis of 2 nd PD, pts who had responded to induction therapy were re-evaluated for RAS status and, after exclusion of RAS mutations, were offered randomization to either rechallenge with cetuximab plus chemotherapy or investigator’s choice. Overall survival in 3 rd -line (OS-3) was evaluated as a primary endpoint. Results: Of the 87 pts entering 3 rd -line treatment in FIRE-4, 45 received (FOLF)IRI plus cetuximab (rechallenge arm), and 42 received investigator’s choice (standard arm). Numerically superior outcome parameters regarding ORR-3 (OR 2.70), PFS-3 (HR 0.87) and OS-3 (HR 0.86) were observed in the rechallenge arm, without, however, reaching the level of statistical significance. To evaluate the relevance of TIS-3, we focused on the median (13.8 months) and the first quartile (9.0 months). Based on these cut-off values, treatment effects were evaluated in pts with longer and shorter TIS-3 intervals (see Table). Conclusions: Longer TIS-3 intervals were associated with longer survival times in 3 rd -line treatment. This observation was particularly true for pts receiving cetuximab rechallenge, but also for those receiving investigator’s choice. Clinical trial information: NCT02934529 . Treatment arm N Interval PFS (mo) HR OS (mo) HR FOLF(IRI) + Cetuximab 21 > 13.8 mo 7.4 0.475P=0.019 20.0 0.639P=0.187 24 < 13.8 mo 4.1 12.6 34 > 9.0 mo 5.9 0.680P=0.274 19.6 0.601P=0.173 11 < 9.0 mo 4.0 10.8 Investigator’s choice 23 > 13.8 mo 5.6 0.772P=0.415 16.2 0.516P=0.055 19 < 13.8 mo 4.4 12.2 32 > 9.0 mo 5.5 0.690P=0.313 16.9 0.458P=0.042 10 < 9.0 mo 4.5 7.8
A multicenter, open-label, single-arm, dose-finding and -expansion phase 1b/2 study to evaluate the safety and tolerability of nesuparib (JPI-547) in combination with irinotecan as a third-line and beyond therapy for recurrent or metastatic gastric cancer.
TPS4247 Background: Recurrent or metastatic gastric cancer (GC) progressing after standard first- and second-line therapies has limited treatment options, leading to poor survival outcomes. Nesuparib is an orally available, next-generation dual inhibitor of tankyrase and poly(ADP-ribose) polymerase (PARP). It disrupts DNA damage repair and induces a “BRCAness” phenotype by modulating Wnt/β-catenin and Hippo signaling pathways. In a previous phase I study, nesuparib monotherapy demonstrated promising clinical activity with an overall response rate (ORR) of 28.2% and a disease control rate (DCR) of 64.1%. Preclinical models have shown synergistic anti-tumor efficacy when nesuparib is combined with irinotecan. This study aims to evaluate the safety, tolerability, and preliminary efficacy of nesuparib plus irinotecan in patients with advanced GC. Methods: This multicenter, open-label, single-arm, dose-finding and expansion phase 1b/2 study enrolls adults with histologically confirmed recurrent or metastatic GC or gastroesophageal junction adenocarcinoma who have progressed after ≥2 prior systemic therapies and have ECOG PS 0–1, measurable disease per RECIST v1.1, and UGT1A1 wild-type genotype. Phase 1b follows a standard 3+3 design with multiple predefined dose levels. Each dose level consists of a fixed combination of (1) a specific nesuparib dose (25–100 mg) administered orally once daily on either a 5-days-on/2-days-off or 3-days-on/4-days-off schedule and (2) irinotecan administered every 2 weeks at 100, 120, or 150 mg/m². The dose-limiting toxicity evaluation window is 28 days. Phase 2 enrolls patients at RP2D to further evaluate anti-tumor activity. The primary endpoint is objective response rate. Secondary endpoints include safety, disease control rate, duration of response, progression-free survival, time to response, and overall survival. Exploratory objectives include population pharmacokinetics, pharmacodynamic biomarkers, homologous recombination deficiency profiling, and circulating tumor DNA analyses. Approximately 43–49 patients are planned (18–24 in phase 1b; 25 in phase 2). Treatment continues until disease progression, unacceptable toxicity, or study withdrawal. Clinical trial information: NCT07364422 .
Spatial immune profiling to identify GPNMB as a mediator of immune suppression that limits response to PD-1 blockade in TNBC.
2582 Background: Breast cancer (BC) is the leading cause of female cancer-related deaths. Triple-negative BC (TNBC), accounting for ~25% of BC-related deaths, carries the poorest prognosis due to limited targeted therapies and the significant, yet still modest overall, benefit achieved with immune checkpoint blockade (ICB). Identifying drivers of immune evasion is essential to expand patient benefit from ICB. Glycoprotein-NMB (GPNMB) is highly expressed in TNBC and associated with immune suppression, metastasis, and poor clinical outcomes. However, its role in shaping the TNBC immune landscape and contributing to ICB resistance remains unclear. We investigated the impact of tumor-derived GPNMB on the tumor immune microenvironment and whether its inhibition enhances ICB efficacy. Methods: Imaging mass cytometry, a high-dimensional spatial proteomics platform enabling simultaneous single-cell and spatial analysis of intact tissue, was used to map the immune landscape of GPNMB-proficient and -deficient EO771 tumors. Therapeutic relevance was evaluated by combining GPNMB loss with anti-PD-1 treatment. Associations between tumor GPNMB expression, immune infiltration, and clinical outcomes were evaluated in human TNBC tumors. Results: GPNMB loss in mammary tumor cells significantly impaired tumor growth in syngeneic, but not athymic (T cell-deficient) mice, suggesting a T cell-dependent mechanism. GPNMB KO tumors showed increased immune infiltration, notably GZMB + /PD-1 + CD8 + T cells, and enhanced formation of stimulatory CD8 + T cell/CD4 + T cell/CD86 + macrophage immune triads. GPNMB loss impaired tumor engraftment in an adoptive OT-1 T cell transfer model and significantly improved response to anti-PD-1 therapy in two independent TNBC models, reducing breast tumor growth and lung metastasis. Therapeutic benefit was accompanied by increased intratumoral T cell infiltration and functional reinvigoration, reflected by increased GZMB + CD8 + T cells. In human TNBC, high tumor GPNMB expression was associated with reduced intratumoral T cell infiltration and poorer clinical outcomes. GPNMB high tumors exhibited reduced infiltration of CD8 + , GZMB + CD8⁺, and CD4 + T cells and were enriched in immune-desert and margin-restricted phenotypes. In contrast, GPNMB low tumors showed increased CD8 + T cell/CD4 + T cell/macrophage triads, indicating enhanced immune activation. Together, these data show that elevated GPNMB expression in human TNBC is associated with T cell exclusion, and an immune-excluded tumor architecture. Conclusions: Our findings identify tumor-derived GPNMB as a clinically relevant mediator of T cell exclusion and suppression in TNBC. Therapeutic targeting of GPNMB in combination with PD-1 blockade may enhance the efficacy of ICB and expand the subset of TNBC patients who derive meaningful clinical benefit, ultimately improving clinical outcomes.