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Gene and isoform transcriptomics to uncover distinct immune and signaling programs across sarcoma subtypes.
e23538 Background: Sarcomas are heterogeneous malignancies arising from diverse mesenchymal lineages. While transcriptomic profiling has revealed distinct signaling dependencies, the contribution of alternative splicing and transcript isoform usage to sarcoma heterogeneity remains poorly defined. We investigated how gene-level and isoform-level transcriptomics jointly shape the molecular and immune landscapes of angiosarcoma (AS, n = 26) and leiomyosarcoma (LMS, n = 11). Methods: Bulk RNA sequencing from a multi-sarcoma cohort was analyzed at both gene and isoform resolution. Unsupervised clustering was performed, followed by cluster annotation using: (i) protein–protein interaction (PPI) network analysis, (ii) immune cell deconvolution using xCell 2.0. Cluster-level molecular programs were integrated to define functional and immune states. Results: Three molecular clusters with distinct functional, immune, and signaling characteristics were identified. Cluster 1 was enriched for AS of the liver, breast, and heart; Cluster 2 comprised head and neck AS; and Cluster 3 was specific to LMS. PPI analysis revealed cluster-specific biological programs: Cluster 1 was enriched for complement activation, endothelial development, and chemokine signaling; Cluster 2 for keratinization-related structural processes; and Cluster 3 for muscle differentiation and stress-response programmes. Immune profiling demonstrated divergent tumor immune microenvironments. Cluster 1 showed enrichment of PD-1–high CD8⁺ T cells and plasma cells, consistent with an immune-infiltrated but exhausted phenotype. Cluster 2 exhibited broad enrichment of adaptive immune populations, including CD4⁺ T cells, Th1/Th17 cells, B cells, and regulatory T cells, indicative of an immune-inflamed and functionally active state. In contrast, Cluster 3 demonstrated minimal immune cell enrichment, consistent with an immune-cold or immune-excluded phenotype. Isoform-level analysis revealed organ-specific patterns within AS. Each primary site demonstrated higher expression of distinct isoforms within its corresponding cluster. Notably, breast and cardiac AS in Cluster 1 preferentially expressed canonical oncogenic isoforms associated with DNA repair and genome stability, cell-cycle regulation, apoptosis, and transcriptional control, compared with liver AS. Conclusions: This integrative gene- and isoform-level transcriptomic analysis identifies functionally distinct sarcoma subtypes driven by differences in immune contexture and signaling pathway activity. Isoform-specific expression patterns further highlight potential therapeutic vulnerabilities, particularly in primary breast and cardiac AS. These findings provide a framework for functional stratification of sarcomas and support the incorporation of isoform-level analyses into future translational and biomarker-driven studies.
What is left in pMMR/MSS BRAF V600E metastatic colorectal cancer (mCRC)? Prognostic role of tumor sidedness and molecular co-mutations.
e15608 Background: BRAF V600E-mutated pMMR/MSS mCRC has poor prognosis. However, real-world outcomes are heterogeneous and have recently improved with the introduction of front-line BRAF inhibitor-based combinations. We investigated the prognostic role of clinical and molecular features in this subset of mCRC, focusing on tumor sidedness and recurrent co-mutations. Methods: This retrospective single-center study included consecutive patients (pts) with pMMR/MSS BRAF V600E mCRC treated between September 2010 and September 2025 at the Veneto Institute of Oncology-IRCCS. Overall survival (OS) was estimated using Kaplan-Meier method and compared by log-rank test. Cox proportional hazards models were used for uni- and multivariable analyses. Next-generation sequencing data were available in a molecularly profiled subcohort. Results: Among 200 pts, 83 (42%) had left-sided primary tumor. Median age was 64 years (IQR 53 - 71) and ECOG PS was 0 in 51% of pts. Primary tumor was resected in 77% and disease presentation was synchronous in 74% of pts. Liver metastases (mts) were present in 64% of pts. Left-sided tumors occurred at a younger age than right-sided (median 58 vs 68 years; p = 0.001) and more frequently presented as early-onset disease (≤50 years: 33% vs 14%; p = 0.001). After median follow-up of 84.7 months (mo), median OS (mOS) in the cohort was 18.6 mo. Right-sided tumors showed significantly longer OS compared with left-sided tumors (22.6 vs 14.8 mo; p = 0.019). Multivariable analysis identified left-sided tumor (HR 1.54, 95% CI 1.12–2.08; p = 0.007), synchronous disease (HR 1.47, 95% CI 1.01–2.12; p = 0.042), unresected primary tumor (HR 1.49, 95% CI 1.03–2.17; p = 0.036), and ECOG performance status ≥1 (HR 1.37, 95% CI 1.01–1.85; p = 0.044) as independent factors associated with worse OS. Liver mts and early-onset disease had no prognostic role in univariable analyses and were not included in multivariable model. Among 80 molecularly profiled pts, BRAF V600E was confirmed in 100% of pts (n = 80). Frequent co-mutations included TP53 (76%), APC (36%), and SMAD4 (20%), RNF43 (17%), PIK3CA (15%), PTEN (15%), IRS2 amplification (11%) and MYC amplification (11%). PIK3CA and SMAD4 mutations were enriched in left-sided tumors (26% vs 7%, p = 0.014; 35% vs 11%, p = 0.008). No significant gene enrichment was observed in early vs average onset tumors. PIK3CA mutations were associated with worse OS compared with wild-type tumors (19.0 vs 27.2 mo; HR 2.32, 95% CI 1.22–4.04; p = 0.010). No significant prognostic impact was observed for APC, TP53, SMAD4, RNF43, PTEN, MYC and IRS2 too. Conclusions: Tumor sidedness is an independent prognostic factor in pMMR/MSS BRAF-mutant mCRC, with worse outcomes observed in left-sided tumors. PIK3CA co-mutations are enriched in left-sided disease and may contribute to unfavorable prognosis, suggesting their potential role in future stratification strategies.
Neoadjuvant dalpiciclib combined with letrozole and dual HER2 blockade in HR+/HER2+ breast cancer: First-stage results of the HELEN HER2 017 trial.
1054 Background: Triple-positive breast cancer (TPBC; HR+/HER2+) represents a distinct subtype with suboptimal responses to conventional neoadjuvant chemotherapy combined with anti-HER2 therapy, with reported pCR rates of only 26%–43.8%, and is associated with significant treatment-related toxicities 1-3 . This highlights an urgent need for more effective and less toxic therapeutic strategies. We hypothesize that simultaneously targeting ER, HER2, and CDK4/6 pathways may enhance antitumor efficacy while enabling chemotherapy de-escalation. This phase II study investigates a response-guided, chemotherapy-free neoadjuvant regimen using dalpiciclib (a CDK4/6 inhibitor), aromatase inhibitor (AI), and dual HER2 blockade. Methods: This prospective, single-arm, two-stage Simon optimal design study planned to enroll 71 patients. In stage one, 20 patients were enrolled; proceeding to stage two required ≥6 pCRs. The final success threshold is ≥24 pCRs in 71 patients (α=0.05, power=80%, H0: pCR≤25% vs. H1: pCR≥40%). Eligible patients had stage II–IIIa HR+/HER2+ invasive breast cancer. Treatment included oral dalpiciclib (150 mg/day, 3 weeks on/1 week off), oral letrozole (2.5 mg/day; with ovarian suppression if premenopausal), and IV trastuzumab (loading 8 mg/kg, then 6 mg/kg) plus pertuzumab (loading 840 mg, then 420 mg) every 3 weeks. This was a response-adaptive design: after 2 cycles, MRI assessed tumor response. Patients achieving PR (≥30% reduction per RECIST 1.1) continued the same regimen for 6 cycles; non-responders switched to TCHP chemotherapy (docetaxel, carboplatin, trastuzumab, pertuzumab). The primary endpoint was pCR (ypT0/is ypN0) in the all-treated population. Secondary endpoints included ORR, RCB 0-1, EFS, and safety. Results: In the first stage, 20 patients were enrolled. Median age was 48 years (range 34–59). All were ER+ and HER2+ by central review. After 2 cycles, 15 of 20 patients (75%) achieved PR and continued on the dalpiciclib, letrozole, and dual HER2 blockade regimen. Of the 20 patients, 8 achieved pCR, with a rate of 40%. Among the MRI responders who continued the experimental arm, the pCR rate was 40% (6/15). Treatment was generally well-tolerated; the most common adverse events were neutropenia, leukopenia, anemia, and thrombocytopenia. No treatment-related discontinuations or cardiac toxicity of grade 3 or higher were observed. Conclusions: The first stage of this response-guided study met its predefined efficacy threshold (≥6 pCR in 20 patients). The neoadjuvant regimen combining dalpiciclib, an AI, and dual HER2 blockade shows promising pCR rates and a favorable safety profile in TPBC, supporting continued evaluation in the second stage of the trial. Clinical trial information: NCT06276868 .
Relationship between immune-mediated adverse events and clinical outcomes in patients with metastatic melanoma treated with immune checkpoint inhibitors (ICIs): A retrospective real-world analysis.
11144 Background: ICIs targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) revolutionized the treatment landscape for advanced melanoma. However, these agents can cause immune-related adverse events (AEs). Several studies have demonstrated a correlation between AEs and improved clinical outcomes. Understanding the co-occurrence patterns and prognostic implications of immune-related adverse events, as well as the impact of concomitant medications such as antibiotics (ATB), immunosuppressants (IS) and/or corticosteroids (CS), and proton pump inhibitors (PPIs), is crucial for immunotherapy management. In this study, we evaluated the relationship between immune-related toxicity, the use of IS and/or CS and ATB, and progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma treated with ICIs. Methods: Retrospective, analytical, multicenter study of patients (pts) with stage IV melanoma treated with ICIs (ipilimumab/nivolumab, nivolumab or pembrolizumab), between 2014 and 2025. Immune-related adverse events were graded according to CTCAE criteria and categorized as none, grade 1-2 or 3-4, demographic characteristics, use of IS and/or CS, ATB and number of toxicities were obtained from medical records. PFS and OS were estimated using the Kaplan-Meier method and compared using Cox proportional hazards models, with statistical significance set at p < 0.05. Results: Among 364 pts included, 275 (77,4%) experienced AEs. Dermatologic end endocrine toxicities, including rash, pruritus, vitiligo, hypothyroidism and hypophysitis were associated with improved survival outcomes. The results regarding PFS in relation to the presence, grade, and number of toxicities, as well as the use of IS and/or CS and ATB, are described in the table below. OS showed a statistically significant association with toxicity grade, with better OS observed among patients with grade 1–2 toxicity (HR 0.55; 95% CI, 0.35-0.87; P = 0.010), as well as who did not use IS and/or CS (HR 1.84; 95% CI, 1.20-2.82; P = 0,005). PFS showed a trend toward improved outcomes in patients who did not use PPI, without statistical significance due to the small number of pts. Conclusions: Our data show that pts who developed grade 1–2 toxicity and did not receive IS and/or CS experienced improved OS and PFS when treated with ICIs. Pts with a greater number of different toxicities and those who did not use ATB experienced better PFS. Parameter HR for PFS 95% CI p-value Toxicity vs. No Toxicity 0.39 0.29-0.52 <0.001 Degree of toxicity 0 vs. Grade 1+2 0.38 0.28-0.51 <0.001 0 vs. Grade 3+4 0.50 0.35-0.73 <0.001 Number of toxicities 0 vs. 1-2 0.50 0.38-0.67 <0.001 0 vs. 3 or + 0.26 0.17-0.38 <0.001 IS and/or CS vs. No IS and/or CS 1.43 1.05-1.95 <0.022 ATB vs. No ATB 1.53 1.11-2.12 <0.010
Perceptions of Medicaid coverage and care experiences among long-term survivors of childhood cancer: Qualitative interviews from the Childhood Cancer Survivor study (CCSS).
10051 Background: Childhood cancer survivors require lifelong, risk-based follow-up care. Survivors insured by Medicaid may face barriers to coverage and care unique to this type of insurance. We identified barriers and facilitators related to coverage, access to quality primary and specialty care, and survivor-provider interactions among Medicaid-insured survivors. Methods: Between May-November 2024, we conducted 23 in-depth interviews with adult survivors in CCSS currently also enrolled in Medicaid or with Medicaid coverage within the prior two years. Participants were recruited using stratified purposive sampling by state Medicaid expansion status, race/ethnicity, and age group. Interviews were audio-recorded, transcribed, and analyzed using thematic analysis. Results: Participants lived in 10 states (6 expansion, 4 non-expansion), 52% rural. At interview, 91% were enrolled in Medicaid. Mean age was 39 years (median 39; range 28-55); 26% were Hispanic and 35% non-Hispanic Black. Cancer types included blood cancers (n=9), brain tumors (n=7), and other solid tumors (n=7). When asked about maintaining coverage, survivors reported barriers including burdensome application/renewal requirements (e.g., in-person processes, extensive documentation); limited navigation guidance; and coverage instability tied to changes in disability status or income. Facilitators included assistance from knowledgeable staff (e.g., social worker), renewal reminder, and auto-renewal tied to Supplemental Security Income eligibility. Survivors expressed a need for hands-on help with application/renewal paperwork. When asked about care access, survivors reported difficulty finding specialists and primary care providers (PCPs) who accept Medicaid and are equipped to address survivor-specific needs (e.g., implement recommended tests in survivorship care plans), appointment delays, and transportation/geographic barriers. Facilitators included long-term relationships with PCPs and effective PCP–specialist communication. When asked about interactions with providers, survivors valued being heard, clear explanations, adequate visit time, and shared decision-making. However, many reported negative specialist encounters—feeling rushed or dismissed, including when new symptoms were repeatedly attributed to childhood cancer history without clear explanation, undermining trust. Conclusions: Medicaid-insured survivors reported challenges in maintaining coverage and accessing primary and specialty care. Streamlining enrollment/renewal, strengthening navigation supports, and improving survivor-centered care within Medicaid are critically needed amid the evolving Medicaid policy landscape. Findings inform a larger study designed to quantify policy-relevant gaps in coverage among aging survivors.
Colon cancer sidedness in relation to sepsis risk and clinical predictors: A National Inpatient Sample analysis.
e15700 Background: Colon cancer patients are at increased risk for developing sepsis during hospitalization. It is unclear if there are differences in risk or clinical predictors of sepsis between right and left-sided colon cancers. Methods: Adult non-elective hospitalizations with colon cancer (ca. colon) were identified from the National Inpatient Sample from 2017 to 2022. Eligible patients were coded with colon cancer (ICD-10: C18.x-C209) and either right or left-sided ca colon. Sepsis was identified by ICD-10 A40–A41. Survey weighted logistic regression was used to assess the association of tumor sidedness on risk of sepsis with adjustment for obstruction, perforation/peritonitis, neutropenia, chronic kidney disease (CKD), cirrhosis, proxies of frailty, colectomy, chemotherapy, weekend admission, demographics. Multiplicative interaction terms were created between sidedness and all predictors of interest to formally assess effect modification. Adjusted marginal probabilities of sepsis by sidedness were also estimated. Results: The weighted study cohort included 301,340 hospitalizations. Patients with left-sided ca. colon had higher adjusted risks of sepsis when compared to right-sided cancers (13.6% vs 11.2%). In multivariable interaction models including sidedness and all predictors of interest, left-sided tumors were associated with higher odds of sepsis compared to right-sided tumors (adjusted odds ratio [aOR] 1.25, 95% CI 1.15–1.35). Perforation/peritonitis (aOR 7.06), neutropenia (aOR 2.83), frailty (aOR 1.98), and CKD (aOR 1.20) were associated with the highest adjusted odds of sepsis overall. Formal tests for effect modification demonstrated statistically significant results for perforation/peritonitis (interaction p-value = 0.003) and colectomy (p-value = 0.017). Neutropenia approached statistical significance (p-value = 0.062). The global test for interaction was statistically significant (p-value = 0.016). Marginal-effects modeling showed large absolute differences in probability of sepsis associated with perforation among both right and left-sided cancers; however effects were modestly higher among right-sided cancers. Conclusions: Hospitalized patients with left-sided ca colon have higher adjusted risk for developing sepsis compared to those with right-sided tumors. Perforation/peritonitis and colectomy were found to have significantly different associations with sepsis by tumor sidedness. Predictor aOR (95% CI) Interaction p-value Right-sided Δ Risk (%) Left-sided Δ Risk (%) Left vs Right sidedness 1.25 (1.15–1.35) Perforation/peritonitis 7.06 (6.48–7.69) 0.003 +30.9 +30.6 Neutropenia 2.83 (2.37–3.38) 0.062 +13.1 +10.9 Frailty proxy 1.98 (1.85–2.12) 0.46 +7.3 +8.1 CKD 1.20 (1.11–1.31) 0.33 +1.7 +2.8 Colectomy proxy 0.66 (0.62–0.71) 0.017 −3.7 −3.0 Δ Risk = absolute change in predicted probability of sepsis from margins.
<i>MACROD2</i> and <i>CDKN2A</i> in multiple myeloma: Insights to germline susceptibility and cytogenetic risk from long-read Nanopore sequencing.
e19566 Background: The MACROD2 gene is a chromosomal fragile site that undergoes frequent intragenic deletions in human carcinomas. Structural features of the deletions have argued against a tumor suppressor role, but functional studies have implicated the MACROD2 mono-ADP-ribosylhydrolase, acting via PARP1, in maintaining chromosomal stability and preventing aneuploidies. The role of this gene in multiple myeloma (MM), a cancer with recurrent aneuploidies that arise at the early MGUS stage, has not been well studied. In contrast, CDKN2A is a classical tumor suppressor whose deletion is linked to aggressive disease and poor prognosis in MM, and it is also a germline susceptibility locus for this disease. Here we present new molecular findings bearing on the roles of these two genes in MM. Methods: To correlate genetic and epigenetic features, we analyzed a series of MM cases, often paired with peripheral blood, using Illumina EPIC Beadchips and long-read Oxford Nanopore sequencing. In total, CD138-positive MM cells from 57 patients were included, of which 49 were profiled using EPIC arrays and 22 underwent whole-genome Nanopore sequencing, with 14 cases analyzed on both platforms. This approach enabled high-resolution characterization of CpG methylation, DNA structural lesions, and chromosomal copy number aberrations (CNAs). Results: Data from both Nanopore and EPIC revealed a 220Kb germline hemizygous deletion spanning MACROD2-AS1 , a lncRNA embedded in the 2Mb MACROD2 gene, in a familial MM case. The patient, whose father had MM and mother had lymphoma, was diagnosed with MGUS at age 50 following unexpected osteopenia, with progression to MM by age 64. In our full series of MM cases, CpG hypermethylation of the MACROD2 promoter was associated with hyperdiploidy and Chr1q gain (Fisher exact test, p = 0.04 and p = 0.02 respectively). In contrast, promoter methylation of CDKN2A was seen in a mostly non-overlapping set of cases and was strongly associated with cytogenetically high-risk disease (Fisher’s exact test, p = 8 × 10⁻⁴), but not with hyperdiploidy. Importantly for mechanisms involving hemizygosity and gene dosage, the Nanopore data revealed allele specific DNA methylation in both genes in MM cells. Conclusions: The hemizygous germline MACROD2-AS1 deletion in the familial MM case and the association of MACROD2 promoter methylation with Chr1q gains and hyperdiploid disease in our case series suggest a role for genetic and epigenetic lesions in this gene at early stages of MM tumor development. In contrast, CDKN2A hypermethylation appears promising as an epigenetic marker for aggressive high-risk MM cases.
Relative benefit of perioperative chemotherapy after resection for stage III colon cancer in the 70s age range: SEER 2004–2015.
e13778 Background: The magnitude of survival benefit associated with perioperative chemotherapy after resection for stage III colon cancer may vary by age in real-world practice due to differential treatment selection. We examined age-stratified associations of chemotherapy with overall and cause-specific mortality in a population-based cohort. Methods: SEER 2004–2015 resected AJCC6 stage III colon cancer. Treatment: surgery+chemotherapy vs surgery only (no/unknown chemo). Multivariable Cox models with age interaction estimated age-stratified HRs for OS. Cause-specific and non–cancer-specific death were evaluated using cause-specific Cox models. Results: Among 72,297 patients, 57.5% received surgery+chemo (41,584) and 42.5% surgery-only (30,713). The chemo group was markedly younger (age ≥80: 9.2% vs 43.0%) and less often widowed (12.6% vs 30.5%); sex and grade were similar, and stage mix was comparable (IIIB most common; IIIC ~35% vs 32%). Chemotherapy was associated with improved OS in all age groups with a consistent U-shaped pattern: HRs were higher in younger patients (45–49: 0.82, 95% CI 0.72–0.92; 50–54: 0.80, 0.73–0.88), decreased to a nadir in the 70s (70–74: 0.56, 0.53–0.58; 75–79: 0.56, 0.53–0.58), then attenuated in older strata (80–84: 0.60, 0.57–0.63; ≥90: 0.64, 0.52–0.78). This non-monotonic age pattern was preserved across AJCC6 IIIA/IIIB/IIIC subgroups (lowest HR typically ~70–79, with wider CIs at extremes). In competing-risk analyses, surgery+chemo was associated with lower hazards of both cancer death (HR range ~0.59–0.86; e.g., 75–79: 0.58, 0.55–0.62; ≥90: 0.75, 0.59–0.96) and non-cancer death (HR range ~0.51–0.62; e.g., 70–74: 0.52, 0.48–0.56; 75–79: 0.52, 0.49–0.56). Conclusions: Perioperative chemotherapy was associated with improved OS and reduced cancer and non-cancer mortality across ages, but the magnitude was non-monotonic—strongest in patients ~70–79 and attenuated at younger and very old extremes—consistent with substantial age-dependent treatment selection in observational data.
Real-world patterns and outcomes of cancer-related distress assessed by the NCCN distress thermometer in community oncology practice in western India.
e13578 Background: Cancer-related distress can adversely affect treatment adherence and quality of life, yet real-world evidence from Indian community oncology settings on this issue remains scarce. Methods: Adult Cancer patients were retrospectively assessed with NCCN Distress Thermometer between April 2025–December 2025. Distress was evaluated across physical, emotional, practical, social and spiritual domains at baseline and follow-up. Associations with age, disease stage and diagnosis were analyzed. Changes over time were assessed using Wilcoxon signed-rank test. Results: Among 2273 patients evaluated, the median age of the cohort was 58.3 years (SD 13.1) with M:F ratio of 1:1.4. Most patients had ECOG PS 0–1 (54.1%) and presented predominantly with stage IV disease (45.8%).The common cancers evaluated were breast (n = 570,25%), gastrointestinal (n = 360, 15.8%), gynaecologic (n = 297,13%) & head & neck cancers ( n = 224,9.8%). Mean distress score significantly reduced from 5.2 at baseline to 3.5 at follow-up (p < 0.001) with median scores improving from 5 to 3. A total of 57.4% had baseline distress scores ≥5 and it was associated with stage IV disease (p = 0.040); baseline distress was higher in patients < 60 years (p < 0.001). Overall 50.7% improved, 42.8% remained stable & 6.5% worsened. Improvement rates were consistently high across cancer types (≈67–79%), most common in Breast (79.3%), lymphoma (76%) and Head & Neck (75.5%). Improvement was significantly higher in younger patients 75% vs 64% in elders (p = 0.014) & in those with early-stage disease (stage I–II) 78% vs stage III–IV 66% (p = 0.016). Most commonly reported concerns were : in the physical (n = 1925,84.6%; including pain 59.5%, fatigue 50.7% & changes in abilities 45.7%), emotional (n = 1804,79.4%; anxiety 69.2%, sadness 26.8%), and practical (n = 1780,78.3%; self-care 84.2%, finances 22.7%); while fewer reported were social (n = 625, 27.5%) or spiritual/religious (n = 365, 16.1%) concerns. Across breast, gastrointestinal, gynecologic, and head and neck cancers, physical (n = 1,258) and emotional (n = 1,199) concerns were the two most prevalent domains. Conclusions: Routine implementation of the NCCN Distress Thermometer in community oncology practice in Western India enabled systematic identification of multidimensional distress and was associated with significant, tumor-agnostic improvement in patient-reported distress, highlighting its clinical utility as a pragmatic supportive care screening tool in real-world Indian settings.
Lipid reprogramming as driver of statin-targetable vulnerability in early-onset prostate cancer.
e17147 Background: Early-onset prostate cancer (EOPC, age ≤55 years) is increasing in incidence and displays distinct clinical features. However, its biological characteristics and therapeutic targets remain insufficiently explored. Methods: We integrated Nuclear Magnetic Resonance (NMR)-based metabolomics, targeted serum proteomics, and whole-genome sequencing data from the UK Biobank with targeted-DNA and bulk RNA sequencing (RNA-seq) from West China Hospital and public repositories to comprehensively characterize metabolic reprogramming in EOPC. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed on 72 specimens from 57 patients (19 age ≤55 years, 38 age > 55 years) to delineate EOPC-specific tumor microenvironmental features. Medication records from the UK Biobank and the West China Prostate Biopsy Database (WCHPBD) were analyzed to identify actionable therapeutic targets, and drug-target Mendelian randomization was conducted for causal validation. Results: Transcriptomic and proteomic analyses consistently revealed hyperactivated lipid metabolism in EOPC, particularly enhanced cholesterol biosynthesis and adipogenesis. scRNA-seq and spatial transcriptomics localized this metabolic program to a malignant epithelial subcluster (epi-0) and SPP1⁺ tumor-associated macrophages, which were enriched and interacting in EOPC. Additionally, serum metabolomics revealed enrichment of lipid related metabolic traits in EOPC, which predicted and causally contributed to EOPC onset. Clinically, statin use was associated with a significantly reduced EOPC risk (HR = 0.30, 95% CI 0.18–0.50, P < 0.001) and improved disease-specific survival (HR = 0.53, 95% CI 0.30–0.94, P = 0.027). Mendelian randomization confirmed that genetic inhibition of HMGCR, the statin target, decreased EOPC risk across independent cohorts. Conclusions: Our findings reveal dysregulated lipid metabolism serves as a defining driver of EOPC and provide convergent molecular, epidemiological, and causal genetic evidence supporting the use of HMGCR inhibitors as an accessible and effective strategy for EOPC prevention and treatment.
Impact of facility type and surgical management on survival outcomes in colon adenocarcinoma stratified by metastatic burden.
11129 Background: Survival for colon cancer varies by facility type, yet the impact of granular metastatic burden and surgical intervention on this disparity remains poorly defined. We examined whether academic survival advantages persist after stratifying by disease extent and evaluated how surgical management contributes to these outcomes. Methods: Using the NCDB (2016–2023), we identified 438,590 adults with colon adenocarcinoma. We compared academic vs. community settings, quantifying metastatic burden by involved organ site count at diagnosis (liver, lung, bone, brain, lymph nodes, viscera; 0–6). Overall survival (OS) was the primary endpoint. Multivariable Cox models adjusted for age, Charlson–Deyo score, clinical stage, and site count. Sequential adjustment for primary tumor resection and metastatic-site surgery was performed to assess potential mediation. Results: Of 438,590 patients, 49.2% were treated at academic centers. Academic cohorts presented with more complex disease, including higher metastatic rates (22.4% vs 20.1%; p < 0.001) and frequent liver involvement (16.9% vs 15.1%; p < 0.001). In stage IV cases, metastatic-site surgery occurred more often at academic facilities (19.1% vs 14.0%). While primary resection rates were high in both cohorts, academic centers achieved superior R0 rates (95.0% vs 94.3%). Adjusted for age, comorbidity, and site count, academic care was associated with a survival benefit (HR 0.93; 95% CI 0.92–0.94). Primary tumor resection strongly predicted OS (HR 0.29; 95% CI 0.29–0.30). Adjusting for primary resection strengthened the academic effect (HR 0.91; 95% CI 0.90–0.92), indicating that surgical management partially mediates this advantage. Conversely, metastatic-site surgery was associated with higher mortality (HR 1.32; 95% CI 1.29–1.34) and did not explain the facility-based survival gap. Conclusions: The survival advantage at academic centers persists regardless of initial metastatic burden and is driven more by primary tumor surgical management than by metastatic-site interventions. These data suggest that improving community outcomes requires broader access to academic-level surgical standards and multidisciplinary care. Ensuring specialized surgical evaluation for high-burden patients is critical, regardless of their initial point of entry into the healthcare system.
c-MET expression by IHC and response to cabozantinib in patients with relapsed, refractory germ-cell tumor: A single-arm phase II trial.
e17015 Background: Cabozantinib, a multi-targeted tyrosine kinase inhibitor targeting c-MET, VEGFR, and AXL, shows clinical benefit in patients (pts) with refractory germ-cell tumor (GCT) 1 . High c-MET expression by immunohistochemistry (IHC) has shown worse prognosis in solid tumors, though MET expression has not shown to correlate with treatment response and outcomes with cabozantinib 2,3 . We evaluate MET expression by IHC as a biomarker of response to cabozantinib in pts with relapsed, refractory GCT. Methods: As part of a previously reported phase II clinical trial of cabozantinib in pts with relapsed, refractory GCT, archival tissue tumor was obtained optionally at enrollment. Formalin-fixed paraffin embedded tumor blocks or freshly cut formalin-fixed paraffin embedded slides were analyzed for IHC analysis of MET protein levels using a lab antibody. MET expression was defined as high or low based on a cutoff of 50% or higher of the tumor tissue staining with an intensity of 2+ or 3+. Progression free survival was estimated using the Kaplan-meier method and compared between groups using the log-rank test. Results: Clinical characteristics of pts included have been described previously 1 . Overall, 44 patients were enrolled and evaluable, and the clinical benefit rate was 43.2%. 21 of 44 (48%) evaluable pts had archival tissue available for analysis. Eight pts (38.1%) had high MET expression; 13 (61.9%) had low expression. Of those with high MET expression, 4 (50%) had progressive disease (PD), while 4 (50%) had stable disease (SD). In those with low MET expression, 4 (30.8%) had PD, 8 (61.5%) had SD, and 1 (7.7%) had a partial response (PR). Clinical benefit rate for high vs low MET expression was 50% vs 69.2%. Median PFS for those with low MET expression was 119.8 days (35.7-204); Median PFS for those with high expression was 59.8 days (14.9-104.6) (p = 0.205). Conclusions: MET expression levels did not correlate with response and outcomes to cabozantinib in pts with relapsed, refractory GCT. 1 King J, et al. A phase II trial of cabozantinib in relapsed, refractory germ-cell tumors. To be presented at GU ASCO 2026. 2 Gibney GT, et al. c-MET is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann Oncol 2013; 24: 343-349. 3 Choueiri TK, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomized, open-label, phase 3 trial. Lancet Oncol 2016; 17: 917-27.
Phase 1 clinical trial investigating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AB821 in adult patients with locally advanced or metastatic melanoma and other solid tumor malignancies (NCT 07027488).
TPS2687 Background: In recent years, T-cell enhancement strategies have achieved notable survival benefits in patients with cancer. While cytokine therapy with both IL-2 and IL-21 demonstrate anti-cancer activity through enhanced proliferation, survival and function of antigen specific CD8+ T cells, their use is limited by off-target effects and rapid clearance. AB821 is a fusion of a CD8-targeting antibody that binds to the CD8αβ heterodimer on CD8+ T cells and an IL-21 mutein containing a mutation that attenuates affinity for the IL-21receptor. In pre-clinical experiments, AB821 promotes CD8+ T-effector cell cytotoxicity and CD8+ T-cell memory and demonstrates both robust tumor growth inhibition and minimal toxicity in immune checkpoint inhibitor refractory tumor models. Notably, AB821 avoids activation of other IL-21R-expressing cell types, including CD4+ T cells, NK cells, B cells, dendritic cells, intermediate monocytes, and nonclassical monocytes, that can act as pharmacologic sinks or contribute to off-target toxicity. Methods: This first-in-human phase 1 dose-escalation clinical trial is designed to assess the safety, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity of AB821 monotherapy administered every 2 weeks (Q2W) in patients (pts.) with recurrent locally advanced or metastatic melanoma and other immune-responsive solid tumor malignancies. Pts. with melanoma are required to have previously been treated with an inhibitor of PD1/L1 while pts. with other cancer types are required to have received a previous systemic treatment regimen. The primary objective of the study is to assess the safety and tolerability of AB821 and identify a candidate recommended phase 2 dose for further evaluation. AB821 is being administered as a 30-minute IV infusion on day 1 of each 2-week treatment cycle with therapy continued for a maximum duration of two years (52 cycles) or as long as participants experience clinical benefit as determined by the treating investigator. Dose-escalation and/or de-escalation decisions is being guided by a BF-BOIN design (Liu 2015; Yuan 2016) employing a target toxicity probability of 0.30 with up to 20 total pts. enrolled in backfill cohorts at the RP2D or lower dose levels determined by the investigators to be potentially efficacious in order to better assess the drug’s safety and efficacy. Accrual is ongoing. Specific dose levels and inclusion/exclusion criteria will be presented. Clinical trial information: NCT07027488 .
Gender representation in first and senior authorship of phase III solid-tumor trials presented at the ASCO Annual Meeting, 2015-2025.
9006 Background: Authorship in clinical trials reflects access to research infrastructure, funding, and academic advancement. While gender gaps have been described, longitudinal trends and structural correlates remain poorly characterized. We examined temporal trends and determinants of gender representation among first and senior authors of phase III solid-tumor trials presented at the ASCO Annual Meeting. Methods: We performed a cross-sectional analysis of all phase III solid-tumor trial abstracts presented at the ASCO Annual Meeting from 2015–2025. Data included year, tumor track (breast, gastrointestinal [GI], other), funding source (industry, academic, other), and first/senior authorship. Countries were classified by World Bank income group (high [HIC], upper-middle [UMIC], lower-middle [LMIC], low-income [LIC]) and global region (North America, Europe & Central Asia, East Asia & Pacific, other). Author gender was assigned using publicly available professional profiles and validated automated tools (≥90% certainty). Temporal trends were assessed using Cochran-Armitage tests. Multivariable logistic regression models evaluated factors associated with women authorship. Results: Across 1,517 abstracts (3,034 authorships), women comprised 845 authors (27.9%). Most trials were industry funded (63.7%), focused on GI malignancies (20.1%), and based in HIC (84.9%). Using first author as reference group, senior author had higher odds of being male in multivariable analysis (OR=1.30, p=0.001). Women had lower odds of senior authorship compared with first authorship (aOR 0.77, 95% CI 0.65–0.90). Female authorship increased over time (24.9% in 2015–2020 vs. 30.0% in 2021–2025, p =0.002; aOR 1.34, 95% CI 1.13–1.58), most pronounced among senior authors (aOR 1.55, 95% CI 1.21–1.99; p =0.006). Women authorship varied by tumor track, with lower odds in GI compared with breast trials (aOR 0.49, 95% CI 0.38-0.64). Compared with North America, East Asia and Pacific affiliation was associated with higher odds of women authorship overall (aOR 1.54, 95% CI 1.15–2.07), strongest among first authors (aOR 1.89, 95% CI 1.25–2.91). Among senior authors, LMIC affiliation was associated with lower odds of women authorship compared to HICs (aOR 0.11, 95% CI 0.01–0.56). Conclusions: In the largest global oncology conference, women authorship in phase III solid-tumor trials has improved over the past decade but remains uneven, with persistent gaps in senior authorship. Authorship role, era, and tumor track by gender. Characteristic Women (N=845, 27.9%) Men (N=2,182, 71.9%) P -value Authorship role 0.002 First author 462 (54.7) 1,055 (48.4) Senior author 383 (45.3) 1,127 (51.6) Era 0.002 2015–2020 310 (36.7) 934 (42.8) 2021–2025 535 (63.3) 1,248 (57.2) Tumor track <0.001 Breast 203 (24.0) 307 (14.1) Gastrointestinal 150 (17.8) 456 (20.9) Other solid tumors 492 (58.2) 1,419 (65.0)
Clinical utility of PET-CT in the management of colorectal liver metastases.
e15547 Background: Patients with colorectal cancer liver metastases (CRCLM) may be considered for potentially curative liver resection. A critical determinant of benefit from surgery is the absence of occult extrahepatic disease, particularly nodal involvement, which may not be detected on conventional imaging. Proceeding to laparotomy in such patients confers limited survival benefit while incurring significant morbidity. Although PET-CT is not routinely recommended in international guidelines for pre-operative assessment in CRCLM, emerging evidence suggests a role in improved patient selection. This study aimed to evaluate the impact of pre-operative PET-CT on surgical decision-making in a large real-world cohort. Methods: Patients with CRCLM discussed at The Mater Misericordiae University Hospital multidisciplinary team (MDT) meeting from 2020–2024 were included. During this period, over 8,700 MDT cases were reviewed, identifying 584 suitable patients. Clinical, radiological, and operative data were extracted, including MDT history, PET-CT results, surgical intent, and operative outcomes. Abandoned surgery was defined as laparotomy in which resection was not performed due to intra-operative findings. The primary outcome was the proportion of abandoned surgeries among patients who underwent pre-operative PET-CT compared with those who did not. Group comparisons were performed using Fisher’s exact test, with odds ratios reported. Overall survival (OS) was calculated from the date of surgery using Kaplan–Meier methods and compared using Cox proportional hazards regression. Results: Of the 584 patients included, 273 underwent surgery with curative intent, while 311 did not proceed to surgery. Among patients who did not undergo surgery, 186(59.8%) had previously undergone PET-CT. Of the 273 patients who proceeded to surgery, 141(51.6%) underwent pre-operative PET-CT. Sixteen surgical procedures were abandoned intraoperatively. This occurred in 12 patients staged without, and 4 patients with PET-CT staging, corresponding to abandonment rates of approximately 9% and 2%, respectively (p = 0.002; OR 0.28). Among patients who underwent resection, median OS from the date of surgery was 55.2 months in the PET-CT group compared with 37.2 months in the non-PET group; this difference did not reach statistical significance (HR 0.61, 95% CI 0.33–1.10; p = 0.10). Conclusions: In this large cohort of patients with CRCLM, pre-operative PET-CT was associated with a significantly lower rate of abandoned surgery, without a statistically significant difference in post-resection overall survival. These findings support the role of PET-CT in improving patient selection by identifying occult disease not evident on standard imaging, thus reducing non-therapeutic laparotomy and associated morbidity. Further prospective studies are warranted to define subgroups most likely to benefit from pre-operative PET-CT.
Differential risk of interstitial lung disease with DXd-based versus non-DXd TROP2 antibody-drug conjugates: A systematic review and meta-analysis.
e15037 Background: TROP2 directed antibody drug conjugates (ADCs) have demonstrated efficacy across multiple solid tumors. Interstitial lung disease (ILD) has emerged as an important safety signal, particularly with ADCs incorporating the deruxtecan (DXd) payload. The magnitude and consistency of ILD risk across TROP2 ADC platforms remain incompletely defined. Methods: We performed a systematic review and meta analysis of prospective phase II and III clinical trials evaluating TROP2 targeted ADCs in advanced solid tumors. Studies reporting ILD or pneumonitis events were included. ADCs were categorized as DXd based or non DXd based on payload chemistry. ILD incidence was pooled using random effects models, and comparative risk was estimated using risk ratios (RRs), odds ratios (ORs), absolute risk differences, and number needed to harm (NNH). Risk of bias (RoB) was assessed using RoB 2.0 and ROBINS-I, and certainty of evidence was evaluated using GRADE. Results: Eight studies comprising 1,202 patients were included (DXd based: 4 studies, n =802; non DXd: 4 studies, n =400). The pooled incidence of ILD was 5.4% (43/802) for DXd based TROP2 ADCs compared with 0.5% (2/400) for non DXd ADCs. DXd based ADCs were associated with a markedly increased risk of ILD (RR 8.59, 95% CI 2.41-30.57; OR 11.26, 95% CI 2.91-96.48; p <0.001). The absolute risk increase was 4.86 percentage points, corresponding to an NNH of 21. Substantial heterogeneity was observed among DXd based studies (I²=74%), whereas no heterogeneity was detected among non DXd studies (I²=0%). ILD related mortality was rare (0.12%) and occurred exclusively in the DXd based group. ILD incidence was numerically higher in non small cell lung cancer than breast cancer across both drug classes. Sensitivity analyses including restriction to randomized trials, exclusion of small studies, and inclusion of combination therapy yielded consistent results. Meta regression identified payload class as the primary determinant of ILD risk, explaining 65.5% of between study variance. RoB was low or had some concerns in studies contributing 87% of patients, and overall certainty of evidence was rated moderate. Conclusions: DXd based TROP2 ADCs are associated with a substantially higher risk of ILD compared with non DXd TROP2 ADCs, supporting a payload related toxicity effect. These findings underscore the need for vigilant monitoring, careful patient selection, and risk benefit stratification as TROP2 ADC use expands across tumor types. Primary Analysis: Comparison of ILD Risk Between Drug Classes. Outcome DXd-Based Non-DXd Comparison Studies included 4 4 — Total patients 802 400 — ILD events 43 2 — ILD incidence 5.4% 0.5% — Heterogeneity (I²) 74.2% 0% — Risk Ratio (95% CI) — — 8.59 (2.41-30.57) Odds Ratio (95% CI) — — 11.26 (2.91-96.48) P-value — — <0.001 Absolute Risk Difference — — 4.86 pp (3.16-6.57) Number Needed to Harm — — 21 (15-32)
Non–small cell lung cancer and the obesity paradox: A retrospective cohort study using the TriNetX database.
e20544 Background: Although obesity is traditionally associated with adverse health outcomes, paradoxical survival benefits have been reported across several malignancies. In non–small cell lung cancer (NSCLC), the prognostic impact of obesity remains uncertain, largely due to small cohorts and limited adjustment for disease and treatment factors. We evaluated the association between obesity and long-term overall survival in NSCLC using a large real-world database. Methods: We conducted a multicenter retrospective cohort study using the TriNetX database, including de-identified records from 94 healthcare organizations. Adults (≥18 years) diagnosed with NSCLC (adenocarcinoma, squamous cell carcinoma, or large cell carcinoma) within the past 15 years were identified. Exclusions included Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and classical or combined small cell histology. Patients were stratified into normal-weight (BMI 20.0-24.9kg/m 2 ) and obese (BMI ≥ 30kg/m 2 ) cohorts based on BMI recorded within 6 months of the index event (diagnosis of NSCLC). Propensity score matching (1:1) controlled for differences in sociodemographics, comorbidities, histologic subtypes, cancer stage, genetic mutations, and cancer-directed treatments. Descriptive statistics summarized baseline characteristics. The primary outcome was 10-year overall survival, analyzed by Cox proportional hazards model and Kaplan-Meier curves. Statistical significance was set at p < 0.05. Results: At baseline, the normal-weight (N = 8,904) and obese (N = 21,748) cohorts were predominantly White (54.2% vs. 65.1%), male (49.5% vs. 48.8%), and non-Hispanic (64.43% vs. 71.92%). The normal-weight cohort was older (66.3 ± 12.2 years) than the obese cohort (61.7 ± 12.0 years, p < 0.0001) and had higher rates of late-stage (III-IV) disease, chemotherapy, and pembrolizumab-based immunotherapy (p < 0.0001). Surgical interventions were equally uncommon, with small standardized differences. Diabetes and hypertensive diseases were more common in the obese cohort (p < 0.0001). Genetic mutations in EGFR, ALK, ERBB3, and ROS1 were slightly more frequent in the normal-weight cohort (p < 0.05). After 1:1 propensity score matching with 7,557 matched pairs, Kaplan-Meier survival analysis showed that normal-weight patients had a median survival of 2,094 days. In contrast, the median survival for obese patients was not reached, with 10-year survival probabilities of 41.7% and 54.7%, respectively (log-rank test, p < 0.0001). A hazard ratio of 1.549 (95% CI: 1.465–1.638) indicated a survival benefit in the obese cohort. Conclusions: This study highlights that future prospective studies should focus on body composition analysis and treatment-related variables to further elucidate the mechanisms underlying the obesity paradox in NSCLC and guide targeted therapies for better outcomes in non-obese patients.
Phase 1 study of induction chemoimmunotherapy (ICI) with cemiplimab in combination with cisplatin and docetaxel (TPI) in locally advanced squaous cell carcinoma of the head and neck (LA SCCHN).
e18085 Background: Despite advances in therapy, overall survival for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) remains suboptimal, with 5-year survival rates depending on HPV status which indicates a need for additional therapeutic approaches. We sought to improve outcomes by adding immunotherapy to induction chemotherapy with cisplatin and docetaxel (TP). ICI potentially is a less toxic and more efficacious alternative to traditional chemotherapy induction regimens. Methods: In this phase 1, non-randomized study (NCT05376553), patients with previously untreated stage IV LA SCCHN were enrolled into two cohorts. Cohort A received cisplatin (100 mg/m²) and docetaxel (75 mg/m²) on day 1 followed by cemiplimab (350 mg) on day 14 for three cycles; Cohort B received cemiplimab every 3 weeks starting on day −7. Patients then underwent standard-of-care surgery and/or concurrent chemoradiation, followed by adjuvant cemiplimab every 3 weeks for eight cycles. Cemiplimab was combined with TP using a standard 3+3 design without dose escalation. Dose-limiting toxicities attributable to cemiplimab were assessed in cycle 1. Twenty-four patients were enrolled with primary tumors in the oropharynx (15; HPV+ 9), larynx (2), oral cavity (3), nasopharynx (1; HPV+), and hypopharynx (3). Results: 24 eligible patients-initiated therapy and all completed ICI and have completed the study.1 death occurred during follow up period unrelated to study drug or disease. 2 deaths due to progression of disease; 4 patients experienced progression of disease, and 1 patient was lost to follow up. 16/24 (67%) of patients who completed the study remain alive in remission. Of among the 24 patients, that completed ICI the overall response rate (ORR) was 83.33% with 4 partial responses, 14 complete responses, and 6 progressions of disease. The disease control rate is 83.33%, with a relapse rate of 18.18%. 5/5 oral cancer patients underwent resection, 3 had complete pathological response, 1 with 85% pathological tumor necrosis and 1 had a minimal pathological response <10%. There was no dose limiting toxicities The median duration follow-up was 21 months. Conclusions: Induction with ICI with cemiplimab combined with cisplatin and docetaxel was feasible and demonstrated an acceptable safety profile in patients with LA SCCHN, indicating a high ORR and disease control rate. These phase I results support further investigation in larger studies. Clinical trial information: NCT05376553 .
Correlation between real-world progression-free survival and time to next treatment and death in advanced ovarian cancer patients receiving non-platinum therapy in second or later lines.
e17578 Background: Advanced ovarian cancer (aOC) is typically treated with platinum-based first-line therapy, but in second or later lines (2L+) some patients receive non-platinum regimens due to platinum resistance, toxicity, comorbidities, or patient/clinician preference. Although progression-free survival (PFS) is a commonly used efficacy endpoint in clinical trials, its assessment in real-world data is often limited by incomplete or delayed documentation of progression, prompting use of time to next treatment or death (TTNTD) as a pragmatic alternative. Because treatment changes can be driven by factors beyond progression, it is important to evaluate the correlation between TTNTD and real-world PFS (rwPFS) among aOC patients receiving non-platinum therapies in 2L+. Methods: This retrospective observational study used the Flatiron Health electronic health record–derived, de-identified database. Adults aged ≥18 years with stage III–IV aOC diagnosed on or after May 1, 2020, who received platinum-based 1L therapy, initiated second-line (2L) treatment and received a non-platinum regimen in 2L+ were included, with follow-up until Feb 28, 2025. TTNTD and rwPFS were both measured from 2L initiation and estimated using Kaplan–Meier methods. Patient-level association between TTNTD and rwPFS was assessed using inverse-probability-of-censoring weighted Kendall tau and Spearman correlation coefficients. Results: Among 306 patients included in the analysis, mean age at diagnosis was 67.8 years; 50.7% had stage III and 48.4% stage IV disease; 39.9% were platinum sensitive (PSOC), 60.1% were platinum resistant (PROC). TTNTD events in 286 (94.7%) and rwPFS events occurred in 273 patients (90.4%). Median TTNTD was 5.9 months and median rwPFS was 6.0 months, with no significant difference (log-rank p>0.05). Kendall’s tau between TTNTD and rwPFS was 0.62 (95% confidence interval [CI] 0.55–0.68) and Spearman correlation was 0.76 (95% CI 0.66–0.83), both were higher in PROC (0.65 and 0.83) than in PSOC (0.59 and 0.69). Among 270 patients with both events, TTNTD event occurred before rwPFS event in 42 (15.6%), on the same day in 30 (11.1%), and after rwPFS event in 198 (73.3%). The median difference between TTNTD event and rwPFS event was 14.5 days. Conclusions: TTNTD and rwPFS from 2L therapy initiation appeared as moderately correlated in the aOC patients receiving non-platinum regimens in 2L+ with relatively short timing offset, suggesting that TTNTD may serve as a practical alternative when progression dates are incomplete or absent in real-world data. Nonetheless, sensitivity analyses and context-specific interpretation are warranted when using TTNTD as a proxy for rwPFS.
SHR-A1811 plus chemotherapy and BP102 as 1L therapy for HER2-expressing mCRC: Data from a phase Ib/II study.
3569 Background: HER2 expression is associated with poor prognosis in mCRC. SHR-A1811 (trastuzumab-rezetecan) is a HER2-directed ADC comprising a humanized monoclonal antibody, a cleavable tetrapeptide linker, and a topoisomerase I inhibitor payload. We evaluated the safety and preliminary efficacy of SHR-A1811 in combination with chemotherapy and BP102 (bevacizumab biosimilar) as 1L therapy for HER2-expressing mCRC. Methods: This open-label, multicenter phase Ib/II study (ClinicalTrials.gov: NCT06015048) used an i3+3 design in phase Ib to evaluate the safety and tolerability of SHR-A1811 + 5-FU/L-LV, ± oxaliplatin and/or BP102, and to select the phase II regimen. Phase II (proof-of-concept) assessed efficacy and safety in the 1L setting using SHR-A1811 3.2 mg/kg Q2W + 5-FU (300 mg/m² IV bolus, 1800 mg/m² continuous infusion over 46–48 h Q2W) + L-LV 200 mg/m² IV Q2W + BP102 5 mg/kg IV Q2W ± oxaliplatin 60 mg/m² IV Q2W. Tumor response was assessed per RECIST v1.1, and AEs were evaluated per CTCAE v5.0. Results: As of Dec 31, 2025 (data cutoff), 39 pts received SHR-A1811 + FOLFOX (-1) + BP102, and 11 pts received SHR-A1811 + 5-FU/L-LV + BP102. All were Asian with pMMR/MSS and BRAF wild-type disease. The median age was 58 (range, 30–71) and 57 (range, 42–72), respectively. 28/39 (71.8%) and 7/11 (63.6%) were male. ECOG PS was 1 in 24/39 (61.5%) and 6/11 (54.5%). HER2 positivity (IHC 3+ or IHC 2+/ISH+) was observed in 21/39 (53.8%) and 5/11 (45.5%). HER2 IHC 2+/ISH− was observed in 18/39 (46.2%) and 5/11 (45.5%). Liver metastases were present in 28/39 (71.8%) and 4/11 (36.4%). 15/39 (38.5%) and 5/11 (45.5%) had RAS mutations. Median follow-up was 10.4 m (range, 6.1–17.0) and 11.9 m (range, 3.3–19.0). ORR was 74.4% (29/39; 95% CI, 57.9–87.0) and 40.0% (4/10; 95% CI, 12.2–73.8). DCR was 97.4% (38/39; 95% CI, 86.5–99.9) and 90.0% (9/10; 95% CI, 55.5–99.8). mPFS was 15.6 m (95% CI, 11.3–NR) and 9.6 m (95% CI, 1.8–NR). In HER2 positive pts received SHR-A1811 + mFOLFOX6(-1) + BP102, ORR was 90.5% (19/21; 95% CI, 69.6-98.8), DCR was 100% (21/21; 95% CI, 83.9-100), 9m-PFS rate was 94.7% (95% CI, 68.1-99.2); among HER2 positive RAS mutant/wild type subgroups, 9m-PFS rate was 83.3% (95%CI, 27.3-97.5) and 100%. OS was immature. Grade ≥3 TRAEs occurred in 31/39 (79.5%) and 6/11 (54.5%) in the two cohorts, with the most common being decreased neutrophil count (56.4% vs 18.2%), decreased white blood cell count (17.9% vs 18.2%), anemia (12.8% vs 9.1%), and stomatitis (12.8% vs 0). TRAEs led to discontinuation of any drug in 4/39 (10.3%) (SHR-A1811: 1; chemo: 1; BP102: 3) and in none. TRAEs led to dose reductions in 12/39 (30.8%) and 3/11 (27.3%) (SHR-A1811: 3 vs 1; chemo: 11 vs 3). No TRAE-related deaths occurred. Conclusions: SHR-A1811 plus chemotherapy and BP102 as 1L therapy for HER2 intermediate or high-expressing mCRC demonstrated manageable safety and encouraging antitumor activity. Clinical trial information: NCT06015048 .