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Neoadjuvant lorlatinib in stage III NSCLC harboring ALK fusion: A phase 2 multicenter study (LORIN).
8002 Background: While adjuvant alectinib has established itself as the new standard for resected anaplastic lymphoma kinase (ALK) fusion non-small cell lung cancer (NSCLC), there is limited data on neoadjuvant treatment for locally advanced ALK fusion NSCLC. Given the groundbreaking efficacy of lorlatinib in advanced NSCLC, it is worth exploring its clinical feasibility as neoadjuvant treatment for stage III ALK+ NSCLC. Methods: This study is an open-label, phase 2 multi-center prospective trial (ClinicalTrials.gov NCT05740943) utilizing a Simon two-stage design. Patients diagnosed with potentially resectable or unresectable stage III ALK+ NSCLC were enrolled, with up to 3 cycles of lorlatinib administered, followed by optional local treatment and consolidation lorlatinib for up to 2 years. The primary endpoint was the pathological complete response (pCR) (H0≤20%, H1≥40%, α=0.05, β=0.2, at least 12 pCR events for 43 patients enrolled), while secondary endpoints included major pathological response (MPR), event-free survival (EFS), overall survival (OS), and safety profile. Xenium as well as spatial proteomics was performing on paired samples collected before and after lorlatinib. Results: As of January 1, 2026, 43 patients with stage III ALK-fusion NSCLC (19 evaluated as potentially resectable and 24 as unresectable) were consecutively enrolled and received 3 cycles neoadjuvant lorlatinib, with 32 completing surgery (including neck dissection and/or contralateral lymph node dissection), 9 continuing TKI therapy, and 2 undergoing radiotherapy. The most common treatment-related adverse events (TRAEs) included hypertriglyceridemia, hypercholesterolemia, and edema. The confirmed objective response rate (ORR) was 83.7% (36/43), without progressive disease (PD). Among patients who underwent surgery, the R0 resection rate was 96.9% (31/32) and 3 patients experiencing conversion to thoracotomy. pCR and MPR rates were 46.9% (15/32) and 81.3% (26/32), respectively, reaching the primary endpoint. Pathological nodal downstaging was seen in 90.6% (29/32) patients. For those with initially unresectable stage III disease, 75.0% (18/24) achieved conversion surgery through multidisciplinary evaluation after neoadjuvant lorlatinib, while others continued TKI or underwent radiotherapy. With a median follow-up of 13 months, the 1-year EFS rate was 97.1% (95% CI, 91.5-100) and no OS events were observed. Only 3 patients experienced local relapse (regional lymph nodes and/or intrapulmonary metastasis) without distant metastasis; all had initially presented with N3 disease and did not receive adjuvant lorlatinib after surgery. Conclusions: Neoadjuvant lorlatinib unveiled overwhelming pathological response and could lead to high conversion surgery for unresectable stage III disease. Further large-scale prospective trial was warranted to testified such treatment modality. Clinical trial information: NCT05740943 .
Durvalumab or pembrolizumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy for advanced cholangiocarcinoma: A meta-analysis.
4160 Background: Cholangiocarcinoma (CCA) is a rare, aggressive malignancy of the bile duct epithelium with rising incidence and mortality. Curative surgery is feasible in few cases; for unresectable or metastatic disease, systemic therapy is standard. Gemcitabine plus cisplatin (GemCis) has been the first-line backbone, but phase 3 trials (TOPAZ-1 and KEYNOTE-966) demonstrated overall survival (OS) benefit with added immune checkpoint inhibitors (durvalumab or pembrolizumab). This systematic review and meta-analysis evaluates the efficacy and safety of immunotherapy (IO) plus GemCis versus GemCis alone in advanced CCA. Methods: We systematically searched PubMed, Embase, Scopus, and Google Scholar for English-language studies (2009–2025) including randomized controlled trials (RCTs) and cohort studies of first-line GemCis alone or with durvalumab or pembrolizumab in unresectable/metastatic CCA. Primary endpoint: OS. Secondary: progression-free survival (PFS) and grade 3-4 adverse events (AEs) per CTCAE. Kaplan-Meier curves were digitized, and individual patient data reconstructed using IPD tools for pooled estimates. Random-effects models generated hazard ratios (HRs) and pooled medians; heterogeneity assessed via I². Results: We included 3,703 patients from TOPAZ-1, KEYNOTE-966, ABC-01/02, and six cohort studies: 1,737 on GemCis alone, 1,433 on GemCis + durvalumab, and 533 on GemCis + pembrolizumab. In the full meta-analysis, GemCis + durvalumab showed the best outcomes (median OS 14.1 months, PFS 7.38 months) versus GemCis + pembrolizumab (OS 12.8 months, PFS 6.62 months) and GemCis alone (OS 9.27 months, PFS 5.81 months). Restricting to RCTs only, IO + GemCis improved OS versus GemCis alone (median 12.82 vs. 11.1 months; HR 0.78, 95% CI 0.71–0.86, p<0.001), with no significant PFS difference (p=0.20). Grade 3-4 AEs were infrequent across arms; thrombocytopenia was higher with pembrolizumab (p=0.0002), but other severe toxicities were comparable. Conclusions: Adding immunotherapy to GemCis significantly enhances survival in unresectable/metastatic CCA, with durvalumab + GemCis providing the most pronounced benefit in this pooled analysis incorporating RCTs and real-world cohorts. Regimens were well-tolerated with manageable toxicity. These findings reinforce chemoimmunotherapy as first-line standard and highlight potential differential efficacy between PD-L1 and PD-1 inhibitors warranting further study.
Biomarker-driven prescribing patterns in <i>ESR1</i> <i> <sup>mut</sup> </i> ER+/HER2- metastatic breast cancer (mBC).
e23373 Background: Multiple biomarker-driven therapies are approved for ER+/HER2- mBC. Oral selective estrogen degraders (SERDs) are approved for ESR1 mut ER+/HER2- mBC, but ESR1 mut may co-occur with other actionable biomarkers, including somatic PIK3CA/AKT1 / PTEN mut , germline BRCA1/2 mut , and HER2-low disease. Optimal timing of matched therapies remains uncertain in patients (pts) with multiple targetable mutations. This study evaluated institutional prescribing patterns, focusing on the first biomarker-matched therapy selected following elacestrant approval, and associated clinical characteristics in pts with ER+/HER2- ESR1 mut mBC with other actionable variants. Methods: Pts with ESR1 mut mBC were included if they had ≥1 additional targetable biomarker and received a matched agent after elacestrant approval (Jan 27, 2023). Genomic and pathology data were assessed for PIK3CA/AKT1/PTEN mut , HER2-low status (IHC 1+ or 2+/FISH negative), and g BRCA1/2 mut . Variants were considered actionable if a matched therapy was available as standard of care or through a clinical trial at treatment selection. Clinical factors annotated included age at therapy start, ECOG, hemoglobin (HgB), HgB A1c, creatinine (Cr), bilirubin, and visceral disease. Comparisons were performed across treatment groups defined by the first matched therapy received (oral SERD vs PI3K/AKTi vs Trastuzumab deruxtecan [T-Dxd]) using Kruskal–Wallis and Chi Square tests. Results: 87 pts with ESR1 mut mBC had ≥1 additional targetable variant at treatment selection (Table 1). Oral SERDs were prescribed first for most pts with concurrent PIK3CA mut , and evenly with T-Dxd for pts with HER2-low mBC. If ≥2 PI3K/AKT pathway mutations were present, a PI3K/AKTi was selected. Median age differed significantly, with older pts more likely to receive oral SERDs (SERD 73, PI3K/AKTi 64, T-Dxd 62 years; p = 0.001). Cr levels differed with lower values in T-Dxd and PI3K/AKTi groups (p = 0.034). In a subanalysis, excluding pts who received a matched agent pre-elacestrant approval (n = 55), median age was higher in oral SERD recipients (75 vs 66 vs 59 years; p < 0.001). All groups had median HgB A1c < 6.5 and no significant difference in Cr. Conclusions: Guidelines for initial biomarker-driven treatment selection in ER+/HER2- ESR1 mut mBC are not well defined. This work shows variability in real-world treatment practices and potential associations with toxicity-related factors. Larger analyses are planned to validate these findings and to evaluate treatment sequencing patterns in this setting. Mutation Profile SERD first (n = 43) PI3K/AKTi first (n = 21) T-Dxd first (n = 23) ESR1 + PIK3CA (n = 28) 20 (71%) 8 (29%) — ESR1 + AKT1 (n = 1) 0 1 (100%) — ESR1 + PTEN (n = 1) 0 1 (100%) — ESR1 + ≥2 PIK3CA/AKT1/PTEN (n = 5) 0 5 (100%) — ESR1 + HER2-low (n = 28) 14 (50%) — 14 (50%) ESR1 + HER2-low + ≥1 PIK3CA/AKT1/PTEN (n = 23) 8 (35%) 6 (26%) 9 (39%) ESR1 + HER2-low + BRCA1/2 + ≥1 PIK3CA/AKT1/PTEN (n = 1) 1 (100%) 0 0
Artificial intelligence surrogate models to predict long-term cardiovascular effects of immune checkpoint inhibitor therapies using electrocardiograms.
12020 Background: Immune checkpoint inhibitors (ICI) revolutionized the treatment landscape for many cancers, with close to 50% of cancer patients now ICI eligible. Acutely, ICI are associated with myocarditis. Long term cardiovascular effects of ICI are less clear. We built artificial intelligence (AI) models as surrogates for predicting long-term cardiovascular disease (CVD) after ICI using electrocardiograms (ECG). Methods: Using data from over 80,000 cancer patients treated from 1986 to 2021 at the University of California, San Francisco, we develop two ECG AI models as surrogates for risk over time of CVD. First, we built a model of observed CVD using true outcomes in a time to event framework. This model is a surrogate for prevalence under the current standard of care. Second, we build a model for causal outcomes using before-and-after data and estimate risk from ECGs for causal analyses. We hold out patients (N=15,277), including all those treated with anthracyclines (N= 3,681), trastuzumab (N=751), or ICI (N= 3,572), for evaluation. Causal effects are estimated with paired pre and post treatment ECGs within three years. Results: Models have average AUC across CVDs and years of 0.78 and 0.77. The observed model estimates ICI treated patients compared to those with any other cancer treatment have higher average 10-year risk of ischemic heart disease (IHD) by 10% (95% CI: 2-18%), venous thromboembolism (VTE) by 10% (1-20%), and critical ventricular arrhythmias (CVA) by 10% (3-19%), largely due to high baseline risk. Anthracycline and trastuzumab treated patients did not have higher 10-year heart failure (HF) risk relative to other treatments in aggregate. The causal framework estimates anthracyclines increased average 10-year risk of HF by 45% and trastuzumab by 46%. Anthracyclines and trastuzumab significantly increased risk of atrial fibrillation, IHD, ischemic stroke, CVA, VTE, and conduction disorders as well. ICI increased risk of each of these significantly by smaller amounts. Notably, after ICI, average 10-year risk of HF increased by 32% and IHD by 17%. Conclusions: Our study demonstrates potential long-term CVD effects of ICI as estimated from ECGs. This framework can be used to evaluate effects of new therapies in the future. 10-year pre/post treatment relative risks. CVD Anthracycline Trastuzumab ICI Atrial fibrillation 1.34 [1.29, 1.39] 1.30 [1.24, 1.36] 1.25 [1.21, 1.28] Ischemic heart disease 1.25 [1.21, 1.28] 1.28 [1.23, 1.32] 1.17 [1.14, 1.19] Heart failure 1.45 [1.39, 1.52] 1.46 [1.38, 1.55] 1.32 [1.27, 1.36] Ischemic stroke 1.41 [1.32, 1.50] 1.31 [1.22, 1.41] 1.28 [1.21, 1.35] Critical ventricular arrhythmia 1.18 [1.15, 1.22] 1.14 [1.09, 1.19] 1.10 [1.07, 1.13] Venous thromboembolism 1.29 [1.24, 1.33] 1.26 [1.21, 1.31] 1.26 [1.21, 1.30] Conduction disorder 1.19 [1.17, 1.21] 1.19 [1.16, 1.21] 1.15 [1.13, 1.17]
Early identification of patients at risk for moderate-to-severe immunotherapy-related adverse events following immune checkpoint inhibitor therapy.
e13695 Background: While immune checkpoint inhibitors (ICIs) are increasingly used for cancer treatment due to favorable tolerability compared with chemotherapy (reference), immune-related adverse events (irAEs) have emerged as a major clinical challenge, as they may lead to treatment interruption and reduced antitumor efficacy. Early identification of patients at high risk for moderate-to-severe irAEs requiring treatment is critical. Although prior studies have shown the utility of machine-learning (ML) models for predicting irAE occurrence, accurate prediction of clinically significant irAEs using pre-treatment data remains limited. Methods: We analyzed data from the All of Us Research Program and identified 998 cancer patients treated with ICIs, including anti-PD-1, anti-PD-L1 and combination regimens. Immune-related adverse events were identified using diagnosis concept sets derived from prior literature, yielding 310 patients with documented irAEs. There were 68 moderate-to-severe irAEs, defined as events requiring systemic corticosteroid initiation within 30 days of irAE onset. Patients without any irAE diagnosis codes served as controls. Baseline features included demographics (age and sex), comorbidities associated with irAE risk (autoimmune disease and others), lifestyle factors (alcohol and smoking history), and available pre-treatment laboratory measurements. We evaluated three supervised machine-learning models: elastic-net regularized logistic regression, XGBoost, and LightGBM. The dataset was split 80/20 for training and testing and trained with five-fold cross-validation. Results: For prediction of any irAE occurrence, elastic-net logistic regression using baseline features achieved the highest performance with AUROC of 0.75, sensitivity of 0.64 and specificity of 0.77. Consistent with literature, the most influential predictors included autoimmune disease, chronic liver disease, ICI combined with chemotherapy, and alcohol consumption. Model performance decreased when predicting moderate-to-severe irAEs using baseline features alone. Including pre-treatment laboratory measurements modestly improved prediction, with the XGBoost being the best-performing model achieving an AUROC of 0.65 (95% CI: 0.48–0.82). While overall discrimination remained modest, SHAP analysis identified metabolic and inflammatory markers, including BMI (body mass index), glucose, and white blood cell count as well as common comorbidities as key contributors. Conclusions: While baseline risk factors predict irAE occurrence, identifying patients at risk for moderate-to-severe irAEs requires personalized immune profiling. Future work will integrate multimodal data, multi-institutional cohorts and biologically informed ML models to enable early risk stratification and guide clinical management.
Assessing the accuracy and clinical utility of an algorithm-based PET/CT service for quantifying treatment response in older adults with metastatic cancer.
e13649 Background: There is substantial variability in PET/CT interpretation, influenced by technical, procedural, and reader-dependent factors. This variability is increased in older adults due to age related physiologic changes, highlighting the need for standardization of PET/CT interpretation. This study aims to assess the accuracy of a novel software, TRAQInform IQ, in evaluating change over time in PET/CT imaging for older adults with metastatic cancer and investigate perceived clinical usefulness. Methods: Serial PET/CT scans for 17 older adults aged 65 and older with metastatic cancer were retrospectively analyzed using the algorithm-based software TRAQInform IQ which assesses spatial location and classification of individual lesions in addition to overall disease response. An independent radiologist reviewed clinically significant lesions as determined by oncologists for contour, matching precision, and treatment classification across serial scans. The software report was compared to existing original PET/CT radiology reports for overall disease assessment. To assess usefulness, 4 oncologists reviewed specialty-specific cases and completed a questionnaire comparing the algorithm-based reports to the PET/CT scans. Descriptive statistics evaluated demographics, report findings, and usefulness. Results: Patients had a mean age of 72 years old and a majority had stage IV (71%) disease at diagnosis. Seven primary cancers were represented, including cervical, melanoma, lymphoma, vulvar, vaginal, uterine, and urothelial. Of 73 lesions deemed clinically significant, the accuracy of lesion contours, matching, and classification across serial scans was 97% per an independent radiologist. The software reported disease that was increasing in 3 (18%), and decreasing in 13 (76%) patients, with 1 patient (6%) with no lesions reported. There were distinctions in overall disease assessment between the software and PET/CT report in 7 (41%) cases. Treating oncologists deemed 54% of the reports useful and found the software most useful for spatial information (75%), followed by systemic treatment decision and patient education (54%). Conclusions: The novel algorithm-based software TRAQInform IQ created to quantify and classify change in lesions across serial PET/CT scans in conjunction with standard radiology reports was highly accurate. There was notable variability in appreciated usefulness across treating physicians. This analysis provides novel data to better understand how this technology can be integrated in practice and assist with standard clinical judgment and management decisions.
NeoRay phase IIa results: A study of [ <sup>177</sup> Lu]Lu-NeoB ( <sup>177</sup> Lu-NeoB) in pts with advanced solid tumors overexpressing gastrin-releasing peptide receptor (GRPR).
3095 Background: GRPR is overexpressed in many solid tumors. NeoB binds to GRPR with high affinity and can be radiolabeled for theranostics. NeoRay is the first-in-human study of 177 Lu-NeoB in pts with advanced solid tumors overexpressing GRPR. Phase (Ph) I reported favorable organ dosimetry and safety, and a recommended Ph II dosage (RP2D) of 9.25 GBq. Here, we report the Ph IIa primary analysis. Methods: This Ph IIa, open-label, multicenter, dosage expansion study enrolled 5 adult cohorts with confirmed [ 68 Ga]Ga-NeoB tumor uptake: A) HR+/HER2- breast cancer; B) prostate cancer (PCa); C) gastrointestinal stromal tumor (GIST); D) impaired renal function; and E) pts eligible for Cohorts A–C who also received sacubitril/valsartan (49/51 mg) at Cycle 1 to assess drug-drug interaction (DDI). There was no formal sample size calculation; the target was ~12 pts in Cohorts A–C, ≤6 pts in D, and ~3 pts in E. 177 Lu-NeoB 9.25 GBq was to be administered every 6 wks for ≤9 cycles, except in DDI Cohort E (5.55 GBq in Cycle 1, then 9.25 GBq). Primary endpoints (descriptive statistics) were individual response (centrally assessed by RECIST v1.1) in Cohorts A–C, and 177 Lu-NeoB PK and dosimetry in Cohort E. Secondary endpoints included safety/tolerability and QoL. Results: Overall, 18 pts (A n = 4; B n = 7; C n = 2; D n = 2; E n = 3) received treatment (median age 65 y; 56% male). Median (range) 177 Lu-NeoB exposure was 9 (6–60) wks; median (range) cumulative activity administered was 12.1 (5.7–81.4) GBq. At data cutoff (7 Jan 2025), 4 pts (B n = 2; C n = 2) had completed treatment (≥3 cycles); 1 pt (GIST) received 9 cycles. Of 10 pts with centrally assessed post-baseline response data, 1 had partial response (PCa), 5 had stable disease (of whom 2 had stable disease ≥20 wks [GIST]), and 4 had progressive disease. Adverse events (AEs) occurred in 17 (94%) pts (serious AEs in 3 [17%] pts; Gr ≥3 AEs in 6 [33%] pts). Treatment-related AEs (TRAEs) occurred in 7 (39%) pts (all non-serious; Gr ≥3 in 2 [11%] pts). The most common TRAEs were fatigue (n = 5, 28%), anemia (n = 2, 11% [Gr ≥3 in 1 pt, 6%]), and bone pain (n = 2, 11%). One pt died of hepatic failure related to disease progression (not a TRAE). No AEs led to dosage reductions/interruptions/discontinuations. Dosimetry evaluated in 12 pts showed favorable biodistribution, similar to Ph I. Projected cumulative absorbed doses in target organs were below EBRT limits; lesion absorbed doses were generally consistent across cohorts. Mean ± SD EORTC QLQ-C30 global health scores in Cohorts A–C were 70 ± 22 at baseline (n = 12) and 73 ± 16 at Cycle 2 (n = 4), suggesting stable QoL. Conclusions: NeoRay Ph IIa data at the 177 Lu-NeoB RP2D (9.25 GBq) reinforce Ph I dosimetry and safety results and support further clinical evaluation. Most AEs were mild/moderate and no new safety signals were identified. Despite the limited sample size, preliminary signs of antitumor activity were observed. Clinical trial information: NCT03872778 .
Assessment of killer-cell immunoglobulin-like receptor (KIR) polymorphisms and their HLA-ligands in epithelial ovarian cancer (EOC).
e17580 Background: EOC carcinogenesis involves the progressive accumulation of genetic, epigenetic, and molecular alterations, resulting in heterogeneous expression of tumor-associated antigens, suggesting a role of the immune system in tumor development and progression. Natural Killer–cell mediated tumor surveillance depends on the balance between inhibitory and activating signals. In this context, characterization of KIR polymorphisms and their HLA ligands may be crucial to understand their influence on EOC susceptibility and prognosis. This study aimed to evaluate the role of KIR polymorphisms and HLA ligands in EOC. Methods: This retrospective longitudinal study included 118 women: 64 EOC patients treated at Hospital Reina Sofia, from 2020 to 2023, and 54 controls. Differences in the distribution of KIR polymorphisms and HLA-A, -B, and -C ligands were analyzed according to disease presence. In the patient group, the association of these variables with a previously established prognostic factor was evaluated: platinum-free interval until relapse (PFI). Clinical and pathological data were analyzed using Kaplan-Meier, Long-rank and Chi-square/Fisher test. Results: HLA-A*11:01 was significantly associated with EOC diagnosis (OR 3.13; 95% CI 1.14–8.58; p=0.022), whereas HLA-B*38:01 was associated with absence of disease (OR 0.19; 95% CI 0.04–0.92; p=0.042). Regarding PFI, HLA-A*23:01, HLA-A*29:02, and HLA-B*37:01 were associated with shorter PFI, while HLA-B*44:03 was associated with longer PFI; as shown in table. With a median follow-up of 50 months (m), univariate survival analysis showed significantly poorer overall survival in carriers of HLA-B*37:01 (4 vs 102 m; p<0.001). A non-significant trend toward shorter survival was observed among HLA-A*29:02 carriers (48 vs 102 m; p=0.191). No significant associations were observed for KIR. Conclusions: Specific HLA ligands may influence both susceptibility and prognosis in EOC. HLA-A*11:01 appears to increase disease risk, while HLA-B*38:01 may exert a protective effect. Moreover, HLA-A*23:01, HLA-A*29:02, and HLA-B*37:01 are associated with shorter PFI, with HLA-B*37:01 also correlating with poorer survival. These findings suggest a potential role of HLA in EOC and may justify further investigation into its relevance for prognostic stratification and personalized therapies. PFI < 6 m PFI > 6 m N N p OR (CI 95%) HLA-A*23:01 Positive: 2Negative: 11 Positive: 0Negative: 51 0,039 0,177 (0,104-0,303) HLA-A*29:02 Positive: 5Negative: 8 Positive: 4Negative: 47 0,013 0,136 (0,030-0,619) HLA-B*37:01 Positive: 3Negative: 10 Positive: 0Negative; 51 0,007 0,164 (0,093-0,289) HLA-B*44:03 Positive: 5Negative: 8 Positive: 7Negative: 44 0,041 0,255 (0,065-1,005)
Secondary multiple myeloma and antecedent cancer lineage.
e22622 Background: The emergence of second primary malignancies (SPM) constitutes a growing clinical burden. However, data describing Multiple Myeloma (MM) as a subsequent malignancy remain limited. Emerging evidence suggests that the risk of developing secondary MM may vary according to the biologic lineage of the antecedent malignancy, however, these associations are understudied. We conducted a study to examine lineage-specific patterns in antecedent malignancies associated with secondary MM. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network. Adult patients who developed MM following a prior cancer diagnosis were identified. The index date was defined as the diagnosis of secondary MM. Demographics and prior malignancy distributions were summarized for the overall cohort. Comparative analyses were performed between patients with prior solid versus hematologic malignancies, and between prior myeloid versus lymphoid malignancies. Outcomes were assessed starting 1 day after the index. Propensity score matching (1:1) was performed for age, sex, race, ethnicity, and comorbidities where applicable. Risk and survival analyses excluded patients with outcomes prior to the analysis window. Results: The cohort included 7,838 patients with secondary MM, mean age of diagnosis of MM 68.4 +/- 13 years, and was predominantly male and white population. Survival probability at the end of 10 years was 46.9%. Antecedent malignancies included malignant neoplasms of lymphoid, hematopoietic and related tissue (28%), Myeloproliferative Neoplasms (12.3%), Myelodysplastic Syndrome (MDS) (10%). Solid neoplasms included breast (5%), gastrointestinal (5%), urinary tract (4%) and respiratory (4%). After propensity score matching, secondary MM was more common after antecedent hematologic compared to solid tumors (risk difference 0.956%, 95% CI 0.908-1.004%; OR 12.08, 95% CI 10.29-14.18; HR 12.44). In myeloid vs lymphoid malignancies, secondary MM occurred in 634 vs 419 patients, (risk difference 0.15%, 95% CI 0.105-0.193; OR 1.51, 95% CI 1.34-1.71, HR 1.51). Conclusions: Secondary MM was more commonly observed following antecedent hematologic malignancies, particularly myeloid neoplasms, than solid tumors in a large real-world cohort. This pattern highlights the need for heightened vigilance in long term survivors of myeloid neoplasms. Further studies should define mortality, disease risk features, and whether management strategies should differ from de novo MM. Characteristics of secondary multiple myeloma cohort. Demographic Characteristics Number of patients % of patients Secondary MM cohort 7,838 100 Male 4,213 54.58 Female 3,503 45.38 White 5,836 75.61 African American 1,109 14.37 Asian 181 2.35 Hispanic 303 3.93
Myeloablative vs reduced-intensity conditioning in PTCy-based allogeneic HCT: A CIBMTR analysis.
6563 Background: Post-transplant cyclophosphamide (PTCy) is widely used in matched unrelated and haploidentical HCT. However, the optimal conditioning intensity in the PTCy era remains unclear. This study compared outcomes of myeloablative versus reduced-intensity conditioning in MUD and haploidentical HCT recipients. Methods: This retrospective multicenter study utilized the Center for International Blood and Marrow Transplant Registry (CIBMTR) to analyze patients who underwent HCT and received PTCy, based on the P-6219 dataset by Modi et al. Clinical outcomes were compared between patients who received MAC and RIC. Kaplan–Meier analysis was used to determine mean overall survival (OS) and graft-vs-host disease (GVHD)-free relapse-free survival (GRFS). Cox proportional hazards regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). Statistical analyses were conducted using SPSS, with p-values less than 0.05 considered statistically significant. Results: A total of 5,873 patients were included, comprising 1,973 MUD recipients (797 MAC, 1,176 RIC) and 3,900 haploidentical recipients (1,485 MAC, 2,415 RIC). All patients received PTCy GVHD prophylaxis. Among MUD recipients, MAC was associated with significantly OS compared with RIC, with a mean OS of 27.8 months (95% CI 26.9–28.7) versus 24.8 months (95% CI 24.1–25.6, p<0.001). RIC was associated with a higher risk of mortality compared with MAC (HR 1.45, 95% CI 1.24–1.68, p<0.001). GRFS was also worse with RIC (mean 21.5 months, 95% CI 20.4–22.5 vs 18.3 months, 95% CI 17.4–19.2; HR 1.33, 95% CI 1.17–1.51, p<0.001). There were no significant differences between MAC and RIC in rates of grade 2–4 acute GVHD (HR 1.00, 95% CI 0.85–1.18, p=1.0), grade 3–4 acute GVHD (HR 1.04, 95% CI 0.72–1.51, p=0.84), or moderate/severe chronic GVHD (HR 0.97, 95% CI 0.86–1.08, p=0.59). Among haploidentical recipients, MAC was also associated with improved OS compared with RIC, with a mean OS of 26.1 months (95% CI 25.4–26.8) versus 24.1 months (95% CI 23.6–24.7, p<0.001), and RIC conferred a higher mortality risk (HR 1.29, 95% CI 1.16–1.43, p<0.001). GRFS was superior with MAC (18.4 months, 95% CI 17.6–19.2 vs 16.5 months, 95% CI 15.9–17.2; HR 1.17, 95% CI 1.08–1.27, p<0.001). Rates of grade 2–4 acute GVHD were lower with RIC (HR 0.88, 95% CI 0.78–0.98, p=0.018). Rates of grade 3–4 acute GVHD (HR 1.06, 95% CI 0.85–1.32, p=0.61) and moderate/severe chronic GVHD (HR 0.98, 95% CI 0.90–1.07, p=0.70) were similar between MAC and RIC. Conclusions: MAC was associated with improved OS and GRFS compared with RIC in MUD and haploidentical transplant recipients, with similar rates of severe acute and chronic GVHD. These findings support the use of MAC when patient comorbidities and performance status permit.
Real-world study of first-line immunotherapy for EGFR/ALK wild-type advanced NSCLC: Analysis from the China National Cancer Center database.
e20584 Background: Immune checkpoint inhibitor (ICI) monotherapy (mono) or combined with chemotherapy (CT) is standard first-line (1 st -L) therapy for advanced NSCLC. However, choosing optimal strategies in real-world settings remains challenging. Methods: We screened the China National Cancer Center Database (609 hospitals, 29 provinces) for stage IIIC/IV (AJCC 8th) EGFR/ALK wild-type NSCLC patients registered 2019-2024, who received 1 st -L ICI±CT. Clinical characteristics and survival outcomes were analyzed. Results: 1,107 patients were included. PD-L1 Tumor Proportion Score (TPS) was as follows: <1% (24.1%), 1-49% (39.4%), and ≥50% (36.5%). Brain metastases (M) occurred in 231 patients (20.9%), liver M in 111 (10.0%). 1 st -L therapy included ICI-mono (10.6%) and ICI+CT (89.4%). In the ICI+CT cohort, the median overall survival (mOS) was similar between TPS 1-49% and <1% groups (19.65 vs. 18.46 months; hazard ratio [HR] 0.91, 95% confidence interval [CI]: 0.73-1.14, P =0.43). However, in TPS ≥50% group, ICI+CT did not improve mOS vs. ICI-mono (26.64 vs. 26.15 months; HR 0.93, 95% CI: 0.60-1.43, P =0.73). OS multivariate analysis (Table 1) showed that in total population and ICI+CT cohort, older age, male and liver metastases were independent adverse prognostic factors, while TPS ≥50% was favorable. In TPS ≥50% group, older age remained adverse and liver M trended toward poor prognosis. Brain M were not adverse prognostic factor in any populations. Conclusions: This real-world study confirms advanced NSCLC patients with PD-L1 TPS <1% had similar OS to TPS 1-49% on 1 st -L ICI+CT. Though TPS ≥50% patients had better OS with ICI+CT, adding CT to ICI did not improve outcomes further. In immunotherapy era, older age and liver M were adverse prognostic factors; brain M were not. Multivariate analysis of OS. Total ICI+CT TPS ≥ 50% N HR (95%CI) P N HR (95%CI) P N HR (95%CI) P Age <65 627 Ref. 574 Ref. 230 Ref. 65-74 382 1.41(1.17，1.70) <0.001 338 1.38(1.14-1.68) 0.0012 142 1.51(1.07-2.14) 0.02 75-84 70 1.43(0.99，2.07) 0.057 57 1.34(0.88-2.03) 0.17 23 2.27(1.24-4.16) 0.0077 ≥85 28 4.03(2.54，6.38) <0.001 21 4.16(2.44-7.09) <0.001 9 5.30(2.37-11.82) <0.001 Sex Female 230 Ref. 202 Ref. 72 Ref. Male 877 1.48(1.17，1.88) 0.0013 788 1.55(1.21-2.00) <0.001 332 0.84(0.56-1.26) 0.40 Stage IIIC 60 Ref. 53 Ref. 27 Ref. IV 1047 1.45(0.94，2.23) 0.095 937 1.48(0.92-2.37) 0.10 377 1.20(0.58-2.47) 0.62 Liver Yes 111 1.43(1.10，1.86) 0.0071 105 1.44(1.10-1.89) 0.0081 29 1.63(0.98-2.72) 0.059 Brain Yes 231 0.87(0.70，1.09) 0.22 217 0.90(0.72-1.12) 0.34 87 0.97(0.66-1.42) 0.86 Treatment ICI 117 Ref. - - 66 Ref IO+CT 990 1.07(0.79，1.46) 0.66 - - 338 1.09(0.70-1.71) 0.70 TPS <1% 267 Ref. 255 Ref. - - 1-49% 436 0.93(0.75，1.16) 0.52 397 0.97(0.77-1.21) 0.78 - - ≥50% 404 0.65(0.57，0.82) <0.001 338 0.66(0.52-0.84) <0.001 - -
PCSK9 inhibitors and association with lower risk of metastasis.
10588 Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates degradation of membrane proteins including the low-density lipoprotein (LDL) receptor and major histocompatibility complex class I (MHC-I) independently. Beyond lipid metabolism, preclinical studies have shown that PCSK9 inhibition reduces metastasis in animal models, suggesting potential to suppress tumor cell proliferation, migration, and immune evasion. However, population-level evidence across malignancies is limited. We evaluated whether PCSK9 inhibitor (PCSK9i) use is associated with risk of cancer metastasis in a large real-world cohort. Methods: In this new-user, active-comparator cohort study using the TriNetX U.S. Collaborative Network (≈134 million patients), eligible patients were adults who initiated PCSK9i or statins alone for hyperlipidemia between 01/01/2015 and 01/01/2025 and subsequently received a cancer diagnosis. Index date was first prescription of PCSK9i or statin, with follow-up period continued until occurrence of study outcomes. To reduce reverse causation and early detection bias from intensified workup around drug initiation, patients with any cancer diagnosis within 6 months after index were excluded. 1:1 propensity score matching (PSM) balanced pre-index demographics, ASCVD and liver comorbidities, cancer screening procedures (low-dose chest CT, Pap smear, colonoscopy), BMI, and LDL. Primary outcome was time to any metastatic cancer (ICD-10 C77–C79); secondary outcomes were site-specific metastases (liver, lung, bone, brain, lymph node, adrenal gland). Cox proportional hazards models estimated hazard ratios (HRs) with 95% CIs. Results: Among 1,149,843 adults newly prescribed PCSK9i or statin (mean age 61.7 years, SD 10.6), median follow-up was 2,926 days. After 1:1 PSM, 8,674 patients remained in each cohort with balanced baseline characteristics (all standardized mean differences <0.1). Metastatic cancer was diagnosed in 435 PCSK9i patients versus 741 statin patients. The overall hazard of metastasis did not differ significantly (HR 0.96, 95% CI 0.85–1.08). In site-specific analyses, PCSK9i use was associated with lower hazards of liver metastasis (HR 0.64, 95% CI 0.50–0.85) and lung metastasis (HR 0.78, 95% CI 0.65–0.94); hazards for lymph node, brain, adrenal, and bone metastases were similar between groups. Sensitivity analyses accounting for competing risk of death showed consistent directionality. Conclusions: In this nationwide cohort study, overall metastatic risk was similar between PCSK9i and statin-only users, but PCSK9i use was associated with lower hazards of liver and lung metastases. Further mechanistic and prospective investigation are warranted to elucidate the role of PCSK9 inhibition in tumor progression and metastasis.
Impact of a whole-food plant-based diet (WFPBD) on weight and metabo-inflammation in men with prostate cancer (PC) receiving androgen deprivation therapy (ADT): A multi-center randomized control trial.
5098 Background: Obesity promotes a chronic inflammatory state associated with PC progression. ADT can cause weight gain, accumulation of body fat, insulin resistance and increased risk of diabetes and cardiovascular disease. A WFPBD promotes weight loss, decreases inflammation, and shifts the gut microbiome to promote insulin sensitivity. We hypothesized that a WFPBD and behavioral intervention will promote weight loss and a reduction in adiposity in overweight/obese patients with PC on ADT. Methods: Pts with PC with BMI ≥ 27 receiving ADT with an LHRH/GnRH analogue for >24 wks pre-study (+ AR pathway inhibitor allowed if stable dose for >3 mos) with plan >26 more wks were eligible. 60 patients were randomized 1:1. WFPBD group: 12 prepared and home delivered WFPBD meals per wks 1-4, 6 meals wks 5-8 and coaching to assist in self-prepping plant-based meals (wks 9-26); Control group: counseling on a general healthful diet from a Registered Dietician weekly for 8 wks, then monthly (wks 9-26). Baseline and serial measurements (pre-intervention, wks 4, 8 and 26): weight, body composition assessment via dual energy x-ray absorptiometry (DXA), and biomarkers of inflammation and metabolism were collected. Primary endpoint was weight loss at 4 weeks (with an 80% power to detect an effect size 0.74 standard deviations with a 2-sided significance level of 0.05 using a two-sample t-test). Secondary objectives were change in body composition, biomarkers of metabolic disorders and cardiovascular risk and quality of life measurements. Results: 60 pts were randomized (31 control, 29 WFPBD). Median age was 73; Race: 65% white, 28% Black, 2% Asian, 5% other/unknown; Median baseline weight 98 kg; No difference in baseline HbA1c or lipid profile between groups. Mean weight loss (kg) at 4, 8 and 26 wks: WFPBD: 3.9, 5.3 and 6.1 kg; Control 1.3, 1.6, 2.1 kg, respectively (each timepoint pair p<0.001). DXA measured BMI change at 4 and 26 wks: WFPBD: -1.1 and -1.93 kg/m 2 , Control: 0.35 and 0.25 kg/m 2 (each timepoint pair p<0.001). DXA measured mean lean (LM), fat (FM) and total mass (TM) showed declines at 4 wks in WFPBD versus Control (LM -2.4 vs -0.64 (p<0.001); FM -1.3 vs -0.35 (p=0.023); TM -3.61 vs -0.88 (p<0.001), whereas at 26 weeks only FM and TM remained significantly less (LM -2.2 vs -1.4 (p=0.143); FM -5.3 vs -0.8 (p=0.001); TM -6.7 vs -2.2 (p<0.001). No significant differences were seen in HbA1c or lipid profiles at 6 mos. Conclusions: Compared with nutritional counseling, obese men with PC on ADT subjected to a home-delivered WFPBD for 2 mos and behavioral coaching experienced significantly greater weight loss, BMI reduction and decreases in total and fat mass that persisted for 6 months. Biomarkers of metabo-inflammation, insulin levels, fecal microbiota and metabolites, and serum for metabolomics collected are undergoing analyses. Clinical trial information: NCT05471414 .
Impact of an electronic best practice advisory on fertility preservation referral and consultation rates in pediatric oncology: A pre–post implementation study.
e13529 Background: Fertility preservation (FP) counseling is recommended as standard of care for pediatric oncology patients receiving gonadotoxic therapy, yet adherence to guidelines remains suboptimal. At our institution, historical data demonstrated low rates of pre-treatment FP counseling and referral. To improve access to FP services, an electronic medical record (Epic) Best Practice Advisory (BPA) was implemented to prompt FP referral at the time of new cancer diagnosis. Methods: A BPA identifying patients assigned female at birth with a new cancer diagnosis and planned gonadotoxic therapy was implemented on January 25, 2023. We conducted a retrospective chart review of all eligible patients for whom a BPA was triggered between January 25, 2023 and December 31, 2025. Outcomes included FP referral rates, FP/gynecology consultation rates, and time to referral and consultation. These outcomes were compared to a historical pre-BPA group (January 2018–January 2021) previously evaluated at our institution. Research ethics approval was obtained. Results: Eighty-seven patients met inclusion criteria in the post-BPA cohort (mean age 7.6±5.5 years; 59.3% prepubertal). The number of pre-treatment FP/gynecology consultations were 32.6% (29/89) and 32.2% (28/87) with the number of referrals to fertility specialists being 13% (12/29) and 10.7% (3/28) and the uptake of FP procedure was 3.4% (1/29) and 3.6% (1/28), in the pre- versus post- BPA groups, respectively. Following BPA implementation, the consultations occurred a median of 5 days after diagnosis and 1 day after referral. Only 42.9% of the FP/gynecology referrals (12/28) were initiated through the BPA, indicating partial uptake of the tool. Conclusions: Despite implementation of an electronic BPA, overall consultation rates, speciality referral, and FP treatment, remained the same. These findings suggest that passive electronic prompts alone are insufficient to achieve guideline-level FP integration which is also reflected in the fact that half of the referrals occurred through other pathways than the BPA. Future work will focus on embedding FP referral into standardized oncology order sets, using a default referral strategy and testing a workflow-anchored hard stop to improve referral reliability while minimizing workflow burden.
Predictive value of PET-CT and tumor biology for pathological complete response in triple-negative breast cancer treated with neoadjuvant pembrolizumab: A real-world analysis.
e12589 Background: Pembrolizumab combined with chemotherapy improves pathological complete response (pCR) in early-stage triple-negative breast cancer (TNBC). However, real-world predictors of response and the reliability of imaging biomarkers remain unclear. We evaluated clinical, biological, and imaging factors associated with pCR in a real-world TNBC cohort treated with neoadjuvant pembrolizumab. Methods: This retrospective study included 35 patients with stage II–III TNBC treated with neoadjuvant chemotherapy plus pembrolizumab. Post-neoadjuvant PET-CT was performed before surgery. Associations between pCR (ypT0/is ypN0) and PET-CT response, HER2-low status, germline homologous recombination repair (HRR) mutations, carboplatin completion, menopausal status, and pembrolizumab dose were analyzed using Fisher’s exact test. Results: The overall pCR rate was 62.8%, comparable to KEYNOTE-522. Complete metabolic response (CMR) on PET-CT was strongly associated with pCR; all patients achieving pCR demonstrated CMR, and no pCR occurred among patients with partial response or stable disease (p = 0.003). PET-CT showed 100% sensitivity and negative predictive value for pCR. HER2-low tumors had lower pCR rates than HER2-0 tumors (45% vs. 70%), despite similar CMR rates, suggesting a discordance between imaging and pathological responses. Germline HRR mutation status did not significantly impact pCR (63.5% vs 62.5%). Carboplatin completion was associated with numerically higher pCR rates (71.5% vs 50%). Pembrolizumab dose and menopausal status were not associated with pCR. Immune-related adverse events were consistent with known safety profiles. Conclusions: In this real-world TNBC cohort, PET-CT CMR strongly predicted pCR after pembrolizumab-based neoadjuvant therapy. However, HER2-low tumors demonstrated reduced pathological response despite favorable metabolic imaging, indicating that tumor biology may modify the predictive value of PET-CT. These findings may refine response assessment and identify subgroups that could benefit from post-neoadjuvant escalation strategies.
Age-based differences in outcomes among small cell lung cancer patients treated with tarlatamab.
8069 Background: Tarlatamab has durable antitumor activity in patients with previously treated Small Cell Lung Cancer (SCLC). A rising fraction of SCLC diagnoses is now observed in older patient groups. To assess real-world outcomes, we analyzed a large, multi-institutional database evaluating age-related differences in survival, treatment patterns, and immune toxicities, including Cytokine Release Syndrome (CRS) and Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS), to clarify factors affecting response and tolerability. Methods: A retrospective cohort study was conducted using de-identified data from the TriNetX Research Network. At the time of data analysis, it included 154,537,377 patients across 113 healthcare organizations. We identified adults aged 18 years or older with lung cancer treated with Tarlatamab. Kaplan-Meier analysis assessed overall survival. Statistical comparisons of survival rates between groups were performed using the log-rank test. Propensity matching was used to adjust for age, comorbidities, and lines of treatment. Results: A total of 616 patients were identified in the TriNetX cohort, with a mean age of 65.8 ± 9.89 years, and 51.9% were female. Age distribution was as follows: 124 patients (20.13%) were younger than 60 years, 271 (43.99%) were 60–70 years, and 221 (35.88%) were older than 70 years. Brain metastases were present in 53 patients (8.60%) in the <60 group, 116 (18.83%) in the 60–70 group, and 90 (14.61%) in the >70 group. Median overall survival of the entire cohort was 13.32 months; it was not reached in the <60 group, 13.32 months in the 60–70 group, and 12.72 months in the >70 group, with no significant differences across age groups or brain metastasis status. In the propensity score–matched cohorts, survival did not differ significantly between <60 and >70 age groups (HR 0.80 (95% CI 0.34–1.22; p=0.39)), and a similar lack of difference was observed between 60–70 and >70 age groups (HR 0.72 (95% CI 0.48–1.07; p=0.10)). In the overall population, 57 patients (9.25%) experienced ICANS and 67 (10.88%) developed CRS. By age group, ICANS and CRS occurred in 16 (2.60%) and 17 (2.76%) patients <60, 23 (3.73%) and 29 (4.71%) patients 60–70, and 18 (2.92%) and 21 (3.40%) patients >70, respectively. Overall, 91 patients (14.77%) required tocilizumab and 23 (3.73%) required vasopressors, with no significant differences across the three age groups. Conclusions: This study offers an extensive evaluation of age-related outcomes with Tarlatamab. Neither age nor brain metastases significantly influenced overall survival, indicating preserved efficacy in older adults. ICANS and CRS were infrequent and evenly distributed across age groups. Tocilizumab and vasopressor use were similar across groups, indicating comparable severity. These results support Tarlatamab’s favorable safety, tolerability, and effectiveness across diverse real-world populations.
FIERCE-HN: A multicenter, randomized, double-blind, placebo-controlled, phase 3 study of ficlatuzumab (HGF/cMET mAb) in combination with cetuximab in participants with recurrent or metastatic (R/M) HPV-negative head and neck squamous cell carcinoma (HNSCC).
TPS6132 Background: Patients with HPV negative R/M HNSCC have a worse median overall survival (OS) than those with HPV positive disease and current treatment options are limited. [1] Ficlatuzumab is a humanized IgG1 mAb that binds HGF, the ligand for the c-MET tyrosine kinase receptor. HGF/c-MET pathway dysregulation is frequently observed in HPV negative HNSCC and has been linked to EGFR inhibitor resistance, limiting the potential efficacy of EGFR-targeting drugs like cetuximab. In a phase 2 study, both pathways were targeted using ficlatuzumab plus cetuximab in patients with HPV negative R/M HNSCC resistant to cetuximab, platinum, and anti-PD1 immune checkpoint inhibitors (ICI) who have a very poor historical prognosis. A PFS of 4.1 months, median OS of 7.4 months, and overall response rate (ORR) of 38% (6/16; 2 CR, 4 PR) was observed. [2] FIERCE-HN compares the efficacy and safety of ficlatuzumab+cetuximab vs placebo+cetuximab in patients with R/M HPV negative HNSCC. Methods: This is an international, multicenter, randomized, double-blind, placebo-controlled phase 3 study. Major enrollment criteria include confirmed diagnosis of R/M HNSCC primary tumors of the oropharynx (p16 negative only), oral cavity, hypopharynx, or larynx. Participants must have progressed on, or be intolerant to, previous anti-PD-1/PD-L1 ICI and platinum-based chemotherapy; have received 2 or fewer prior lines of anticancer therapy in the R/M setting; and have had no prior treatment with cetuximab/alternative EGFR inhibitors in the R/M setting. Patients with feeding tubes are eligible. The primary endpoint is OS; key secondary endpoints include PFS and ORR. Other secondary endpoints are DCR, DoR, safety, PK, immunogenicity and QoL. Patients will receive cetuximab 500mg/m2 and are randomized 1:1:1 to Arm A: ficlatuzumab 10mg/kg, Arm B: ficlatuzumab 20mg/kg, or Arm C: placebo. Treatments will be on Days 1 and 15 of a 28-day cycle. This is an adaptive study with two interim analyses (IAs). IA-1 is ongoing to select the optimal dose. Participants enrolled after IA-1 will be randomized 1:1 to the optimal ficlatuzumab dose or placebo, plus cetuximab. IA-2 will be conducted after ~ 163 OS events to assess whether an event count re-estimation is needed. The final analysis will occur after ~ 232 (or up to 279) OS events, depending on the re-estimation outcome. The study has statistical power of 80%, assuming a true OS hazard ratio of 0.667. Between 410 to 500 patients will be enrolled. The study is ongoing and actively recruiting in North America, Europe, United Kingdom, and Asia-Pacific. Clinical trial information: NCT06064877 (Eli Lilly provided cetuximab in N. America and Merck KGaA, Darmstadt, Germany in Europe, United Kingdom and Asia-Pacific). 1. JITC. 2019;7:184. 2. JCO. 2023. 41:3851. Clinical trial information: NCT06064877 .
Intracranial efficacy of osimertinib in <i>EGFR</i> -mutated non–small cell lung cancer with brain metastases: A meta-analysis.
e20765 Background: Brain metastases are a major cause of morbidity and mortality in EGFR-mutated non-small cell lung cancer (NSCLC). Osimertinib demonstrates central nervous system (CNS) activity, but intracranial efficacy estimates remain heterogeneous, particularly by treatment line. Methods: Pubmed, Cochrane Library and Scopus were searched for studies reporting intracranial outcomes in adults with EGFR-mutated non-small cell lung cancer and brain metastases treated with Osimertinib. Studies reporting patient-level intracranial objective response rate (ORR) and/or disease control rate (DCR) were included. Pooled intracranial ORR and DCR were estimated using random-effects meta-analyses. Heterogeneity was assessed using the I² statistic. A subgroup analysis was performed for first-line osimertinib. Safety outcomes were pooled when grade ≥3 adverse events were reported. Results: Nine studies with 299 patients were included in the primary analysis. The pooled intracranial ORR across all treatment lines was 62.1% (95% CI, 45.2%-76.5%; I² = 77.3%), while the pooled intracranial DCR was 92.5% (95% CI, 86.8%-95.8%; I² = 11.4%). In the subgroup analysis of Osimertinib as first-line, pooled intracranial ORR was 86.6% (95% CI, 71.1%-94.5%; I² = 23.9%), and pooled intracranial DCR was 97.5% (95% CI, 76.5%-99.8%; I² = 0%). Median overall survival was longer in first-line Osimertinib cohorts (23.7–35.2 months) than in later-line cohorts (5.9–16.2 months). Across studies reporting safety outcomes (N = 235 patients), the pooled incidence of grade ≥3 adverse events was 11.0% (95% CI, 5.0%-22.5%; I² = 39.8%). In studies (N = 3) evaluating Osimertinib plus chemotherapy, the sample-size–weighted intracranial median PFS was approximately 23.2 months. Conclusions: Osimertinib provides durable intracranial disease control in EGFR-mutated NSCLC with brain metastases, with the higher efficacy observed in the first-line setting. These findings support Osimertinib as a CNS-active systemic therapy and underscore the need for CNS-focused endpoints in future trials. Analysis Group Outcome Estimate (95% CI) I² (%) P - Value Overall Intracranial ORR 62.1% (45.2–76.5) 77.3 <0.0001 Intracranial DCR 92.5% (86.8–95.8) 11.4 0.338 First-line Osimertinib Intracranial ORR 86.6% (71.1–94.5) 23.9 0.267 Intracranial DCR 97.5% (76.5–99.8) 0 0.526 Safety Grade ≥3 adverse events 11.0% (5.0–22.5) 39.8 0.156 Osimertinib + Chemotherapy Intracranial Median PFS 23.2 months (NA) _ _
Burden of non-Hodgkin lymphoma in South Asia, 1990–2023: Analysis of the Global Burden of Disease study 2023.
e19086 Background: Non-Hodgkin lymphoma (NHL) contributes substantially to the global cancer burden, yet long-term, sex-specific trends in mortality, prevalence, and overall disease burden across South Asia remain incompletely characterised. Using Global Burden of Disease (GBD) 2023 estimates, we quantified temporal changes in NHL burden in the South Asian region from 1990 to 2023. Methods: Using Global Burden of Disease (GBD) 2023 estimates, we analysed age-standardised mortality, prevalence, disability-adjusted life years (DALYs), and years of life lost (YLLs) for non-Hodgkin lymphoma in South Asia from 1990–2023, stratified by sex and country. Temporal trends were quantified using average annual percent change (AAPC) with 95% uncertainty intervals (UI). Results: Between 1990 and 2023, the age-standardised mortality rate for non-Hodgkin lymphoma in South Asia increased from 2.38 (95% UI: 1.78–3.12) per 100,000 to 2.59 (1.90–3.41), with a persistent male excess (2023: males 3.18 [2.10–4.63] vs females 2.02 [1.22–2.96]). Mortality increased in Pakistan (both sexes AAPC: 0.30%; 95% UI: 0.21–0.39) and India (0.16%; 0.05–0.26), remained modestly positive in Bhutan (0.10%; 0.04–0.17), and declined in Nepal (−0.35%; −0.42 to −0.27), where female mortality fell most rapidly (−0.57%; −0.70 to −0.43). Age-standardised prevalence rose substantially across all countries and outpaced mortality trends. In South Asia, prevalence increased from 4.84 (3.35–7.07) per 100,000 in 1990 to 11.0 (6.22–18.9) in 2023 (AAPC: 2.46%; 2.26–2.67). Prevalence more than doubled in Bangladesh (5.08 to 11.9) and India (4.49 to 11.0), and nearly tripled among South Asian females (3.93 to 9.57; female AAPC: 2.70% vs male: 2.34%), likely reflecting improved survival. Country-level prevalence growth was highest in Bangladesh (AAPC: 2.56%; 2.35–2.77) and Pakistan (2.25%; 2.09–2.41), and lowest in Nepal (1.44%; 1.34–1.54). DALY rates declined in Nepal (66.9 [47.0–90.0] to 57.1 [40.0–79.7]; AAPC: −0.46%; −0.55 to −0.37) and Bangladesh (86.3 [61.4–113.0] to 76.1 [52.3–104.9]; −0.29%; −0.38 to −0.20), driven largely by reductions in YLLs. In contrast, DALYs increased in Pakistan (117.5 [83.0–156.9] to 129.9 [93.1–177.2]; AAPC: 0.49%; 0.39–0.59), with the steepest rise among females (0.80%; 0.67–0.92). Regionally, DALY (0.03%; −0.07 to 0.14) and YLL (0.02%; −0.08 to 0.12) trends remained broadly stable due to offsetting country-level patterns. Conclusions: NHL burden in South Asia is characterised by rapidly rising prevalence, persistent male excess mortality, and pronounced cross-country heterogeneity, underscoring the need for country-specific cancer control strategies.
Discovery of novel biomarkers for glioblastoma using VHH antibodies.
e14068 Background: Although comprehensive genomic profiling has revealed the molecular features of glioblastoma (GBM), most identified genomic alterations fail to translate into effective therapeutic targets to date, underscoring a critical gap between molecular characterization and druggable GBM biology. Tumor cell surface antigens play a crucial role in novel cancer therapies such as CAR-T and antibody-drug conjugates. The lack of clinically actionable, tumor-selective cell-surface biomarkers remains a fundamental obstacle to such novel approaches for GBM. Alpaca-derived variable domain of heavy chain of heavy chain (VHH) antibodies possess a simple structure, are easily digitized through sequencing, and enable AI-driven biomarker discovery. Methods: We established Inverse BioMarker Exploration Technology (IBMET) using VHH, a fundamentally different biomarker discovery approach that treats antibodies as structural sensors rather than affinity reagents. A large-scale alpaca-derived VHH repertoire was generated through immunization using multiple GBM cell lines, followed by phage display and deep sequencing. Instead of selecting antibodies against predefined targets, IBMET applies enrichment-based statistical analysis across millions of VHHs to identify convergent binding patterns indicative of shared tumor-specific structural epitopes. Candidate VHHs were validated by immunohistochemistry and immunofluorescence using extensive panels of GBM and normal human tissues. Antigen identity was resolved by cross-linking immunoprecipitation and LC–MS/MS. Clinical relevance was assessed in an independent GBM cohort (n = 20). Results: IBMET uncovered multiple previously inaccessible structural biomarker candidates in GBM. The lead clone, VHH19, selectively recognized a novel antigen protein not previously implicated in GBM biology. VHH19 demonstrated robust and highly tumor-specific staining in GBM tissues, with negligible reactivity across normal organs. Notably, VHH19 positivity was observed in over 20% of GBM cases, defining a clinically relevant tumor subset unified by a shared structural epitope rather than genomic alteration or expression level. These findings reveal a previously unrecognized layer of tumor stratification based on conformational antigen states. Conclusions: IBMET represents a paradigm shift in biomarker discovery by enabling direct, high-throughput identification of structurally defined tumor-selective targets independent of prior molecular assumptions. By bridging antibody-level structural recognition with translational validation, this approach opens a new route to actionable targets in GBM, with immediate implications for antibody–drug conjugates, radioligand therapies, and companion diagnostics. Four GBM-selective VHH antibodies identified through IBMET will be released for research use in June 2026, facilitating rapid downstream translation.