BACKGROUND: Germline alterations and smoking status in lung cancer could inform etiology and clinical decisions. We investigated the prevalence of germline alterations in predisposition genes across various lung cancer h...BACKGROUND: Germline alterations and smoking status in lung cancer could inform etiology and clinical decisions. We investigated the prevalence of germline alterations in predisposition genes across various lung cancer histologies in two large populations. PATIENTS AND METHODS: Germline sequencing of 11 740 primary lung cancers was carried out with Tempus xT tumor-normal matched assay (DNA sequencing of 648 genes at an average coverage of 500×, normal specimens at 150× coverage, full transcriptome RNA sequencing). Pathogenic/likely pathogenic (P/LP) potential germline alterations in 46 genes were compared between smokers and never smokers; never smokers somatic EGFR altered (sEGFRalt) and wild type (sEGFRwt); non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) histologies; and NSCLC sEGFRalt and NSCLC sEGFRwt. P/LP variants were investigated in these 46 genes in 1330 patients with lung cancer from the UK Biobank by smoking status. RESULTS: Tempus sequencing revealed P/LP alterations in 4.8% of smokers and 5.8% of never smokers, with most alterations in MUTYH (1.3% versus 1.1%), ATM (0.7% versus 1.0%), BRCA2 (0.6% versus 0.9%), and EGFR (<0.1% versus 0.4%). Never smoker sEGFRalt (n = 549) and sEGFRwt (n = 1025) tumors had alterations in MUTYH (1.1% versus 1.1%), ATM (0.7% versus 1.1%), and EGFR (1.1% versus 0%). NSCLC and SCLC tumors had alterations in MUTYH (1.3% versus 0.3%), ATM (0.8% versus 0.3%), and BRCA2 (0.7% versus 0%). sEGFRalt and sEGFRwt NSCLC tumors had germline alterations in MUTYH (1.6% versus 1.3%), ATM (0.5% versus 0.8%), EGFR (1.3% versus 0%), and BRCA2 (0.8% versus 0.6%). UK Biobank patients had similar P/LP alterations: 4.3% of smokers and 5.1% of never smokers, with most germline alterations in ATM (0.8%), BRCA2 (0.79%), and MUTYH (0.62%) in smokers and MUTYH (1.5%) and CHEK2 (1.01%) in never smokers. CONCLUSION: Similar distribution of P/LP potential germline alterations in lung cancer subtypes from distinct populations by smoking status suggests that increased next-generation germline sequencing may improve risk assessment.
Aldea M, Zullo L, Levrat V
… +28 more, Bennouna J, Schneider S, Mercier O, Mougenot E, Bergot E, Dujon C, Cloarec N, Audigier Valette C, Nuccio A, Deloger M, Helissey C, Simon S, Carpentier A, Djarallah A, Rolland P, Louis JC, Ancillon L, Vignal B, Rambaud F, Tessier P, Chuttoo L, Siby K, Poplu A, Zarca K, Michiels S, Barlesi F, Le Ouay F, Besse B
BACKGROUND: Manual abstraction of real-world data (RWD) from unstructured health records (HRs) remains resource intensive, error prone, and highly variable across institutions. Large language models (LLMs) offer a scalab...BACKGROUND: Manual abstraction of real-world data (RWD) from unstructured health records (HRs) remains resource intensive, error prone, and highly variable across institutions. Large language models (LLMs) offer a scalable alternative, but their performance in multicenter oncology settings is not fully validated. PATIENTS AND METHODS: We conducted a multicenter study within the French Large & Unified Cancer Cohort (LUCC) consortium to compare the accuracy of artificial intelligence (AI)-based data extraction against manual abstraction by clinical research professionals. A fine-tuned LLM was applied to de-identified unstructured HRs in PDF format to extract 31 variables from lung cancer patients across 10 centers. Ground truth was defined as concordant values across sources, with discrepant cases adjudicated by a blinded expert. The primary endpoint was the extraction error rates. Secondary endpoints included per-variable performance, interinstitutional variability, F1-score for multiple-choice variables, added value of hybrid AI-human workflows, and survival analyses. RESULTS: Among 10 327 patients with AI-based extraction, 311 were included in the test cohort. Across 8708 datapoints for 28 variables with only one correct answer, the LLM achieved a 7.0% error rate, outperforming manual abstraction (14.2%, P <0.001). The F1-scores of three multiple-choice variables were superior (gene alterations 0.97 versus 0.86, comorbidities 0.86 versus 0.76, metastatic sites 0.71 versus 0.69). Interinstitutional variance was lower with AI (0.12% versus 0.39%). A hybrid approach with targeted human review of 30% of low-confidence AI outputs further decreased error rates to 4.4%. Survival analyses based on AI-extracted data closely matched ground truth, with similar median overall and progression-free survival. CONCLUSIONS: In a multicenter setting, our AI pipeline yielded lower error rates and greater consistency than manual abstraction. These findings support the feasibility of next-generation, AI-enabled multicenter studies to generate high-quality RWD at scale, with potential applicability in prospective clinical trials.
Jhaveri KL, Neven P, Casalnuovo ML
… +19 more, Kim SB, Tokunaga E, Aftimos P, Saura C, O'Shaughnessy J, Harbeck N, Carey LA, Curigliano G, Watanabe J, Lim E, Huang J, Qingyuan Z, Llombart-Cussac A, Huang C, Desai B, Limay Y, Wang XA, Cao S, Bidard FC
BACKGROUND: At the primary progression-free survival (PFS) analysis, the phase III EMBER-3 trial in endocrine therapy-pretreated patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HE...BACKGROUND: At the primary progression-free survival (PFS) analysis, the phase III EMBER-3 trial in endocrine therapy-pretreated patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) demonstrated significant PFS benefit with imlunestrant versus standard of care (SOC: fulvestrant or exemestane) in patients with ESR1 mutations (ESR1m) and with imlunestrant-abemaciclib versus imlunestrant in all patients, regardless of ESR1m. In this article, we report updated efficacy from a prespecified interim overall survival (OS) analysis. PATIENTS AND METHODS: Patients with ER-positive, HER2-negative ABC previously treated with aromatase inhibitors ± cyclin-dependent kinase 4 and 6 inhibitors were randomly assigned (1 : 1 : 1) to receive imlunestrant, SOC, and imlunestrant-abemaciclib. Primary endpoints were PFS in imlunestrant versus SOC in patients with ESR1m and all patients, and versus imlunestrant-abemaciclib in all concurrently randomized patients. OS was a key secondary endpoint (tested if the corresponding PFS was statistically significant). Due to only two of three PFS endpoints being met, a limited significance level was passed to the OS comparisons. Exploratory endpoints included time to chemotherapy, chemotherapy-free survival, and PFS2. RESULTS: A total of 874 patients were randomized (imlunestrant, n = 331; SOC, n = 330; imlunestrant-abemaciclib, n = 213). Median follow-up was 28.5 months; 10.1% of patients remained on treatment (data cut-off: 18 August 2025).In patients with ESR1m, median OS (mOS) was 34.5 months for imlunestrant versus 23.1 months for SOC [hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.43-0.86, P = 0.0043, boundary for significance not reached]. In all patients regardless of ESR1m, mOS was not reached with imlunestrant-abemaciclib versus 34.4 months with imlunestrant (HR 0.82, 95% CI 0.59-1.16, P = 0.2622). Updated PFS demonstrated sustained benefit. Notably, in all patients regardless of ESR1m, the median PFS of imlunestrant-abemaciclib versus imlunestrant was 10.9 versus 5.5 months (HR 0.59, 95% CI 0.47-0.74, nominal P < 0.0001). All prespecified exploratory endpoints favored imlunestrant-based regimens. Safety remains consistent with prior reports. CONCLUSIONS: These findings reinforce the clinical benefit of imlunestrant-based regimens as a potential all-oral, chemotherapy-free treatment option for endocrine-pretreated patients with ER-positive, HER2-negative ABC.
Sacco M, Pietroluongo E, Di Lello A
… +10 more, Marino M, McGeough A, Esposito A, Sharma R, Husain AN, Arif Q, Elsebaie MA, Pearson AT, Dolezal JM, Garassino MC
BACKGROUND: Thymic epithelial tumors (TETs) are rare malignancies that pose significant diagnostic challenges due to their heterogeneous histological patterns and substantial interobserver variability in classification....BACKGROUND: Thymic epithelial tumors (TETs) are rare malignancies that pose significant diagnostic challenges due to their heterogeneous histological patterns and substantial interobserver variability in classification. Despite standardized World Health Organization (WHO) classification criteria, diagnostic concordance remains suboptimal, particularly in nonexpert settings, where second-opinion reviews lead to diagnostic reclassification in up to 57% of cases. Deep learning may offer a tool to reduce diagnostic variability and improve the consistency of histological classification. MATERIALS AND METHODS: We trained a deep learning-based model using hematoxylin-eosin (H&E) whole-slide images from The Cancer Genome Atlas as a training dataset. The model incorporated a novel hierarchical loss function designed to reflect clinically relevant tumor groupings based on treatment strategies and patient outcomes. We validated the model on 112 consecutive cases from the University of Chicago, with diagnoses confirmed by an expert thoracic pathologist. Model performances were evaluated using both a three-group hierarchical scheme and the six-class WHO classification. RESULTS: In the clinically relevant hierarchical three-group classification (As: A + AB; Bs: B1 + B2 + B3; and thymic carcinoma), the model achieved an accuracy of 91.1% with Cohen's κ = 0.859, indicating almost perfect agreement. In the six-class classification (A, AB, B1, B2, B3, and thymic carcinoma), the accuracy was 77.7% with κ = 0.716. The model demonstrated 100% sensitivity and 94.6% accuracy for thymic carcinoma detection. Notably, 60% of misclassifications occurred within the same clinical management group, thereby limiting their impact on therapeutic decision making. CONCLUSION: This deep learning model demonstrates strong potential as a diagnostic tool for TETs classification, particularly in settings with limited thoracic pathology expertise. The high sensitivity for thymic carcinoma detection and robust performance across different tissue processing conditions suggest its clinical applicability for improving diagnostic consistency and supporting pathological decision making in both specialized and nonspecialized settings.
Twenty years after its initial approval, trastuzumab remains a cornerstone in the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC). Long-term follow-up from pi...Twenty years after its initial approval, trastuzumab remains a cornerstone in the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC). Long-term follow-up from pivotal adjuvant trials has consistently demonstrated significant and durable improvements in survival outcomes across various risk groups and chemotherapy backbones. In parallel, trastuzumab-induced cardiotoxicity (TIC) remains overall infrequent, particularly in patients without prior exposure to anthracycline and appears comparable to the incidence observed in the general population after treatment completion. While real-world data further support the long-term efficacy and safety of trastuzumab, advancements such as more convenient subcutaneous formulations and the widespread availability of more accessible cost-effective biosimilars solidify its ongoing relevance in clinical practice. Conversely, despite two decades of clinical and translational research, no predictive biomarker beyond HER2 overexpression or amplification has yet been validated to guide trastuzumab use. Emerging candidates, including stromal tumor-infiltrating lymphocytes, circulating tumor DNA, and the HER2DX genomic assay, are not yet validated for use in clinical practice, although prospective studies are ongoing. Similarly, while clinical factors and imaging tools may help identify early on patients at higher risk of experiencing TIC, no cardioprotective strategy has yet demonstrated robust and conclusive benefit. Despite the emergence of newer anti-HER2 agents and evolving treatment paradigms, trastuzumab will probably continue to serve as a key therapeutic backbone, especially for patients with lower-risk HER2-positive eBC.
BACKGROUND: Despite treatment advances in newly diagnosed advanced-stage ovarian cancer (aOC), improved outcomes are needed. PATIENTS AND METHODS: DUO-O (NCT03737643), a phase III placebo-controlled trial, enrolled patie...BACKGROUND: Despite treatment advances in newly diagnosed advanced-stage ovarian cancer (aOC), improved outcomes are needed. PATIENTS AND METHODS: DUO-O (NCT03737643), a phase III placebo-controlled trial, enrolled patients with newly diagnosed aOC. Following one cycle of carboplatin/paclitaxel ± bevacizumab, patients without a tumor BRCA mutation (non-tBRCAm) were randomly assigned (1 : 1 : 1) at cycle 2 to carboplatin/paclitaxel plus bevacizumab followed by bevacizumab (control); carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab plus durvalumab (durvalumab arm); or carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab, durvalumab plus olaparib (durvalumab + olaparib arm). Investigator-assessed progression-free survival (PFS; primary endpoint) was tested for the durvalumab + olaparib arm versus control in the non-tBRCAm homologous recombination deficiency (HRD)-positive and non-tBRCAm intention-to-treat (ITT) populations. RESULTS: One thousand one hundred and thirty patients were randomly allocated to the study. The prespecified interim PFS analysis [data cut-off (DCO): 5 December 2022] qualified as the primary analysis; PFS hazard ratio (HR) for the durvalumab + olaparib arm versus control was 0.49 [95% confidence interval (CI) 0.34-0.69, P < 0.0001; median (m) PFS 37.3 versus 23.0 months] in the non-tBRCAm HRD-positive and 0.63 (95% CI 0.52-0.76, P < 0.0001; mPFS 24.2 versus 19.3 months) in the non-tBRCAm ITT population. For the durvalumab arm versus control, PFS HR was 0.87 (95% CI 0.73-1.04, P = 0.13; mPFS 20.6 versus 19.3 months) in the non-tBRCAm ITT population. At final PFS and interim overall survival (OS) analysis (DCO: 18 September 2023), PFS results were consistent with primary analysis; interim OS HR for the durvalumab + olaparib arm versus control was 0.95 (95% CI 0.76-1.20, P = 0.68; 39.0% maturity) in the non-tBRCAm ITT population. Safety was generally consistent with the profiles of the individual agents. CONCLUSIONS: DUO-O met its primary PFS endpoints for first-line durvalumab plus carboplatin/paclitaxel and bevacizumab followed by durvalumab, bevacizumab plus olaparib maintenance versus carboplatin/paclitaxel and bevacizumab followed by bevacizumab in the non-tBRCAm HRD-positive and non-tBRCAm ITT populations. Further insight into long-term benefit is anticipated with additional follow-up.
D'Ambrosio L, Merlini A, Brunello A
… +23 more, Ferraresi V, Paioli A, Vincenzi B, Pantaleo MA, De Pas TM, Gurrieri L, Sanfilippo R, Buonadonna A, Baldi GG, Badalamenti G, Marchiò C, Pignochino Y, Berrino E, Bellomo SE, Sbaraglia M, Righi L, Rabino M, Tolomeo F, Aliberti S, Sangiolo D, Dei Tos AP, Stacchiotti S, Grignani G
BACKGROUND: Advanced/metastatic soft tissue sarcomas (STSs) remain an unmet clinical need. We previously reported the feasibility and preliminary activity of trabectedin-olaparib combination in patients with advanced STS...BACKGROUND: Advanced/metastatic soft tissue sarcomas (STSs) remain an unmet clinical need. We previously reported the feasibility and preliminary activity of trabectedin-olaparib combination in patients with advanced STS progressing after anthracycline-based regimens. PATIENTS AND METHODS: In this investigator-initiated, open-label, phase II randomized trial, adult patients with advanced STS progressing after one or more prior lines of therapy, including at least one anthracycline-based regimen, were randomly assigned 1 : 1 to trabectedin 1.1 mg/m every 21 days (q21d) intravenous (i.v.) plus olaparib tablets 150 mg twice a day, or trabectedin 1.5 mg/m q21d i.v. Randomization stratified patients by histology (L-sarcoma, i.e. leiomyosarcoma and liposarcoma versus non-L-sarcoma) and number of prior therapies (one versus two or more). The primary endpoint was progression-free survival (PFS) rate at 6 months (PFS6m) per RECIST1.1. Secondary endpoints included PFS, overall survival (OS), RECIST1.1 overall response rate (ORR), and safety. Exploratory endpoints encompassed biomarker/molecular analyses. RESULTS: Between 25 May 2020 and 2 November 2022, 130 patients were enrolled at 13 Italian Sarcoma Group centers (81 female; 67 L-sarcoma; 93 one prior line). With a median follow-up of 37.4 months, PFS6m and median PFS were 32% [95% confidence interval (CI) 22% to 46%] and 3.9 months (95% CI 2.7-5.2 months) with trabectedin-olaparib versus 28% (95% CI 19% to 42%) and 2.9 months (95% CI 2.2-3.6 months) with trabectedin [hazard ratio (HR) 0.722, 95% CI 0.501-1.041, P = 0.081]. Among 126 assessable patients, ORR was 12.7% (95% CI 6.1% to 22.7%) versus 7.9% (95% CI 3.0% to 16.7%), respectively (odds ratio 1.60, 95% CI 0.50-5.16, P = 0.43). In the uterine leiomyosarcoma subgroup, 12-month PFS was 42.9% with trabectedin-olaparib versus 0% with trabectedin. PARP1 expression significantly correlated with improved PFS with trabectedin-olaparib (PFS6m and median PFS were 41.5% and 4.3 months versus 27.8% and 2.5 months; HR 0.537, 95% CI 0.337-0.855, P = 0.009). Grade ≥3 hematological toxicities were significantly more frequent with trabectedin-olaparib. CONCLUSIONS: Although trabectedin-olaparib combination reached the prespecified threshold for statistical significance for PFS (P < 0.10), the benefit was marginal in the all-comers STS population. Nonetheless, patients affected by PARP1-expressing STS and uterine leiomyosarcoma derived substantial benefit from the combination, supporting further histology- and biomarker-driven investigation in these settings.
Wang C, Wang W, Liu H
… +25 more, Chen Q, Chen C, Liu L, Zhang P, Zhao G, Yang F, Han G, Yu B, Yang Y, Chen H, Jiang J, Tan L, Xu S, Mao N, Hu J, Zhang L, Zhang Z, Yao B, Wang S, Leaw S, Naicker K, Zheng W, Yu C, Yue D, RATIONALE-315 investigators
BACKGROUND: Perioperative immunotherapy, particularly anti-programmed cell death protein 1 therapy, combined with neoadjuvant chemotherapy has emerged as one of the standard-of-care options for resectable non-small-cell...BACKGROUND: Perioperative immunotherapy, particularly anti-programmed cell death protein 1 therapy, combined with neoadjuvant chemotherapy has emerged as one of the standard-of-care options for resectable non-small-cell lung cancer (NSCLC). We report the final analysis of RATIONALE-315, a randomized, double-blind, phase III trial evaluating the efficacy and safety of perioperative tislelizumab plus neoadjuvant chemotherapy versus neoadjuvant chemotherapy alone in patients with resectable, stage II-IIIA NSCLC. PATIENTS AND METHODS: Adult patients in China were randomized (1 : 1) to receive either perioperative tislelizumab or placebo in combination with neoadjuvant chemotherapy. The dual primary endpoints were event-free survival (EFS) and major pathological response, assessed by blinded independent central review. The secondary endpoints included pathological complete response, overall survival (OS), disease-free survival, and safety. RESULTS: In total, 453 patients were randomized (226 to tislelizumab and 227 to placebo). At the final analysis (median study follow-up of 38.5 months), patients in the tislelizumab group experienced statistically significantly improved OS versus those in the placebo group {hazard ratio (HR) 0.65 [95% confidence interval (CI) 0.45-0.93]; P = 0.009}. The median OS was not reached in either group. The 36-month OS rate was 79.3% in the tislelizumab group versus 69.3% in the placebo group. The median EFS was not reached in the tislelizumab group versus 30.6 months in the placebo group [HR 0.58 (95% CI 0.43-0.79)]. Survival benefits were generally consistent across subgroups. The safety profile of tislelizumab plus chemotherapy was tolerable and consistent with known profiles of the individual therapies. CONCLUSIONS: Neoadjuvant tislelizumab plus chemotherapy and adjuvant tislelizumab demonstrated a statistically significant, clinically meaningful OS benefit and sustained, clinically meaningful EFS improvement compared with neoadjuvant chemotherapy, with a tolerable safety profile in patients with resectable stage II-IIIA NSCLC. These results support the use of this regimen in this patient population. CLINICAL TRIAL NUMBER: NCT04379635.
Zhu Y, Jiang S, Shi Y
… +22 more, Wang S, Yuan F, Zhou F, Jiang K, Zhang X, Seneviratne L, Yu G, Zhang M, Liu T, Li X, Chen X, Wang X, Zhang S, Liu Y, Ge Y, Chen M, Blumenthal G, Akala O, Li Y, Li X, Ge J, Ye D
BACKGROUND: Trophoblast cell-surface antigen 2 (TROP2) is overexpressed in advanced or metastatic urothelial cancer (UC), representing a promising therapeutic target. Sacituzumab tirumotecan (sac-TMT) is a TROP2-directed...BACKGROUND: Trophoblast cell-surface antigen 2 (TROP2) is overexpressed in advanced or metastatic urothelial cancer (UC), representing a promising therapeutic target. Sacituzumab tirumotecan (sac-TMT) is a TROP2-directed antibody-drug conjugate with a unique, bifunctional linker that maximizes payload delivery to tumor cells. We present preliminary results for sac-TMT monotherapy from cohort 9 of the phase 1/2 2870-001/KL264-01 study in participants with advanced or metastatic UC. PARTICIPANTS AND METHODS: Eligible participants with locally advanced or metastatic UC and disease progression on one or more prior line of platinum-based chemotherapy and anti-programmed cell death protein 1/programmed cell death-ligand 1 therapy received sac-TMT 5 mg/kg intravenously every 2 weeks until disease progression, unacceptable toxicity, or participant/physician decision. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST version 1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: By data cut-off (17 February 2025), 49 participants were treated with sac-TMT; 37 (76%) had received two or more prior lines of therapy. Median follow-up for this analysis was 18.8 months. The confirmed ORR was 31% [95% confidence interval (CI), 18% to 45%] and the disease control rate was 71% (95% CI 57% to 83%). Median DOR was not reached [range 2.1-22.2+ (+ indicates censored data for the longest DOR, suggesting that patients may have achieved longer remission duration) months], and the 12-month probability of sustained response was 53%. Median PFS and OS were 5.5 months (95% CI 3.6-7.2 months) and 12.1 months (95% CI, 9.9-15.3 months), with 18-month rates of 26% and 33%, respectively. Grade 3/4 treatment-related adverse events (AEs) occurred in 31 participants (63%), and the most common (≥5%) were anemia (41%), decreased neutrophil count (35%), decreased white blood cell count (20%), stomatitis (12%), and decreased platelet count (8%). There were no grade 5 treatment-related AEs or febrile neutropenia events. CONCLUSIONS: Sac-TMT 5 mg/kg monotherapy every 2 weeks demonstrated promising antitumor activity in participants with heavily pretreated advanced or metastatic UC, with a manageable safety profile, warranting further evaluation of sac-TMT in this population.
Hurvitz SA, Loi S, O'Shaughnessy J
… +27 more, Okines AFC, Tolaney SM, Sohn J, Saura C, Zhu X, Cameron D, Bachelot T, Hamilton E, Curigliano G, Wolff AC, Harbeck N, Masuda N, Vahdat L, Zaman K, Valdes-Albini F, Block M, Pluard T, Tan TJ, Gawryletz C, Chan A, Bedard PL, Yerushalmi R, Xu B, Schmitt M, Xie D, Borges VF, HER2CLIMB-02 study investigators
BACKGROUND: Trastuzumab emtansine (T-DM1) is a standard treatment option in patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (LA/MBC)....BACKGROUND: Trastuzumab emtansine (T-DM1) is a standard treatment option in patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (LA/MBC). Here, we report the efficacy and safety of tucatinib in combination with T-DM1 compared with T-DM1 alone from the phase III HER2CLIMB-02 study (NCT03975647). PATIENTS AND METHODS: Eligible patients had HER2-positive LA/MBC that had been previously treated with trastuzumab and a taxane in any setting; these included patients with brain metastases (BMs). Patients were randomly assigned 1 : 1 to receive T-DM1 (3.6 mg/kg intravenously every 21 days) combined with either tucatinib (300 mg orally twice daily) in the tucatinib arm or placebo (orally twice daily) in the control arm. RESULTS: In total, 463 patients were randomly assigned. After a median follow-up duration of 24.4 months, the median progression-free survival (PFS) was 9.5 months in the tucatinib arm and 7.4 months in the control arm [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.61-0.95, P = 0.0163]. A PFS benefit was observed across all prespecified subgroups, including in patients with BMs. Interim overall survival analysis results were immature. The median OS was not reached in the tucatinib arm and was 38.0 months in the control arm (HR 1.23, 95% CI 0.87-1.74). The incidences of treatment-emergent adverse events (TEAEs) associated with any treatment discontinuation and of grade ≥3 TEAEs were higher in the tucatinib arm than in the control arm (22.1% versus 11.6% and 68.8% versus 41.2%, respectively). The most common grade ≥3 TEAEs in the tucatinib arm were elevated alanine aminotransferase (16.5%) and aspartate aminotransferase levels (16.5%) (versus 2.6% for both in the control arm). CONCLUSION: The addition of tucatinib to T-DM1 improved PFS in patients with previously treated HER2-positive LA/MBC, including patients with BMs, and exhibited a manageable safety profile.
BACKGROUND: PADA-1 was the first prospective randomized trial to show that early therapeutic targeting of blood ESR1 mutations (bESR1-mut) with fulvestrant provides significant clinical benefit in patients with estrogen...BACKGROUND: PADA-1 was the first prospective randomized trial to show that early therapeutic targeting of blood ESR1 mutations (bESR1-mut) with fulvestrant provides significant clinical benefit in patients with estrogen receptor α-positive/human epidermal growth factor receptor 2-negative advanced breast cancer treated with an aromatase inhibitor and palbociclib. Here, we describe the kinetics and determinants of bESR1-mut in the 1017 patients who participated in PADA-1. PATIENTS AND METHODS: PADA-1 was an open-label, randomized, controlled, phase III trial conducted at 83 hospitals in France. Patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer were recruited and monitored by multiplex droplet digital PCR for rising bESR1-mut during first-line treatment with aromatase inhibitor and palbociclib, after one cycle and then every two cycles. Patients with newly present or increased bESR1-mut in circulating tumor DNA and no synchronous disease progression were randomly assigned to continue with the same therapy or to switch to fulvestrant and palbociclib. RESULTS: Baseline bESR1-mut was detected in 3.2% of patients. Prior adjuvant treatment with aromatase inhibitor (6.8%) and lower body mass index were independently associated with a higher detection rate of bESR1-mut at baseline. Through real-time analysis of >12 500 blood samples, we observed that detection of rising bESR1-mut was not linear over time, occurring more frequently after 6 months and before 3 years of treatment. We found that high estrogen receptor expression, the presence of bone metastases, younger age, and lactate dehydrogenase elevation were associated with a higher rate of rising bESR1-mut detection. Finally, updated survival results of PADA-1 substantiate the clinical benefit of intercepting bESR1-mut emergence before clinical progression, with improved progression-free survival (PFS), hazard ratio 0.54, 95% confidence interval 0.38-0.75, and progression-free survival 2, hazard ratio 0.35, 95% confidence interval 0.22-0.54. CONCLUSION: We identified factors associated with the detection of bESR1-mut at baseline and during treatment that could help identify patients who may benefit from ESR1-targeted therapies.
Saura C, Cortés J, Modi S
… +13 more, Kim SB, Hamilton E, Hurvitz SA, Krop IE, Curigliano G, Iwata H, Im SA, Herbolsheimer P, Karnoub M, Boran A, Kuwahara Y, Egorov A, André F
BACKGROUND: Objective response rates in the DESTINY-Breast01/02/03 trials, which evaluated trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC), were 6...BACKGROUND: Objective response rates in the DESTINY-Breast01/02/03 trials, which evaluated trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC), were 62%/70%/79%, respectively. PATIENTS AND METHODS: This exploratory pooled analysis investigated associations between best confirmed response to T-DXd and baseline characteristics/long-term outcomes in patients who received T-DXd 5.4 mg/kg in DESTINY-Breast01/02/03. Endpoints included best confirmed response per (blinded) independent central review [(B)ICR] using RECIST v1.1, progression-free survival (PFS) by (B)ICR, overall survival (OS), safety, and biomarker analyses of expression levels/alterations of genes relevant to HER2-positive mBC or T-DXd activity. RESULTS: A total of 834 patients who received T-DXd in DESTINY-Breast01/02/03 were assessable for response; 125 (15.0%) experienced complete response (CR), 477 (57.2%) experienced partial response (PR), and 232 (27.8%) were considered non-responders (stable disease/progressive disease). The median number of prior regimens in the metastatic setting was two for patients with CR versus three for patients with PR and non-responders; visceral disease and baseline brain or bone metastases were less frequently observed in patients with CR. The 24-month PFS rates in patients with CR, PR, and no response, respectively, were 77.8%, 46.3%, and 20.6%, and 36-month OS rates were 88.6%, 54.0%, and 35.9%. Rates of serious adverse events, T-DXd discontinuation, and interstitial lung disease/pneumonitis were numerically lower in patients with CR. In exploratory biomarker analyses, responders had tumors with numerically higher HER2 plasma copy number, lower ESR1 gene expression and ESR1 mutation frequency, and lower circulating tumor DNA levels at baseline. CONCLUSIONS: Patients with objective response to T-DXd, particularly those with CR, showed prolonged median PFS and OS. These results support T-DXd use across broad patient groups with HER2-positive mBC, including those with lower disease burden. Patients whose disease does not respond to T-DXd represent an unmet medical need, and research into more effective treatment approaches for these patients is warranted.
BACKGROUND: Artificial intelligence (AI) is expected to introduce an increasing number of biomarkers in oncology. To bridge the gap between oncology and computer science, it is timely to define recommendations for AI-bas...BACKGROUND: Artificial intelligence (AI) is expected to introduce an increasing number of biomarkers in oncology. To bridge the gap between oncology and computer science, it is timely to define recommendations for AI-based biomarkers suitable for routine clinical use. Here, we propose the ESMO (European Society for Medical Oncology) Basic Requirements for AI-based Biomarkers In Oncology (EBAI). DESIGN: The EBAI framework was developed using a modified Delphi methodology, involving a multidisciplinary panel of 37 experts who participated in four structured consensus rounds. RESULTS: AI-based biomarkers were classified as 'class A' (AI quantification of established biomarkers), 'class B' (indirect measure of known biomarkers using AI-based alternative methods, to be deployed as pre-screening tests), and 'class C' (novel AI-derived biomarkers, with C1 for prognosis and C2 for prediction of treatment effect). The EBAI framework addresses AI biomarkers for clinical use. Ground truth, performance, and generalisability were considered essential; fairness was recommended. Minimal validation requirements indicate that class A requires concordance studies, class B analytical validation, class C1 high-quality retrospective real-world or clinical trial data, and class C2 additionally requires clinical validation in prospective clinical trials for the prediction of response to a new treatment. All biomarker studies should report multiple evaluation and calibration metrics, with a clearly defined primary objective. Generalisability should be demonstrated across all intended use settings, including variability in data acquisition, post-processing, and population characteristics. Biomarkers must not be applied to other cancer types or modalities without supporting evidence. CONCLUSIONS: EBAI defines criteria for AI-based biomarker adoption in routine use, providing a common language for physicians, AI developers, and researchers.
Toss A, Blondeaux E, Tenedini E
… +56 more, Bonamici L, Graffeo R, Livraghi L, Villarreal-Garza C, Bernstein Molho R, Kwong A, Balmana J, Wildiers H, Agostinetto E, Phillips KA, Pogoda K, Renaud T, Rousset-Jablonski C, Ferrari A, Moore HCF, Peccatori FA, Paluch-Shimon S, Fruscio R, Micheri C, Wong SM, Cui W, Vernieri C, Lee MK, De Marchis L, Couch FJ, Del Mastro L, Puglisi F, Meireles PA, Kemp Z, Matikas A, Plichta J, Del Pilar Estevez-Diz M, Di Meglio A, Cichowska-Cwalinska N, Gianni C, Yerushalmi R, Sanchez-Bayona R, Mrinakova B, Matos L, Bianchini G, Caleffi M, Krivokuca A, Abdou Y, Mariño-Mariño M, Parokonnaya A, Okano M, Antone N, Saavedra C, Sonnenblick A, Duchnowska R, Pais HL, Harbeck N, Cortesi L, Delucchi V, De Angelis C, Lambertini M
BACKGROUND: The clinical implications of specific pathogenic and likely pathogenic variant (LP/PV) types and locations in the BRCA1 orBRCA2 tumor-suppressor genes remain to be elucidated. PATIENTS AND METHODS: The BRCA B...BACKGROUND: The clinical implications of specific pathogenic and likely pathogenic variant (LP/PV) types and locations in the BRCA1 orBRCA2 tumor-suppressor genes remain to be elucidated. PATIENTS AND METHODS: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included BRCA carriers diagnosed with invasive breast cancer at the age of ≤40 years between January 2000 and December 2020. In this analysis, only patients with detailed available information on LP/PVs in the BRCA genes were included. Clinicopathological features and survival outcomes [disease-free survival (DFS) and overall survival (OS)] were investigated according to LP/PV type [insertion-deletion (indel) versus single-nucleotide variants versus copy number variations; truncating versus non-truncating LP/PVs; frameshift versus nonsense versus splicing versus missense LP/PVs] and location (exon involved and protein domain). RESULTS: Out of 5660 patients from 109 centers worldwide, 3294 were eligible for the present analysis (2080 BRCA1 and 1214 BRCA2). The distribution of LP/PV types showed no meaningful associations with baseline clinicopathological features. BRCA1 protein-truncating variants were associated with worse OS compared with non-truncating variants [hazard ratio (HR) 2.00, 95% confidence interval (CI) 1.17-3.41]. A similar, though non-significant, trend was observed for BRCA2. Missense variants were linked to better OS for both BRCA1 (HR 0.48, 95% CI 0.28-0.84) and BRCA2 carriers (HR 0.17, CI 0.03-0.96). Regarding variant location, BRCA1 LP/PVs outside exons 2, 10, and 19 were associated with improved OS. In BRCA2, LP/PVs located in exons 15-26 and other regions were linked to worse DFS compared with those in exon 10, with no significant differences in OS. CONCLUSIONS: This study advances our understanding of the influence of specific types of BRCA LP/PVs on breast cancer characteristics and outcomes. A deeper understanding of these variant-specific features will drive future research and support the development of tailored clinical strategies based on individual BRCA variant.
BACKGROUND: Preliminary reports suggest interim positron emission tomography (PET) could drive treatment duration in limited-stage diffuse large B-cell lymphoma (DLBCL). This phase III randomized study in first-line ther...BACKGROUND: Preliminary reports suggest interim positron emission tomography (PET) could drive treatment duration in limited-stage diffuse large B-cell lymphoma (DLBCL). This phase III randomized study in first-line therapy for DLBCL patients with adjusted-age international prognostic index (aaIPI) risk = 0, evaluates an experimental PET-response adapted approach using PET response after two cycles of R-CHOP to de-escalate treatment duration. PATIENTS AND METHODS: LNH2009-1B study is a two-arm, open-label, multicenter, prospective, randomized phase III noninferiority trial, evaluating treatment de-escalation based on PET after two cycles of R-CHOP in previously untreated DLBCL patients aged 18-80 years, with aaIPI = 0. In the experimental PET-adapted arm, patients with a negative PET after two cycles received four cycles in total of R-CHOP, whereas those with a positive PET after two cycles received a total of six cycles. In the standard arm, treatment was six cycles regardless of PET results after two cycles. No radiotherapy was planned. The primary endpoint was 3 years progression-free survival (PFS). The primary analysis was carried out in the intention-to-treat population. The trial is registered with ClinicalTrial.gov, NCT01285765, recruitment is completed. RESULTS: A total of 650 patients were enrolled, of whom 319 were randomly assigned to the PET-adapted arm and 331 to the standard arm. In the PET-adapted arm, 77.7% of patients had a negative PET scan after two cycles and received a total of four cycles of R-CHOP. The 3-year PFS in PET-adapted and standard arms were 92.0% [95% confidence interval (CI) 88.3% to 94.5%] and 89.2% (95% CI 85.3% to 92.2%), respectively (P value = 0.070). The noninferiority of the experimental PET-adapted arm was demonstrated (hazard ratio 0.72, 95% CI 0.47-1.12, P value < 0.0001). Patients in the PET-adapted arm had fewer adverse events of grades ≥3 (54.7% versus 62.7%, P = 0.046) and serious adverse events (9.5% versus 14.2%, P = 0.039). CONCLUSION: A risk-adapted approach using early PET after two cycles of R-CHOP was beneficial, minimizing toxicity without compromising efficacy in patients treated in first-line therapy for low-risk DLBCL.