Kaidar-Person O, Weltens CG, Fortpied C
… +22 more, Scheijmans LJEE, Kirkove CY, Budach V, Peignaux-Casasnovas K, Valli M, Peters M, van der Leij F, Rivera S, Weidner N, van den Bongard DHJG, Linsenmeier C, Abdah-Bortnyak R, Hosni S, Koiter E, Engelen AM, Baten A, Champezou L, Fourquet A, Bartelink HGMM, Struikmans H, Poortmans PMP, EORTC Radiation Oncology and Breast Cancer Groups
BACKGROUND: Results from several studies, including our 15-year analysis, showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overa...BACKGROUND: Results from several studies, including our 15-year analysis, showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. Here, we present the scheduled 20-year analysis of the EORTC trial 22922/10925, evaluating the role of internal mammary and medial-supraclavicular (IM-MS) nodal irradiation in patients with stage I-III breast cancer. Patients without confirmed axillary nodal involvement (pathological N stage 0 [pN0]) were eligible for the trial when the primary tumours were centrally or medially located. METHODS: EORTC 22922/10925 was a randomised, open-label, phase 3 trial done across 46 radiation oncology departments from 13 countries. Eligible participants were women up to 75 years of age with unilateral, histologically confirmed, stage I-III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumour. Patients were randomly assigned (1:1) centrally using minimisation to receive IM-MS irradiation at 50 Gy in 25 fractions (IM-MS irradiation group) or no IM-MS irradiation (control group). Stratification was done for institution, menopausal status, site of the primary tumour within the breast, type of breast and axillary surgery, and pathological T and N stage. Patients and investigators were not masked to treatment allocation. Only patients without clinically and histopathologically confirmed nodal involvement (pN0) were included in this unplanned subgroup analysis. The primary outcome was overall survival analysed according to the intention-to-treat principle. Safety analyses were conducted in the subset of eligible patients treated per protocol. This trial is registered with ClinicalTrials.gov (on Nov 1, 1999; NCT00002851) and closed after its final analysis. FINDINGS: Between Aug 5, 1996, and Jan 13, 2004, 4004 patients were randomly assigned. 890 (44·5%) of 2002 patients in the IM-MS irradiation group and 888 (44·4%) of 2002 patients in the control group had pN0 disease. The median age of participants was 55 years (IQR 48-63). At a median follow-up of 22·2 years (IQR 20·1-24·5), 276 (31·1%) of 888 patients in the IM-MS irradiation group and 277 (31·1%) of 890 patients in the control group died because of any cause; 87 (31·5%) of 276 and 122 (44·0%) of 277 patients died due to breast cancer, respectively. At 20 years, the overall survival rate was 69·0% (95% CI 65·4-72·3) in the IM-MS irradiation group and 68·4% (64·8-71·6%) in the control group (hazard ratio [HR] 0·98 [95% CI 0·83-1·15], p=0·77). The breast cancer mortality rate was 10·0% (8·0-12·3) in the IM-MS irradiation group and 14·2% (11·9-16·8) in the control group (HR 0·70 [95% CI 0·53-0·92], p=0·010), but cumulative mortality of unknown cause or not breast cancer cause was 20·9% (95% CI 17·9-24·1) in the IM-MS irradiation group and 17·4% (14·7-20·3) in the control group (HR 1·24 [95% CI 1·00-1·53]; p=0·048). In patients with left-sided breast cancer, late cardiac fibrosis occurred in 15 (3·4%) of 445 patients in the IM-MS irradiation group and 12 (2·8%) of 436 patients in the control group. Lung fibrosis at any grade occurred in 55 (6·4%) of 855 patients in the IM-MS irradiation group and 18 (2·1%) of 877 patients in the control group. INTERPRETATION: Breast cancer mortality at 20 years was significantly lower in the IM-MS irradiation group, whereas non-breast cancer mortality was numerically higher in the IM-MS irradiation group after 15 years, resulting in no long-term benefit of IM-MS irradiation on overall survival. Our results emphasise the importance of very long-term follow-up and advanced irradiation techniques to reduce the dose to organs of interest. FUNDING: Ligue Nationale contre le Cancer, KWF Kankerbestrijding, and EORTC Cancer Research Fund.
BACKGROUND: Indications for postoperative locoregional radiotherapy in cT1-2N1 breast cancer after primary systemic therapy are disputed. The previously published 5-year outcomes of the RAPCHEM study showed excellent loc...BACKGROUND: Indications for postoperative locoregional radiotherapy in cT1-2N1 breast cancer after primary systemic therapy are disputed. The previously published 5-year outcomes of the RAPCHEM study showed excellent locoregional control when radiotherapy was tailored to the nodal response after primary chemotherapy. Here, we present 10-year results. METHODS: In this prospective registry study (RAPCHEM, BOOG 2010-03), patients referred to one of 17 participating Dutch radiation oncology centres between Jan 1, 2011, and Jan 1, 2015, with cT1-2N1 breast cancer (with ≤3 suspicious nodes at imaging) treated with primary chemotherapy, followed by breast and axillary surgery, were included. Three risk groups, with corresponding radiotherapy guideline were defined: the low-risk group received whole breast radiotherapy after lumpectomy and no radiotherapy after mastectomy; the intermediate-risk group received whole breast or chest wall radiotherapy without regional nodal radiotherapy; and the high-risk group received whole breast or chest wall radiotherapy and regional nodal radiotherapy of levels III-IV. The current analysis presents the prespecified secondary endpoints of the study of 10-year isolated locoregional recurrence rate, 10-year recurrence-free interval, and 10-year overall survival. This trial is registered with ClinicalTrials.gov, NCT01279304. FINDINGS: 838 patients were included in the 10-year follow-up analysis: 291 in the low-risk group, 370 in the intermediate-risk group, and 177 in the high-risk group. The 10-year locoregional recurrence rate in all patients was 2·9% (95% CI 1·9-4·2), with locoregional recurrence rates of 2·4% (95% CI 1·1-4·7) in the low-risk group, 3·2% (1·8-5·4) in the intermediate-risk group, and 2·8% (1·1-6·1) in the high-risk group. No significant differences were seen in locoregional recurrence between the groups. The 10-year recurrence-free interval for all patients was 79·2% (76·2-81·8), and the 10-year overall survival for all patients was 83·0% (80·3-85·4). INTERPRETATION: Tailoring locoregional radiotherapy in cT1-2N1 breast cancer (with ≤3 nodes at imaging) to the nodal response after primary systemic therapy resulted in a low 10-year locoregional recurrence rate, with promising recurrence-free interval and overall survival. By (partially) omitting radiotherapy based on nodal response after primary systemic treatment, possible morbidity caused by the radiotherapy can be avoided, which could improve patients' quality of life. FUNDING: Dutch Cancer Society.
Seefat RL, Vliek SB, de Jong VMT
… +42 more, Balduzzi S, Mandjes IA, Retèl VP, Eekhout I, Delfos M, Schot M, Holtkamp MJ, van Rosmalen MM, Leeneman B, Blommestein H, Huitema ADR, Rosenberg EH, Nederlof PM, Chan TWS, van Rhenen A, Wondergem MJ, Schaap NPM, Snijders TJF, Van der Poel MWM, Plattel WJ, van Werkhoven E, van Tinteren H, Smidt ML, Wesseling J, Jonkers J, Rottenberg S, Vrancken Peeters MTFD, Voermans C, Maduro JH, Kroep JR, Schroder CP, Kuip EJM, Gonçalves A, Nuver J, Wymenga ANM, Bijlsma RM, van der Wall E, Konings IRHM, Tjan-Heijnen VCG, Jongen-Lavrencic M, Jager A, Linn SC
BACKGROUND: Patients with stage III, human epidermal-growth-factor-receptor 2 (HER2; also known as ERBB2)-negative breast cancer with homologous recombination deficiency (HRD) had a 4-year overall survival of 35% after a...BACKGROUND: Patients with stage III, human epidermal-growth-factor-receptor 2 (HER2; also known as ERBB2)-negative breast cancer with homologous recombination deficiency (HRD) had a 4-year overall survival of 35% after anthracycline-based chemotherapy versus 78% after intensified alkylating chemotherapy with autologous stem cell rescue (IACT) in a post-hoc analysis of an earlier randomised controlled trial. In this study, we aimed to prospectively assess 4-year overall survival with IACT and establish whether this approach remains superior to a contemporary HRD-targeting regimen in patients with HER2-negative breast cancer with HRD. METHODS: This open-label, randomised, controlled, phase 3 trial included patients from eight hospitals and one cancer centre in the Netherlands and one cancer centre in France. Newly diagnosed patients aged between 18-66 years with stage IIIA-C, HER2-negative, HRD breast cancer without distant metastases who had a pathogenic germline BRCA1/2 mutation or evidence of a HRD tumour on testing were randomly assigned (1:1) to receive IACT or conventional chemotherapy using interactive response technology. IACT comprised dose-dense alkylating chemotherapy (ddAC; four cycles of doxorubicin 60 mg/m and cyclophosphamide 600 mg/m every 2 weeks intravenously), supported by 6 mg prophylactic pegfilgrastim subcutaneously every 2 weeks. 2 weeks after stem cell mobilisation, patients received two IACT cycles 3 weeks apart (3000 mg/m cyclophosphamide on day 1, 250 mg/m thiotepa on day 2, and 400 mg/m carboplatin intravenously on days 1 and 2), followed by autologous stem cell transplantation. Conventional chemotherapy comprised four ddAC cycles, followed by four cycles of intravenous carboplatin area under the curve 6 every 3 weeks, and 80 mg/m paclitaxel every week for 12 weeks (carboplatin-paclitaxel intravenously), followed by 1 year of oral olaparib (300 mg twice daily). All patients proceeded to surgery and radiotherapy according to local practice. Stratification factors were treatment centre, age, stage, and oestrogen receptor status. The primary endpoint was overall survival in the intention-to-treat population (all randomly allocated patients). The trial was registered at ClinicalTrials.gov, NCT02810743, and is ongoing, but is closed for inclusion. FINDINGS: From Jan 25, 2017, through to Oct 5, 2023, 356 patients were screened for eligibility, and 174 patients were randomly assigned to receive IACT (n=87) or olaparib (n=87). All patients were female, and median age was 42 years (IQR 37-50). We did not ask explicit informed consent for collecting data on ethnicity of patients, because we focused on a very rare patient subgroup and therefore used pragmatic eligibility criteria following standard General Data Protection Regulation. 28 (32%) in the IACT group and 22 (25%) patients in the olaparib group had germline BRCA1/2 mutations. With a median follow-up of 41 months (IQR 27-59), the 4-year overall survival was 77·0% (95% CI 67·7-87·7 in the IACT group and 76·4% (66·9-87·4) in the olaparib group (hazard ratio for death 1·11 [95% CI 0·57-2·17]; p=0·37).The most common grade 3-4 adverse events were platelet count decreased (80 [99%] in the IACT group vs 18 [19%] in the olaparib group), neutrophil count decreased (77 [95%] in the IACT group vs 56 [61%] in the olaparib group), and anaemia (50 [62%] in the IACT group vs 37 [41%] in the olaparib group). Treatment-emergent serious adverse events occurred in 38 (47%) of 81 patients in the IACT group versus 24 (26%) of 91 patients in the olaparib group. Febrile neutropenia was the most common serious adverse event in both groups (36 [44%] in the IACT group; 11 [12%] in the olaparib group). No treatment-related deaths were reported. INTERPRETATION: These data demonstrate that targeting HRD yields promising outcomes in stage III, HER2-negative, HRD breast cancer and that intensified chemotherapy with autologous stem cell rescue does not provide any advantage over state-of-the-art chemotherapy plus olaparib. FUNDING: Dutch Cancer Society, the Dutch Ministry of Health, the Netherlands Organization for Health Research and Development, A Sister's Hope, [Z]aan de Wandel, AstraZeneca, MSD, and Eurocept Pharmaceuticals.
BACKGROUND: Response evaluation in pleural mesothelioma is challenging because its crescent growth pattern is poorly captured by diameter-based criteria. We aimed to develop and validate artificial intelligence (AI)-assi...BACKGROUND: Response evaluation in pleural mesothelioma is challenging because its crescent growth pattern is poorly captured by diameter-based criteria. We aimed to develop and validate artificial intelligence (AI)-assisted volumetric response criteria (ARTIMES) based on automated tumour segmentation and biologically derived thresholds. METHODS: In this retrospective, multicentre study, we included 10 926 CT scans from 2080 patients from 14 cohorts. A subset totalling 1176 CT scans from routine care (Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital) and trial cohorts (INITIATE, NivoMes, PEMMELA, LUME-MESO, NVALT19, and MiST1 trials) was annotated by 12 radiologists and 1 pulmonologist, supplemented by 100 negative CT scans, to train a deep-learning segmentation model. Internal testing included 98 CT scans from independent international hospitals in LUME-MESO. External testing included data from the MEDUSA cohort (101 CT scans with radiologist-corrected segmentations) and two fully independent manual segmentation datasets from SAKK17/18 (22 CT scans) and the University of Chicago (15 CT scans). AI segmentations were evaluated through dice similarity coefficient (DSC) and normalised surface distance (NSD) at 3 mm. Progressive disease thresholds were derived using data from patients with multiple CT scans before first-line therapy or receiving only supportive care after first-line treatment (611 CT scans), and partial response thresholds from inter-reader variability (derived from 451 CT scans). ARTIMES was validated using data from eight clinical trials (4674 CT scans; 943 patients) and compared with modified Response Evaluation Criteria in Solid Tumors (mRECIST) using time-varying Cox proportional hazards models and trial-level surrogate endpoint analysis against overall survival using R and surrogate threshold effect. FINDINGS: DSC was 94-95% in internal testing and 71-80% with manual segmentations. NSD was 98% and 81-93%, respectively. ARTIMES demonstrated superior patient-level prognostic performance compared with mRECIST (concordance index 0·83 [95% CI 0·79-0·87] vs 0·73 [0·66-0·80]; p=0·023) and detected progression a median of 5 weeks earlier (124 days [95% CI 115-126] vs 162 days [138-167]; p<0·0001). At the trial level, ARTIMES-based progression-free survival showed stronger correlation with overall survival (R 88% [95% CI 42-100]) than did mRECIST-based progression-free survival (R 6% [0-97]) and demonstrated a surrogate threshold effect at a progression-free survival hazard ratio of less than 0·82; no threshold was observed for mRECIST. Baseline AI-derived tumour volume independently predicted overall survival and outperformed T stage and WHO performance status. INTERPRETATION: ARTIMES-based progression-free survival improves prognostic stratification and shows better trial-level surrogacy for overall survival compared with mRECIST-based progression-free survival. Pending prospective validation, ARTIMES could potentially facilitate a more reliable response evaluation in pleural mesothelioma. FUNDING: Asbestos-Related Disease Section (SAGA) of the Dutch Society of Pulmonology and Tuberculosis (NVALT), Dutch Cancer Society, and Dutch Ministry of Health, Welfare and Sport.
Li Z, Hu J, Chen J
… +19 more, Yu Y, Meng X, Dong X, Hu Y, Ji Y, Liu H, Wang W, Ning F, Zhang Z, Liu C, Zhang Z, Wang Q, Zheng W, Wang H, Qu X, Chen Z, Fan S, Zhang X, Lu S
BACKGROUND: Although third-generation epidermal growth-factor receptor (EGFR)-tyrosine-kinase inhibitors (TKIs) are standard first-line therapies for patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC)...BACKGROUND: Although third-generation epidermal growth-factor receptor (EGFR)-tyrosine-kinase inhibitors (TKIs) are standard first-line therapies for patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC), their effectiveness is often limited by the emergence of drug resistance and subsequent disease progression. Given the previously established clinical efficacy and adverse event profile of aumolertinib, we aimed to evaluate the efficacy and adverse event profile of aumolertinib in combination with platinum-based chemotherapy versus aumolertinib monotherapy as first-line treatment for patients with locally advanced or metastatic NSCLC patients with EGFR-sensitive mutations. METHODS: The open-label, multicentre, randomised, controlled, phase 3 AENEAS2 trial was done across 60 hospitals in China. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1; treatment-naive; histologically or cytologically confirmed locally advanced or metastatic NSCLC harbouring EGFR-sensitive mutations (ex19del/L858R with or without other EGFR mutations) were eligible. Brain metastases were allowed if neurologically stable. Previous EGFR-TKI therapy was an exclusion criterion. Patients were randomly assigned (1:1) with block randomisation (block size of 6), stratified by EGFR mutation type and baseline brain metastasis, to receive aumolertinib monotherapy (110 mg orally once a day) or combination therapy (aumolertinib 110 mg orally once a day plus pemetrexed 500 mg/m intravenously with cisplatin [75 mg/m] or carboplatin [area under the plasma concentration-time curve 5] intravenously on day 1 of 21-day cycles for 4-6 cycles), followed by maintenance therapy (aumolertinib 110 mg orally once a day and pemetrexed 500 mg/m intravenously once every 3 weeks). The primary endpoint was progression-free survival assessed by blinded independent central review (BICR; RECIST version 1.1). Efficacy was analysed in the full-analysis set, which included all randomly assigned patients, and safety was analysed in patients who received at least one dose of the actual trial treatment. The trial is registered at ClinicalTrials.gov, NCT04923906, and is ongoing, but closed to enrolment. FINDINGS: Between Aug 4, 2021, to June 18, 2024, of 1011 patients assessed for eligibility, 624 randomly assigned patients (median age 59·0 years [IQR 52·0-66·0]; 337 [54%] were female, 287 [46%] were male) were randomly assigned. 310 (50%) patients received combination therapy and 314 (50%) received monotherapy. As of the data cutoff date (June 18, 2024), the median follow-up was 23·4 months (IQR 20·5-26·5), In the full-analysis set, median BICR-assessed progression-free survival was 28·9 months (95% CI 26.3, NA) in the combination therapy versus 18·9 months (17·8-21·1) in the monotherapy (hazard ratio [HR] 0·47, 95% CI 0·37-0·60; log-rank p<0·0001). The most common grade 3-4 adverse events (occurring in at least 20% in any group) were neutrophil count decreased (168 [55%] of 304 in the combination group versus four [1%] of 316 in monotherapy group), white blood cell count decreased (103 [34%] vs one [<1%]), and platelet count decreased (62 [20%] vs two [1%]). Serious adverse events occurred in 109 (36%) patients in the combination group and 53 (17%) in the monotherapy group, the most common of which were platelet count decreased (22 [7%] vs 0), neutrophil count decreased (17 [6%] vs 0), white blood cell count decreased (13 [4%] vs 0), and anaemia (ten [3%] vs two [1%]). Treatment-related deaths occurred in one (<1%) patient in the combination group (encephalopathy) and two (1%) in the monotherapy group (pulmonary embolism and respiratory failure with circulatory collapse). INTERPRETATION: Aumolertinib in combination with chemotherapy significantly improved progression-free survival. Although this regimen was associated with increased toxicity, the side-effects were managed with dose adjustment and supportive treatment aligned with clinical practice. Long-term follow-up is required to assess overall survival. The AENEAS2 study provides evidence to guide clinical practice regarding EGFR-TKIs and their combination use in treating patients with advanced EGFR-mutated NSCLC. FUNDING: Jiangsu Hansoh Pharmaceutical Group, and the Collaborative Innovation Center for Clinical and Translational Science by Ministry of Education & Shanghai. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.
BACKGROUND: Clinical trials evaluating CD3-based T cell-engaging bispecific antibodies for cancer therapy have rapidly progressed from early investigations to clinical application. As these agents enter practice, it is e...BACKGROUND: Clinical trials evaluating CD3-based T cell-engaging bispecific antibodies for cancer therapy have rapidly progressed from early investigations to clinical application. As these agents enter practice, it is essential to systematically characterise and summarise the range of treatment-related adverse events associated with these antibodies. METHODS: We conducted a meta-analysis by searching Cochrane, Embase, PubMed, and Web of Science for English-language clinical trials worldwide reporting treatment-related adverse events in patients receiving CD3-based T cell-engaging bispecific antibodies for cancer, published up to July 31, 2025. The primary outcomes were the overall incidence of treatment-related adverse events, and toxicity profiles (ie, the incidence of each specified adverse event, for both all-grade and grade 3 or worse treatment-related adverse events). Pooled overall incidence and profile estimates with 95% CIs for both all-grade and grade 3 or worse treatment-related adverse events were calculated using logit-transformed random-effects models. Heterogeneity across studies was quantified with the I statistic. The study is registered at PROSPERO (CRD420251130333). FINDINGS: A total of 104 clinical trials enrolling 10 353 patients (7311 with haematological malignancies and 3042 with solid tumours) were included. For haematological malignancies, the overall incidence of all-grade treatment-related adverse events was 97·5% (95% CI 95·2-98·7; I=88·2%), and 70·3% (62·6-77·0; I=94·4%) for grade 3 or worse adverse events. For solid tumours, corresponding incidences were 97·9% (95·7-99·0; I=57·0%) and 45·3% (38·4-52·4; I=87·0%), respectively. The most frequently observed all-grade treatment-related adverse events were cytokine release syndrome in haematological malignancies (43·3% [95% CI 33·9-53·1]) and solid tumours (46·3% [25·5-67·1]). The most frequent grade 3 or worse treatment-related adverse events were neutropenia (18·1% [11·1-26·9]) in haematological cancers and increased γ-glutamyltransferase (3·68% [0·86-6·98]) in solid tumours. Treatment-related deaths occurred in 94 of 9206 patients (1·0% [95% CI 0·8-1·3]; I=0·0%). The predominant causes were sepsis, pneumonia, neutropenic infection, respiratory failure, septic shock, and multi-organ failure. INTERPRETATION: The toxicity profile of T cell-engaging bispecific antibodies varies substantially across cancer types and antibody classes. This meta-analysis provides a comprehensive overview of treatment-related adverse event incidence and patterns, offering a valuable reference for optimising patient management in clinical practice. FUNDING: The National Natural Science Foundation of China and the Changsha Natural Science Foundation of Hunan Province of China.