Pub Date : 2026-02-01Epub Date: 2026-01-19DOI: 10.1016/j.annonc.2025.12.016
H. Tawbi , D. Massi
{"title":"Optimizing pathological response assessment after neoadjuvant immunotherapy: linking clinical practice to drug development","authors":"H. Tawbi , D. Massi","doi":"10.1016/j.annonc.2025.12.016","DOIUrl":"10.1016/j.annonc.2025.12.016","url":null,"abstract":"","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 2","pages":"Pages 139-140"},"PeriodicalIF":65.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145993555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-18DOI: 10.1016/j.annonc.2025.10.013
L.L. Siu , T. Powles
{"title":"Antibody–drug conjugates in combination therapy: defining the next chapter☆","authors":"L.L. Siu , T. Powles","doi":"10.1016/j.annonc.2025.10.013","DOIUrl":"10.1016/j.annonc.2025.10.013","url":null,"abstract":"","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 2","pages":"Pages 129-132"},"PeriodicalIF":65.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-16DOI: 10.1016/j.annonc.2025.10.016
L. Malorni , S. Tyekucheva , A. Gombos , U. Hasler-Strub , C. Zamagni , C. Chakiba-Brugère , M. Colleoni , A. Mueller , A.M. Minisini , D. Taylor , J.P. Salmon , E. Gallerani , A. Cariello , A. Fontana , H. Roschitzki-Voser , R. Kammler , B. Ruepp , S. Loi , G. Viale , M.M. Regan , L. Biganzoli
Background
Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a heterogeneous disease with low pathological complete response (pCR) to standard neoadjuvant treatment. Cyclin-dependent kinase 4 and 6 inhibitors with endocrine and anti-HER2 therapy have shown a potential for chemotherapy omission in this context.
Patients and methods
TOUCH is an international, open-label, phase II trial for postmenopausal patients with cT >1 cm, cN0 or cN1, HR-positive/HER2-positive BC, randomly assigned to 16 weeks of neoadjuvant weekly paclitaxel or palbociclib and letrozole, both with trastuzumab + pertuzumab (HP). The primary objective investigated the interaction between a gene signature of E2F pathway activity (RBsig) and pCR (ypT0N0 or ypTisN0), hypothesizing higher pCR for RBsig-high tumors in the paclitaxel + HP group and for RBsig-low tumors in the palbociclib + letrozole + HP group. RBsig was assessed by RNA-sequencing from pre-treatment biopsies; intrinsic subtypes were estimated by absolute intrinsic molecular subtyping Treatment-by-biomarker interaction was estimated using logistic regression in 115 assessable patients.
Results
A total of 147 patients were randomly assigned (74 paclitaxel + HP, 73 palbociclib + letrozole + HP) and 145 constituted the treated population, with a median age of 69 years (interquartile range 63-73 years). More patients completed palbociclib versus paclitaxel (94.4% versus 79.5%). The most frequent grade 3-4 adverse events were neutropenia and diarrhea (6.9% versus 43.1% and 11% versus 8.3% in the paclitaxel + HP versus the palbociclib + letrozole + HP groups, respectively). The pCR rate was 32.9% [95% confidence interval (CI) 22.3% to 44.9%] in the paclitaxel + HP group and 33.3% (95% CI 22.7% to 45.4%) in the palbociclib + letrozole + HP group. No significant treatment-by-RBsig interaction was observed (P = 0.18): pCR in RBsig high versus low was 31.3% (95% CI 16.1% to 50.0%) versus 42.3% (95% CI 23.4% to 63.1%) in the paclitaxel + HP group, and 38.5% (95% CI 20.2% to 59.4%) versus 25.8% (95% CI 11.9% to 44.6%) in the palbociclib group. pCR was higher in non-luminal versus luminal subtypes (45.5% versus 18.4%), with no interaction with treatment.
Conclusions
Although the primary hypothesis was not supported, TOUCH shows that dual anti-HER2 blockade with a chemotherapy-free backbone of palbociclib + letrozole yields pCR rates similar to paclitaxel, representing an attractive alternative treatment strategy.
{"title":"Palbociclib plus letrozole versus weekly paclitaxel, both in combination with trastuzumab plus pertuzumab, as neoadjuvant treatment for patients with HR-positive/HER2-positive early breast cancer: primary results from the randomized phase II TOUCH trial (IBCSG 55-17)☆","authors":"L. Malorni , S. Tyekucheva , A. Gombos , U. Hasler-Strub , C. Zamagni , C. Chakiba-Brugère , M. Colleoni , A. Mueller , A.M. Minisini , D. Taylor , J.P. Salmon , E. Gallerani , A. Cariello , A. Fontana , H. Roschitzki-Voser , R. Kammler , B. Ruepp , S. Loi , G. Viale , M.M. Regan , L. Biganzoli","doi":"10.1016/j.annonc.2025.10.016","DOIUrl":"10.1016/j.annonc.2025.10.016","url":null,"abstract":"<div><h3>Background</h3><div>Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a heterogeneous disease with low pathological complete response (pCR) to standard neoadjuvant treatment. Cyclin-dependent kinase 4 and 6 inhibitors with endocrine and anti-HER2 therapy have shown a potential for chemotherapy omission in this context.</div></div><div><h3>Patients and methods</h3><div>TOUCH is an international, open-label, phase II trial for postmenopausal patients with cT >1 cm, cN0 or cN1, HR-positive/HER2-positive BC, randomly assigned to 16 weeks of neoadjuvant weekly paclitaxel or palbociclib and letrozole, both with trastuzumab + pertuzumab (HP). The primary objective investigated the interaction between a gene signature of E2F pathway activity (RBsig) and pCR (ypT0N0 or ypTisN0), hypothesizing higher pCR for RBsig-high tumors in the paclitaxel + HP group and for RBsig-low tumors in the palbociclib + letrozole + HP group. RBsig was assessed by RNA-sequencing from pre-treatment biopsies; intrinsic subtypes were estimated by absolute intrinsic molecular subtyping Treatment-by-biomarker interaction was estimated using logistic regression in 115 assessable patients.</div></div><div><h3>Results</h3><div>A total of 147 patients were randomly assigned (74 paclitaxel + HP, 73 palbociclib + letrozole + HP) and 145 constituted the treated population, with a median age of 69 years (interquartile range 63-73 years). More patients completed palbociclib versus paclitaxel (94.4% versus 79.5%). The most frequent grade 3-4 adverse events were neutropenia and diarrhea (6.9% versus 43.1% and 11% versus 8.3% in the paclitaxel + HP versus the palbociclib + letrozole + HP groups, respectively). The pCR rate was 32.9% [95% confidence interval (CI) 22.3% to 44.9%] in the paclitaxel + HP group and 33.3% (95% CI 22.7% to 45.4%) in the palbociclib + letrozole + HP group. No significant treatment-by-RBsig interaction was observed (<em>P</em> = 0.18): pCR in RBsig high versus low was 31.3% (95% CI 16.1% to 50.0%) versus 42.3% (95% CI 23.4% to 63.1%) in the paclitaxel + HP group, and 38.5% (95% CI 20.2% to 59.4%) versus 25.8% (95% CI 11.9% to 44.6%) in the palbociclib group. pCR was higher in non-luminal versus luminal subtypes (45.5% versus 18.4%), with no interaction with treatment.</div></div><div><h3>Conclusions</h3><div>Although the primary hypothesis was not supported, TOUCH shows that dual anti-HER2 blockade with a chemotherapy-free backbone of palbociclib + letrozole yields pCR rates similar to paclitaxel, representing an attractive alternative treatment strategy.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 2","pages":"Pages 194-205"},"PeriodicalIF":65.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-17DOI: 10.1016/j.annonc.2025.10.003
E.L. Mayer , D. Hlauschek , M. Gnant , P.J. O'Brien , M. Bellet-Ezquerra , M.P. Goetz , M. Ruiz-Borrego , A. Chan , K. Clifton , D. Egle , D. Lake , P. Cabrera , T. Mamounas , G. Pristauz-Telsnigg , Z. Dayao , M. Gil Gil , D. Cameron , T. Traina , P.G. Morris , D. Sabanathan , A. DeMichele
Background
In the phase III PALLAS trial, the addition of 2 years of palbociclib to adjuvant endocrine therapy (ET) did not improve short-term invasive disease-free survival (iDFS) compared with ET alone in high-risk early-stage hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this article, we report 5-year efficacy outcomes, including updated iDFS and overall survival (OS).
Patients and methods
PALLAS is an international, open-label, randomized phase III trial evaluating the addition of 2 years of palbociclib to adjuvant ET in patients with stage II-III HR-positive/HER2-negative breast cancer. The primary endpoint was iDFS.
Results
The trial enrolled 5753 patients, with 2883 randomized to receive palbociclib plus ET and 2870 to receive ET alone. With a median follow-up of 59.8 months, the 5-year iDFS was 84.2% [95% confidence interval (CI) 82.7% to 85.6%] in the palbociclib plus ET arm and 82.4% (95% CI 80.8% to 83.9%) in the ET-alone arm [hazard ratio (HR) 0.88, 95% CI 0.77-1.01, log-rank P = 0.0614]. No significant iDFS benefit of palbociclib was observed in any subgroup, including analyses by anatomic stage, T-stage, N-stage, tumor grade, prior (neo)adjuvant chemotherapy, age, or clinical risk. The 5-year OS was 92.6% (95% CI 91.5% to 93.6%) in the palbociclib plus ET arm and 93.2% (95% CI 92.1% to 94.1%) in the ET-alone arm (HR 1.09, 95% CI 0.89-1.33, log-rank P = 0.4051). More patients in the ET-alone arm (65.7%) than in the palbociclib plus ET arm (33.0%) received cyclin-dependent kinase 4/6 inhibitors after recurrence. Conversely, more patients in the palbociclib plus ET arm (52.5%) than in the ET-alone arm (41.0%) received chemotherapy after recurrence.
Conclusions
In conclusion, 5-year follow-up from the PALLAS trial confirms initially reported results. These long-term findings will provide investigators with important benchmarks for clinical outcomes in the contemporary management of HR-positive/HER2-negative breast cancer, and may be further used to guide adjuvant therapy for patients with high-risk early-stage HR-positive/HER2-negative breast cancer.
{"title":"Palbociclib with adjuvant endocrine therapy in early breast cancer: 5-year follow-up analysis of the global multicenter, open-label, randomized phase III PALLAS trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13)","authors":"E.L. Mayer , D. Hlauschek , M. Gnant , P.J. O'Brien , M. Bellet-Ezquerra , M.P. Goetz , M. Ruiz-Borrego , A. Chan , K. Clifton , D. Egle , D. Lake , P. Cabrera , T. Mamounas , G. Pristauz-Telsnigg , Z. Dayao , M. Gil Gil , D. Cameron , T. Traina , P.G. Morris , D. Sabanathan , A. DeMichele","doi":"10.1016/j.annonc.2025.10.003","DOIUrl":"10.1016/j.annonc.2025.10.003","url":null,"abstract":"<div><h3>Background</h3><div>In the phase III PALLAS trial, the addition of 2 years of palbociclib to adjuvant endocrine therapy (ET) did not improve short-term invasive disease-free survival (iDFS) compared with ET alone in high-risk early-stage hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this article, we report 5-year efficacy outcomes, including updated iDFS and overall survival (OS).</div></div><div><h3>Patients and methods</h3><div>PALLAS is an international, open-label, randomized phase III trial evaluating the addition of 2 years of palbociclib to adjuvant ET in patients with stage II-III HR-positive/HER2-negative breast cancer. The primary endpoint was iDFS.</div></div><div><h3>Results</h3><div>The trial enrolled 5753 patients, with 2883 randomized to receive palbociclib plus ET and 2870 to receive ET alone. With a median follow-up of 59.8 months, the 5-year iDFS was 84.2% [95% confidence interval (CI) 82.7% to 85.6%] in the palbociclib plus ET arm and 82.4% (95% CI 80.8% to 83.9%) in the ET-alone arm [hazard ratio (HR) 0.88, 95% CI 0.77-1.01, log-rank <em>P</em> = 0.0614]. No significant iDFS benefit of palbociclib was observed in any subgroup, including analyses by anatomic stage, T-stage, N-stage, tumor grade, prior (neo)adjuvant chemotherapy, age, or clinical risk. The 5-year OS was 92.6% (95% CI 91.5% to 93.6%) in the palbociclib plus ET arm and 93.2% (95% CI 92.1% to 94.1%) in the ET-alone arm (HR 1.09, 95% CI 0.89-1.33, log-rank <em>P</em> = 0.4051). More patients in the ET-alone arm (65.7%) than in the palbociclib plus ET arm (33.0%) received cyclin-dependent kinase 4/6 inhibitors after recurrence. Conversely, more patients in the palbociclib plus ET arm (52.5%) than in the ET-alone arm (41.0%) received chemotherapy after recurrence.</div></div><div><h3>Conclusions</h3><div>In conclusion, 5-year follow-up from the PALLAS trial confirms initially reported results. These long-term findings will provide investigators with important benchmarks for clinical outcomes in the contemporary management of HR-positive/HER2-negative breast cancer, and may be further used to guide adjuvant therapy for patients with high-risk early-stage HR-positive/HER2-negative breast cancer.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 2","pages":"Pages 271-277"},"PeriodicalIF":65.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-20DOI: 10.1016/j.annonc.2025.10.006
E.L. Mayer , F.-C. Bidard , Y.H. Park , W. Janni , C. Ma , M. Cristofanilli , H. Iwata , G. Bianchini , K. Kalinsky , S. Chia , A. Brufsky , P.A. Fasching , Z. Nowecki , S.-C. Chen , J. Pascual , L. Moreau , M. Ruiz-Borrego , A. Shai , N. Karadurmus , J.H. Sohn , N. Turner
Background
In SERENA-6, switching from aromatase inhibitor (AI) to camizestrant with continuation of CDK4/6 inhibitor (CDK4/6i) guided by emergence of ESR1 mutations (ESR1-mut) during first-line AI-CDK4/6i in patients with hormone receptor (HR)-positive advanced breast cancer (ABC) resulted in statistically significant and clinically meaningful improvement in progression-free survival compared with AI-CDK4/6i and reduction in the risk of deterioration in global health status (GHS)/quality of life (QoL) (hazard ratio 0.54). Here we report additional data from patient-reported outcomes (PROs).
Patients and methods
Patients completed PRO questionnaires at pre-specified timepoints, including the European Organisation for Research and Treatment of Cancer (EORTC) oncology-specific EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and breast cancer-specific (QLQ-BR23) and Patient Global Impression of Treatment Tolerability (PGI-TT). All PRO endpoints and analyses were pre-defined, including secondary endpoints of time to deterioration (TTD) in pain, physical functioning, breast symptoms and arm symptoms.
Results
EORTC QLQ-C30 and EORTC QLQ-BR23 baseline scores were similar between treatment arms. Switching to camizestrant-CDK4/6i delayed TTD and reduced the risk of deterioration in patient-reported cancer symptoms [pain (hazard ratio 0.57, 95% confidence interval 0.37-0.86), fatigue (0.75, 0.46-1.24), shortness of breath/dyspnoea (0.52, 0.28-0.93), breast symptoms (0.59, 0.28-1.24) and arm symptoms (0.69, 0.34-1.39)] and functioning [physical (0.74, 0.44-1.24), role (0.73, 0.48-1.10) and emotional (0.51, 0.29-0.87)] compared with AI-CDK4/6i. Most patients reported they were ‘not at all’ or ‘a little bit’ bothered by the side effects of cancer therapy across timepoints (e.g. week 2: 86% camizestrant-CDK4/6i versus 82% AI-CDK4/6i).
Conclusions
Together with the clinical efficacy and manageable safety profile of camizestrant-CDK4/6i, and reduced risk of GHS/QoL deterioration, the PROs from the SERENA-6 trial support switching to this combination as a potential new treatment strategy to optimise and improve outcomes in patients with HR-positive/HER2-negative ABC and ESR1-mut emergence, ahead of disease progression, during first-line AI-CDK4/6i.
背景：在SERENA-6中，HR+晚期乳腺癌患者在一线AI-CDK4/6i期间，在ESR1m的引导下，从芳香酶抑制剂（AI）切换到camizestrant并继续使用CDK4/6i，与AI-CDK4/6i相比，无进展生存期（progression-free survival）有统计学意义和临床意义的改善，总体健康状况(GHS)/生活质量（QoL）恶化的风险降低（风险比0.54）。在这里，我们报告了来自患者报告结果（PROs）的额外数据。患者和方法：患者在预先指定的时间点完成PRO问卷，包括欧洲癌症研究和治疗组织（EORTC）肿瘤特异性EORTC生活质量问卷核心30 （QLQ-C30）和乳腺癌特异性（QLQ-BR23）和患者整体治疗耐受性印象（PGI-TT）。所有PRO终点和分析都是预先定义的，包括疼痛、身体功能、乳房症状和手臂症状恶化时间（TTD）的次要终点。结果：EORTC QLQ-C30和EORTC QLQ-BR23基线评分在治疗组之间相似。与AI-CDK4/6i相比，改用camizestran - cdk4 /6i延迟了TTD，降低了患者报告的癌症症状（疼痛[风险比0.57;95% CI 0.37-0.86]、疲劳[0.75;0.46-1.24]、呼吸短促/呼吸困难[0.52;0.28-0.93]、乳房症状[0.59;0.28-1.24]和手臂症状[0.69;0.34-1.39]）和功能（身体[0.74;0.44-1.24]、角色[0.73;0.48-1.10]和情绪[0.51;0.29-0.87]）恶化的风险。大多数患者报告说，他们“完全不”或“有点”担心癌症治疗的副作用（例如，第2周：86% camizestrant-CDK4/6i vs 82% AI-CDK4/6i）。结论：结合camizestran - cdk4 /6i的临床疗效和可管理的安全性，以及GHS/QoL恶化的风险降低，SERENA-6试验的PROs支持将该组合作为一种潜在的新治疗策略，以优化和改善一线AI-CDK4/6i期间HR+/HER2-晚期乳腺癌和ESR1m出现患者的预后。
{"title":"Patient-reported outcomes in the SERENA-6 trial of camizestrant plus CDK4/6 inhibitor in patients with advanced breast cancer and emergent ESR1 mutations during first-line endocrine-based therapy☆","authors":"E.L. Mayer , F.-C. Bidard , Y.H. Park , W. Janni , C. Ma , M. Cristofanilli , H. Iwata , G. Bianchini , K. Kalinsky , S. Chia , A. Brufsky , P.A. Fasching , Z. Nowecki , S.-C. Chen , J. Pascual , L. Moreau , M. Ruiz-Borrego , A. Shai , N. Karadurmus , J.H. Sohn , N. Turner","doi":"10.1016/j.annonc.2025.10.006","DOIUrl":"10.1016/j.annonc.2025.10.006","url":null,"abstract":"<div><h3>Background</h3><div>In SERENA-6, switching from aromatase inhibitor (AI) to camizestrant with continuation of CDK4/6 inhibitor (CDK4/6i) guided by emergence of <em>ESR1</em> mutations (<em>ESR1</em>-mut) during first-line AI-CDK4/6i in patients with hormone receptor (HR)-positive advanced breast cancer (ABC) resulted in statistically significant and clinically meaningful improvement in progression-free survival compared with AI-CDK4/6i and reduction in the risk of deterioration in global health status (GHS)/quality of life (QoL) (hazard ratio 0.54). Here we report additional data from patient-reported outcomes (PROs).</div></div><div><h3>Patients and methods</h3><div>Patients completed PRO questionnaires at pre-specified timepoints, including the European Organisation for Research and Treatment of Cancer (EORTC) oncology-specific EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and breast cancer-specific (QLQ-BR23) and Patient Global Impression of Treatment Tolerability (PGI-TT). All PRO endpoints and analyses were pre-defined, including secondary endpoints of time to deterioration (TTD) in pain, physical functioning, breast symptoms and arm symptoms.</div></div><div><h3>Results</h3><div>EORTC QLQ-C30 and EORTC QLQ-BR23 baseline scores were similar between treatment arms. Switching to camizestrant-CDK4/6i delayed TTD and reduced the risk of deterioration in patient-reported cancer symptoms [pain (hazard ratio 0.57, 95% confidence interval 0.37-0.86), fatigue (0.75, 0.46-1.24), shortness of breath/dyspnoea (0.52, 0.28-0.93), breast symptoms (0.59, 0.28-1.24) and arm symptoms (0.69, 0.34-1.39)] and functioning [physical (0.74, 0.44-1.24), role (0.73, 0.48-1.10) and emotional (0.51, 0.29-0.87)] compared with AI-CDK4/6i. Most patients reported they were ‘not at all’ or ‘a little bit’ bothered by the side effects of cancer therapy across timepoints (e.g. week 2: 86% camizestrant-CDK4/6i versus 82% AI-CDK4/6i).</div></div><div><h3>Conclusions</h3><div>Together with the clinical efficacy and manageable safety profile of camizestrant-CDK4/6i, and reduced risk of GHS/QoL deterioration, the PROs from the SERENA-6 trial support switching to this combination as a potential new treatment strategy to optimise and improve outcomes in patients with HR-positive/HER2-negative ABC and <em>ESR1</em>-mut emergence, ahead of disease progression, during first-line AI-CDK4/6i.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 2","pages":"Pages 180-193"},"PeriodicalIF":65.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-01DOI: 10.1016/j.annonc.2025.10.1237
R.V. Rawson , N.G. Maher , A.M. Menzies , S.N. Lo , N. Mesbah Ardakani , L.A. Jackett , I.A. Vergara , T.E. Pennington , K.F. Shannon , S. Ch’ng , M. Gonzalez , E.M. Burton , M.W. Lucas , I.L.M. Reijers , E.A. Rozeman , D.E. Gyorki , S. Sandhu , M.S. Carlino , J. Howle , M. Khattak , R.A. Scolyer
Background
Neoadjuvant immunotherapy produces event-free survival advantage over adjuvant therapy for patients with surgically resectable macroscopic stage IIIB/C/D melanoma. Pathological response, determined as percentage residual viable tumor (% RVT), provides critical prognostic information and informs management decisions. Here, we assessed accuracy of %RVT calculation when reduced tumor bed (TB) was examined and leverage these results proposing streamlined protocols for pathological examination.
Patients and methods
Comprehensive histopathological examination was carried out on 134 patient specimens after neoadjuvant immunotherapy with ipilimumab and nivolumab. Impact on %RVT when evaluating less TB than recommended by the initial International Neoadjuvant Melanoma Consortium (INMC) protocol was assessed. Firstly, % RVT of each case was recalculated using seven modified protocols and compared with % RVT obtained under INMC protocol. Next, a simulation study was carried out recalculating % RVT by random sampling 50%, 33%, and 25% of TB slides per specimen.
Results
There was excellent accuracy in %RVT (R2 > 0.97) for all the modified protocols and >90% accuracy in five protocols. Accuracy of major pathological response (MPR)/non-MPR and pathological response category classification was ≥96% in six protocols. The decrease in average slides examined per specimen ranged from 9% to 58%. In total, 85%, 79%, and 74% of simulations recalculating %RVT were within 5% of the INMC calculation when 50%, 33%, and 25% of TB slides were examined, respectively. If TB slide examination is capped at 20, %RVT calculation remains 93% accurate.
Conclusions
TB embedded for histopathological examination in neoadjuvant stage IIIB/C/D melanoma specimens can be reduced without significantly compromising accuracy of %RVT calculation. We recommend an updated pathological assessment protocol: lymph nodes ≤3 cm examined in entirety; macroscopically involved lymph nodes >3 cm should have a modified examination protocol of at least a full cross-sectional transverse slice. Capping TB slides examined at 20 appears reasonable. This refined approach results in high accuracy and significant reduction in the slides examined.
{"title":"Pathological response calculation assessment remains accurate with reduced tumor bed examination after neoadjuvant immunotherapy in clinically detectable stage III melanoma","authors":"R.V. Rawson , N.G. Maher , A.M. Menzies , S.N. Lo , N. Mesbah Ardakani , L.A. Jackett , I.A. Vergara , T.E. Pennington , K.F. Shannon , S. Ch’ng , M. Gonzalez , E.M. Burton , M.W. Lucas , I.L.M. Reijers , E.A. Rozeman , D.E. Gyorki , S. Sandhu , M.S. Carlino , J. Howle , M. Khattak , R.A. Scolyer","doi":"10.1016/j.annonc.2025.10.1237","DOIUrl":"10.1016/j.annonc.2025.10.1237","url":null,"abstract":"<div><h3>Background</h3><div>Neoadjuvant immunotherapy produces event-free survival advantage over adjuvant therapy for patients with surgically resectable macroscopic stage IIIB/C/D melanoma. Pathological response, determined as percentage residual viable tumor (% RVT), provides critical prognostic information and informs management decisions. Here, we assessed accuracy of %RVT calculation when reduced tumor bed (TB) was examined and leverage these results proposing streamlined protocols for pathological examination.</div></div><div><h3>Patients and methods</h3><div>Comprehensive histopathological examination was carried out on 134 patient specimens after neoadjuvant immunotherapy with ipilimumab and nivolumab. Impact on %RVT when evaluating less TB than recommended by the initial International Neoadjuvant Melanoma Consortium (INMC) protocol was assessed. Firstly, % RVT of each case was recalculated using seven modified protocols and compared with % RVT obtained under INMC protocol. Next, a simulation study was carried out recalculating % RVT by random sampling 50%, 33%, and 25% of TB slides per specimen.</div></div><div><h3>Results</h3><div>There was excellent accuracy in %RVT (R<sup>2</sup> > 0.97) for all the modified protocols and >90% accuracy in five protocols. Accuracy of major pathological response (MPR)/non-MPR and pathological response category classification was ≥96% in six protocols. The decrease in average slides examined per specimen ranged from 9% to 58%. In total, 85%, 79%, and 74% of simulations recalculating %RVT were within 5% of the INMC calculation when 50%, 33%, and 25% of TB slides were examined, respectively. If TB slide examination is capped at 20, %RVT calculation remains 93% accurate.</div></div><div><h3>Conclusions</h3><div>TB embedded for histopathological examination in neoadjuvant stage IIIB/C/D melanoma specimens can be reduced without significantly compromising accuracy of %RVT calculation. We recommend an updated pathological assessment protocol: lymph nodes ≤3 cm examined in entirety; macroscopically involved lymph nodes >3 cm should have a modified examination protocol of at least a full cross-sectional transverse slice. Capping TB slides examined at 20 appears reasonable. This refined approach results in high accuracy and significant reduction in the slides examined.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 2","pages":"Pages 206-216"},"PeriodicalIF":65.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145436837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-18DOI: 10.1016/j.annonc.2025.10.007
R.S. Kristeleit , S. Ghamande , A. Lisyanskaya , A. Oaknin , E. Prendergast , Y.B. Kim , J. Fuentes Pradera , R.D. Littell , B. Gao , G. Valabrega , D.M. O’Malley , A. Dean , C. Pisano , J. Buscema , D. Provencher , F. Zagouri , L.P. Martin , H.-H. Chou , F. Demirkiran , F. Ueland , B.J. Monk
Background
We report the long-term efficacy and safety from the multicenter, randomized, double-blind, placebo-controlled, phase III ATHENA-MONO/GOG-3020/ENGOT-ov45 (NCT03522246) study of first-line rucaparib maintenance for advanced ovarian cancer.
Patients and methods
Patients were randomized 4 : 1 to oral rucaparib + intravenous (i.v.) placebo or oral + i.v. placebo. Stratification factors were homologous recombination deficiency (HRD; BRCA mutation and loss of heterozygosity status) classification, residual disease post-chemotherapy, and surgical timing. The primary endpoint was investigator-assessed progression-free survival (invPFS) in HRD and intent-to-treat (ITT) populations. Overall survival (OS) and safety were secondary endpoints. Second event of progression (PFS2) and time to first subsequent treatment (TFST) were exploratory. Interim OS and final safety analyses data cut-off was 9 March 2023. Updated invPFS, PFS2, and TFST analyses data cut-off was 5 May 2025.
Results
Median invPFS follow-up was ∼59 months for both rucaparib (HRD, n = 185; ITT, n = 427) and placebo (HRD, n = 49; ITT, n = 111). invPFS was significantly longer with rucaparib versus placebo in the HRD [31.4 versus 12.0 months; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.35-0.76] and ITT (20.2 versus 9.2 months; HR 0.53, 95% CI 0.42-0.69) populations. Interim OS was immature (OS maturity: ITT 35%) with the median (95% CI) OS not reached with rucaparib and 46.2 (34.6-not reached) months with placebo for the ITT population (HR 0.83, 95% CI 0.58-1.17). ITT TFST (median 23.6 versus 12.1 months) and PFS2 (35.1 versus 26.9 months) were longer with rucaparib versus placebo. Overall, 34.6% of patients receiving rucaparib completed the 24-month treatment cap versus 17.3% receiving placebo. As of 5 May 2025, 40.0% of patients on rucaparib were still on study and in long-term follow-up. Safety remained consistent with the primary analysis.
Conclusions
Rucaparib monotherapy provides significant and durable long-term benefit as first-line maintenance for patients with advanced ovarian cancer with and without HRD.
背景：我们报告了一项多中心、随机、双盲、安慰剂对照的III期ATHENA-MONO/GOG-3020/ENGOT-ov45 （NCT03522246）一线鲁卡帕尼维持治疗晚期卵巢癌的长期疗效和安全性。患者和方法：患者以4:1随机分为口服鲁卡帕尼+静脉（IV）安慰剂或口服+静脉（IV）安慰剂。分层因素为同源重组缺陷（HRD； BRCA突变和杂合状态丧失）、化疗后残留疾病和手术时间。主要终点是研究者评估的HRD和意向治疗人群的无进展生存期（invPFS）。总生存期（OS）和安全性是次要终点。第二次进展事件（PFS2）和到第一次后续治疗的时间（TFST）是探索性的。中期操作系统和最终安全分析数据截止日期为2023年3月9日。更新的invPFS、PFS2和TFST分析数据截止日期为2025年5月5日。结果：鲁卡帕尼（HRD, n = 185； ITT, n = 427）和安慰剂（HRD, n = 49； ITT, n = 111）的中位invPFS随访约为59个月。在HRD人群（31.4个月vs 12.0个月；HR 0.52, 95% CI 0.35-0.76）和ITT人群（20.2个月vs 9.2个月；HR 0.53, 95% CI 0.42-0.69）中，鲁卡帕尼组的invPFS明显长于安慰剂组。中期OS未成熟（OS成熟度：ITT， 35%）， ITT人群未达到鲁卡帕尼的中位（95% CI） OS，安慰剂未达到46.2 （34.6 nr）个月（HR 0.83, 95% CI 0.58-1.17）。鲁卡帕尼组的ITT TFST（中位数23.6个月对12.1个月）和PFS2（中位数35.1个月对26.9个月）比安慰剂组更长。总体而言，接受rucaparib的患者中有34.6%完成了24个月的治疗上限，而接受安慰剂的患者中有17.3%完成了治疗上限。截至2025年5月5日，40.0%的鲁卡帕尼患者仍在研究和长期随访中。安全性与初步分析一致。结论：鲁卡帕尼单药治疗作为有或无HRD的晚期卵巢癌患者的一线维持治疗提供了显著和持久的长期获益。
{"title":"Rucaparib maintenance for newly diagnosed advanced ovarian cancer: interim overall survival, progression-free survival, and safety at 5 years of follow-up from the phase III ATHENA-MONO/GOG-3020/ENGOT-ov45 study☆","authors":"R.S. Kristeleit , S. Ghamande , A. Lisyanskaya , A. Oaknin , E. Prendergast , Y.B. Kim , J. Fuentes Pradera , R.D. Littell , B. Gao , G. Valabrega , D.M. O’Malley , A. Dean , C. Pisano , J. Buscema , D. Provencher , F. Zagouri , L.P. Martin , H.-H. Chou , F. Demirkiran , F. Ueland , B.J. Monk","doi":"10.1016/j.annonc.2025.10.007","DOIUrl":"10.1016/j.annonc.2025.10.007","url":null,"abstract":"<div><h3>Background</h3><div>We report the long-term efficacy and safety from the multicenter, randomized, double-blind, placebo-controlled, phase III ATHENA-MONO/GOG-3020/ENGOT-ov45 (NCT03522246) study of first-line rucaparib maintenance for advanced ovarian cancer.</div></div><div><h3>Patients and methods</h3><div>Patients were randomized 4 : 1 to oral rucaparib + intravenous (i.v.) placebo or oral + i.v. placebo. Stratification factors were homologous recombination deficiency (HRD; <em>BRCA</em> mutation and loss of heterozygosity status) classification, residual disease post-chemotherapy, and surgical timing. The primary endpoint was investigator-assessed progression-free survival (invPFS) in HRD and intent-to-treat (ITT) populations. Overall survival (OS) and safety were secondary endpoints. Second event of progression (PFS2) and time to first subsequent treatment (TFST) were exploratory. Interim OS and final safety analyses data cut-off was 9 March 2023. Updated invPFS, PFS2, and TFST analyses data cut-off was 5 May 2025.</div></div><div><h3>Results</h3><div>Median invPFS follow-up was ∼59 months for both rucaparib (HRD, <em>n</em> = 185; ITT, <em>n</em> = 427) and placebo (HRD, <em>n</em> = 49; ITT, <em>n</em> = 111). invPFS was significantly longer with rucaparib versus placebo in the HRD [31.4 versus 12.0 months; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.35-0.76] and ITT (20.2 versus 9.2 months; HR 0.53, 95% CI 0.42-0.69) populations. Interim OS was immature (OS maturity: ITT 35%) with the median (95% CI) OS not reached with rucaparib and 46.2 (34.6-not reached) months with placebo for the ITT population (HR 0.83, 95% CI 0.58-1.17). ITT TFST (median 23.6 versus 12.1 months) and PFS2 (35.1 versus 26.9 months) were longer with rucaparib versus placebo. Overall, 34.6% of patients receiving rucaparib completed the 24-month treatment cap versus 17.3% receiving placebo. As of 5 May 2025, 40.0% of patients on rucaparib were still on study and in long-term follow-up. Safety remained consistent with the primary analysis.</div></div><div><h3>Conclusions</h3><div>Rucaparib monotherapy provides significant and durable long-term benefit as first-line maintenance for patients with advanced ovarian cancer with and without HRD.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 2","pages":"Pages 217-228"},"PeriodicalIF":65.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-17DOI: 10.1016/j.annonc.2025.10.017
A. Molassiotis , K. Jordan , M. Karthaus , G. Dranitsaris , E.J. Roeland , L. Schwartzberg , V. Stimamiglio , A. Alonzi , S. Olivari Tilola , E. Bonizzoni , E. Brozos Vázquez , T. Buchler , Y. Cheng , D.C. Christoph , P. García Alfonso , X. Lu , M. Majem , D. Mavroudis , K. Syrigos , E. Tomlins , M. Aapro
Background
Patients receiving moderately emetogenic chemotherapy (MEC) are commonly prescribed a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist (RA) and dexamethasone (DEX) as standard-of-care (SOC) antiemetic prophylaxis. However, in patients with an elevated risk of chemotherapy-induced nausea and vomiting (CINV) due to individual risk factors, prophylaxis with an neurokinin-1 (NK1) RA-containing regimen may optimise their antiemetic prevention. To address this unmet need for a more personalised antiemetic strategy, the MyRisk trial incorporated a predictive risk factor algorithm to select patients at increased risk of CINV who may benefit from enhanced antiemetic prophylaxis.
Patients and methods
MyRisk was a phase IV, randomised, open-label, multicentre, multinational trial. Adult patients scheduled to receive three cycles of MEC with a high-risk CINV score were randomly assigned to NEPA (a fixed combination of an NK1 RA, netupitant, and 5-HT3 RA, palonosetron) + DEX or SOC. The CINV risk score was calculated based on an algorithm that considered seven risk factors. The primary endpoint was complete response (CR: no emesis/no rescue medication) during the overall phase (0-120 h) across three consecutive cycles.
Results
Of 401 randomly allocated patients, 388 were included in the efficacy analysis. The most common cancers were colorectal and lung; oxaliplatin and carboplatin were the most common MECs. Patients randomly assigned to NEPA were significantly more likely to experience a CR compared with SOC (odds ratio 1.67, 95% confidence interval 1.12-2.49, P = 0.012). The NEPA group had a significantly higher probability of CR, no nausea, no emesis, and complete protection (81.0%, 63.7%, 95.4%, and 71.8%, respectively) compared with the SOC arm (71.8%, 54.9%, 86.7%, and 62.4%, respectively) across three cycles of chemotherapy.
Conclusions
When individual risk factors are considered before MEC, a three-drug regimen including NEPA provides superior CINV prevention across multiple cycles compared with the standard two-drug approach. These findings underscore the value of personalised risk-adapted antiemetic strategies and have practice-changing potential for optimising antiemetic control.
{"title":"Personalised antiemetic prophylaxis with NEPA for patients at high risk of chemotherapy-induced nausea and vomiting receiving moderately emetogenic chemotherapy: results from the randomised, multinational MyRisk trial☆","authors":"A. Molassiotis , K. Jordan , M. Karthaus , G. Dranitsaris , E.J. Roeland , L. Schwartzberg , V. Stimamiglio , A. Alonzi , S. Olivari Tilola , E. Bonizzoni , E. Brozos Vázquez , T. Buchler , Y. Cheng , D.C. Christoph , P. García Alfonso , X. Lu , M. Majem , D. Mavroudis , K. Syrigos , E. Tomlins , M. Aapro","doi":"10.1016/j.annonc.2025.10.017","DOIUrl":"10.1016/j.annonc.2025.10.017","url":null,"abstract":"<div><h3>Background</h3><div>Patients receiving moderately emetogenic chemotherapy (MEC) are commonly prescribed a 5-hydroxytryptamine-3 (5-HT<sub>3</sub>) receptor antagonist (RA) and dexamethasone (DEX) as standard-of-care (SOC) antiemetic prophylaxis. However, in patients with an elevated risk of chemotherapy-induced nausea and vomiting (CINV) due to individual risk factors, prophylaxis with an neurokinin-1 (NK<sub>1</sub>) RA-containing regimen may optimise their antiemetic prevention. To address this unmet need for a more personalised antiemetic strategy, the MyRisk trial incorporated a predictive risk factor algorithm to select patients at increased risk of CINV who may benefit from enhanced antiemetic prophylaxis.</div></div><div><h3>Patients and methods</h3><div>MyRisk was a phase IV, randomised, open-label, multicentre, multinational trial. Adult patients scheduled to receive three cycles of MEC with a high-risk CINV score were randomly assigned to NEPA (a fixed combination of an NK<sub>1</sub> RA, netupitant, and 5-HT<sub>3</sub> RA, palonosetron) + DEX or SOC. The CINV risk score was calculated based on an algorithm that considered seven risk factors. The primary endpoint was complete response (CR: no emesis/no rescue medication) during the overall phase (0-120 h) across three consecutive cycles.</div></div><div><h3>Results</h3><div>Of 401 randomly allocated patients, 388 were included in the efficacy analysis. The most common cancers were colorectal and lung; oxaliplatin and carboplatin were the most common MECs. Patients randomly assigned to NEPA were significantly more likely to experience a CR compared with SOC (odds ratio 1.67, 95% confidence interval 1.12-2.49, <em>P</em> = 0.012). The NEPA group had a significantly higher probability of CR, no nausea, no emesis, and complete protection (81.0%, 63.7%, 95.4%, and 71.8%, respectively) compared with the SOC arm (71.8%, 54.9%, 86.7%, and 62.4%, respectively) across three cycles of chemotherapy.</div></div><div><h3>Conclusions</h3><div>When individual risk factors are considered before MEC, a three-drug regimen including NEPA provides superior CINV prevention across multiple cycles compared with the standard two-drug approach. These findings underscore the value of personalised risk-adapted antiemetic strategies and have practice-changing potential for optimising antiemetic control.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 2","pages":"Pages 260-270"},"PeriodicalIF":65.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1016/j.annonc.2026.01.009
S-D Hong, Y-S Wang, H-Y Zhao, Y-Y Zhao, Q-M Wang, Y-X Ma, Y-S Li, Y Huang, Y-P Yang, Z-M Fu, L-K Chen, F Zhou, J Yang, X-Y Li, X Hou, N-N Zhou, L-H Sun, G-F Zhang, J-W Cui, L Wu, G Chen, Y-X Zhang, H-Y Wang, D-Q Lv, J-H Shi, B Jiang, C Li, X-L Li, K-J Tang, Y Yu, Y-H Ji, Z-Y He, Y Zhu, H Zhu, S Xiao, C-C Zhou, L Zhang, W-F Fang
Background: Therapeutic options after progression on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain limited for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Izalontamab brengitecan (Iza-bren; BL-B01D1) is a first-in-class bispecific antibody-drug conjugate targeting EGFR and human epidermal growth factor receptor 3 (HER3) with preclinical and early clinical activity.
Patients and methods: We pooled individual patient data from a phase Ia/Ib dose-escalation/expansion trial (BL-B01D1-101; NCT05194982) and a phase II multicohort trial (BL-B01D1-203; NCT05880706) in patients with advanced EGFR-mutated NSCLC who had disease progression on prior EGFR TKI therapy. Key endpoints were confirmed objective response rate (cORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The recommended phase II dose (RP2D) was 2.5 mg/kg on days 1 and 8 every 3 weeks.
Results: A total of 171 patients were included (data cut-off 30 June 2025; median follow-up 20.5 months). In the pooled population, cORR was 47.4% [95% confidence interval (CI) 39.7% to 55.1%] and DCR was 81.3% (95% CI 74.6% to 86.8%); median DoR was 8.5 months (95% CI 6.9-11.2 months), median PFS was 6.9 months (95% CI 5.5-9.6 months), and median OS was 24.8 months (95% CI 18.5 months to not reached). Efficacy at the RP2D (n = 121) was consistent (cORR 48.8%; DCR 81.0%; median PFS 6.9 months; median OS 24.8 months). In chemotherapy-naive, post-TKI patients treated at the RP2D (n = 50), cORR was 56.0%, DCR was 90.0%, median DoR was 13.7 months, median PFS was 12.5 months, and median OS was not reached. Treatment-related adverse events occurred in 98.8% (grade ≥3: 70.2%), predominantly hematologic; interstitial lung disease was rare (0.6%, all grade 1). Discontinuation for treatment-related adverse events was 1.2%; no treatment-related deaths were reported.
Conclusions: In this exploratory post hoc pooled analysis, Iza-bren demonstrated promising antitumor activity and a manageable safety profile in heavily pretreated EGFR-mutated NSCLC. These findings are hypothesis-generating and are being further evaluated in ongoing randomized trials.
{"title":"Izalontamab brengitecan (Iza-bren; BL-B01D1), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, for patients with EGFR-mutated NSCLC: pooled analysis of phase I and phase II trials.","authors":"S-D Hong, Y-S Wang, H-Y Zhao, Y-Y Zhao, Q-M Wang, Y-X Ma, Y-S Li, Y Huang, Y-P Yang, Z-M Fu, L-K Chen, F Zhou, J Yang, X-Y Li, X Hou, N-N Zhou, L-H Sun, G-F Zhang, J-W Cui, L Wu, G Chen, Y-X Zhang, H-Y Wang, D-Q Lv, J-H Shi, B Jiang, C Li, X-L Li, K-J Tang, Y Yu, Y-H Ji, Z-Y He, Y Zhu, H Zhu, S Xiao, C-C Zhou, L Zhang, W-F Fang","doi":"10.1016/j.annonc.2026.01.009","DOIUrl":"10.1016/j.annonc.2026.01.009","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic options after progression on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain limited for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Izalontamab brengitecan (Iza-bren; BL-B01D1) is a first-in-class bispecific antibody-drug conjugate targeting EGFR and human epidermal growth factor receptor 3 (HER3) with preclinical and early clinical activity.</p><p><strong>Patients and methods: </strong>We pooled individual patient data from a phase Ia/Ib dose-escalation/expansion trial (BL-B01D1-101; NCT05194982) and a phase II multicohort trial (BL-B01D1-203; NCT05880706) in patients with advanced EGFR-mutated NSCLC who had disease progression on prior EGFR TKI therapy. Key endpoints were confirmed objective response rate (cORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The recommended phase II dose (RP2D) was 2.5 mg/kg on days 1 and 8 every 3 weeks.</p><p><strong>Results: </strong>A total of 171 patients were included (data cut-off 30 June 2025; median follow-up 20.5 months). In the pooled population, cORR was 47.4% [95% confidence interval (CI) 39.7% to 55.1%] and DCR was 81.3% (95% CI 74.6% to 86.8%); median DoR was 8.5 months (95% CI 6.9-11.2 months), median PFS was 6.9 months (95% CI 5.5-9.6 months), and median OS was 24.8 months (95% CI 18.5 months to not reached). Efficacy at the RP2D (n = 121) was consistent (cORR 48.8%; DCR 81.0%; median PFS 6.9 months; median OS 24.8 months). In chemotherapy-naive, post-TKI patients treated at the RP2D (n = 50), cORR was 56.0%, DCR was 90.0%, median DoR was 13.7 months, median PFS was 12.5 months, and median OS was not reached. Treatment-related adverse events occurred in 98.8% (grade ≥3: 70.2%), predominantly hematologic; interstitial lung disease was rare (0.6%, all grade 1). Discontinuation for treatment-related adverse events was 1.2%; no treatment-related deaths were reported.</p><p><strong>Conclusions: </strong>In this exploratory post hoc pooled analysis, Iza-bren demonstrated promising antitumor activity and a manageable safety profile in heavily pretreated EGFR-mutated NSCLC. These findings are hypothesis-generating and are being further evaluated in ongoing randomized trials.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":65.4,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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