Annals of Oncology最新文献

{"title":"Five-Year Outcomes of Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer From the Randomized KEYNOTE-671 Study.","authors":"H Wakelee, J D Spicer, S Gao, M Liberman, M Tsuboi, T Kato, K-N Chen, C Dooms, M Majem, G L Martinengo, O Bylicki, D Rodríguez-Abreu, B Halmos, D R Jones, J E Chaft, M Reck, E Jensen, S M Keller, A Samkari, M C Garassino","doi":"10.1016/j.annonc.2026.08.005","DOIUrl":"https://doi.org/10.1016/j.annonc.2026.08.005","url":null,"abstract":"<p><strong>Background: </strong>Adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved survival outcomes compared with neoadjuvant chemotherapy and surgery alone in participants with early-stage non-small-cell lung cancer (NSCLC) in the phase 3, randomized KEYNOTE-671 study. We report results from KEYNOTE-671 after 5 years of follow-up.</p><p><strong>Patients and methods: </strong>Eligible participants with previously untreated, resectable stage II, IIIA, or IIIB (N2) NSCLC were randomized 1:1 to 4 cycles of pembrolizumab 200 mg or placebo every 3 weeks, plus platinum-doublet chemotherapy, followed by surgery then adjuvant pembrolizumab or placebo every 3 weeks for up to 13 cycles. Dual primary endpoints were event-free survival (EFS) per RECIST v1.1 by investigator assessment and overall survival (OS).</p><p><strong>Results: </strong>797 participants were randomized to pembrolizumab (n=397) or placebo (n=400). Median time from randomization to data cutoff (July 3, 2025) was 60.4 (range, 42.6‒85.8) months. Five-year EFS was 49.9% (95% CI, 44.6‒55.0) in the pembrolizumab arm and 26.5% (95% CI, 21.7‒31.5) in the placebo arm (HR, 0.58; 95% CI, 0.48‒0.69); 5-year OS was 64.6% (95% CI, 59.5‒69.2) and 53.6% (95% CI, 48.3‒58.6), respectively (HR, 0.74; 95% CI, 0.59‒0.92). No detriment to health-related quality of life was identified in the pembrolizumab versus placebo arm with longer follow-up. Safety was consistent with the known profiles of each treatment.</p><p><strong>Conclusions: </strong>After 5 years of follow-up, EFS was nearly double with perioperative pembrolizumab plus neoadjuvant chemotherapy, along with continued improvement in OS compared with neoadjuvant chemotherapy and surgery alone. The durable and clinically meaningful benefits observed support use of this treatment as a standard of care for patients with resectable early-stage NSCLC (ClinicalTrials.gov, NCT03425643).</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":80.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787511","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}

{"title":"ESMO Clinical Practice Guideline Express Update on daraxonrasib in the treatment of metastatic pancreatic cancer.","authors":"T Conroy, M Ducreux","doi":"10.1016/j.annonc.2026.08.003","DOIUrl":"10.1016/j.annonc.2026.08.003","url":null,"abstract":"","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":80.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787491","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}

{"title":"Therapeutic targeting of RAS-mediated resistance in oncogene-driven lung cancer.","authors":"F Facchinetti, L Friboulet, L Liao, M Peroni, S Nakazawa, L Zullo, M Aldea, F Pecci, M Makarem, I Alonso Garcia, R Minari, B Tuladhar, K Ngo, A Da Silva, L Bigot, I Odintsov, M K A Koivu, A Leonetti, J Samaniego, E Bernard, D J Kwiatkowski, B Ricciuti, J K Rotow, J Luo, J LoPiccolo, N Florez, M M Awad, J Remon, Y Loriot, B Besse, F Barlesi, A Italiano, D A Barbie, C P Paweletz, P C Gokhale, W W Feng, M Tiseo, D Planchard, A T Shaw, P A Jänne","doi":"10.1016/j.annonc.2026.08.004","DOIUrl":"10.1016/j.annonc.2026.08.004","url":null,"abstract":"<p><strong>Background: </strong>Despite the dramatic activity of next-generation targeted therapies, most patients with oncogene-driven lung cancers eventually relapse. Novel inhibitors are particularly active against on-target resistance, fostering the emergence of off-target resistance mechanisms. The current clinical development of RAS inhibitors hints at their potential role in overcoming off-target resistance mediated by RAS alterations.</p><p><strong>Patients and methods: </strong>Using tissue and liquid biopsies, we assessed resistance mechanisms to first-line osimertinib in patients with epidermal growth factor receptor-mutant lung cancer and to ALK, MET, ROS1, and RET inhibitors, for a total of 590 patients. We established two patient-derived models with acquired KRAS mutations obtained at osimertinib progression, enabling in vitro and in vivo functional experiments.</p><p><strong>Results: </strong>Among 312 patients progressing on first-line osimertinib, we observed a major complementary role of tissue and liquid biopsies in identifying resistance mechanisms. We identified RAS alterations in 35 of 312 patients (11.2%), with an enrichment in KRAS G12D (n = 10) and a paucity of KRAS G12C (n = 1) mutations. In patients with ALK-positive disease (n = 148), RAS alterations were more common at resistance to lorlatinib compared with second-generation inhibitors (14.7% versus 5%, P = 0.0444). Across MET-, ROS1-, and RET-driven lung cancers at progression to targeted agents, RAS alterations were detected in 7%-16% of the cases. In the two patient-derived models established at osimertinib resistance with acquired KRAS mutations (G12D and G12R, respectively), we tested the combinatorial effect of osimertinib with either the selective KRAS G12D inhibitor zoldonrasib or the pan-RAS inhibitor daraxonrasib. Both combinations demonstrated marked synergistic activity in vitro and in vivo.</p><p><strong>Conclusions: </strong>RAS alterations mediate resistance to targeted agents in ∼10% of oncogene-driven lung cancer. Rational combinations with novel RAS inhibitors are effective in preclinical models, providing the basis for their clinical investigation and extending the paradigm of precision oncology.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":80.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787436","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}

{"title":"Eight-year outcomes of testosterone suppression plus enzalutamide or a nonsteroidal antiandrogen for metastatic hormone-sensitive prostate cancer (ENZAMET; ANZUP 1304).","authors":"A Y Zhang, H Thomas, S Begbie, L Cheung, K N Chi, S Chowdhury, M Frydenberg, C Herberstein, L G Horvath, A M Joshua, N J Lawrence, G Marx, J McCaffrey, R McDermott, R A McLaughlin, S A North, F Parnis, W Parulekar, D W Pook, M N Reaume, S K Sandhu, A Tan, T H Tan, A Thomson, F Vera-Badillo, S G Williams, R R Zielinski, M R Stockler, I D Davis, C J Sweeney","doi":"10.1016/j.annonc.2026.07.412","DOIUrl":"10.1016/j.annonc.2026.07.412","url":null,"abstract":"<p><strong>Background: </strong>We previously reported that, at median follow-ups of 34 and 68 months, enzalutamide improved overall survival (OS) compared with a first-generation nonsteroidal antiandrogen (NSAA) when used with testosterone suppression for metastatic hormone-sensitive prostate cancer (mHSPC). We now report longer-term outcomes with a focus on adverse events (AEs) and causes of death.</p><p><strong>Patients and methods: </strong>Participants with mHSPC were randomly assigned (1 : 1) to receive daily enzalutamide or NSAA in addition to testosterone suppression; concurrent early docetaxel was permitted at clinician discretion. OS was the primary endpoint; secondary endpoints included progression-free survival (PFS), cause-specific survival, duration of treatment, and AEs.</p><p><strong>Results: </strong>At a median follow-up of 8.1 years (97 months), deaths occurred in 285 of 563 (51%) participants assigned enzalutamide versus 337 of 562 (60%) assigned NSAA. OS was longer with enzalutamide than with NSAA [median 7.9 versus 5.8 years; OS at 8 years 50% versus 40%; hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.63-0.86, P = 0.0001]. Clinical PFS at 8 years also favoured enzalutamide (43% versus 20%; HR 0.49, 95% CI 0.42-0.57, P < 0.0001). Of the 622 deaths, 468 were attributed to prostate cancer, of which fewer were associated with enzalutamide than with NSAA (207 versus 261), whereas deaths attributed to other causes occurred with similar frequency in the two groups (78 versus 76). Median treatment duration was 4.8 years with enzalutamide and 1.9 years with NSAA. Of 185 of 563 (33%) participants still receiving enzalutamide at data cut-off, most (163 of 185, 88%) remain on the full 160-mg dose. Rates of grade 3-5 AEs per 100 person-years were similar between groups for cardiac (2.2 versus 2.2) and nervous system disorders (2.3 versus 2.0), with more falls observed with enzalutamide (0.70 versus 0.24).</p><p><strong>Conclusion: </strong>Enzalutamide continues to provide substantial long-term OS benefit at 8 years, with sustained efficacy, maintenance of full dose in most participants, and no increase in non-prostate cancer mortality.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":80.4,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787444","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}

{"title":"Nivolumab plus chemotherapy or ipilimumab versus chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma: 5-year follow-up results from CheckMate 648.","authors":"K Kato, J Ajani, Y Doki, J Xu, L Wyrwicz, S Motoyama, T Ogata, H Kawakami, C-H Hsu, A Adenis, F El Hajbi, M Di Bartolomeo, M Ignez Braghiroli, E Holtved, T Makino, M Blum Murphy, J Zhang, P Sharma, B He, M Lei, Y Matsumura, Y Kitagawa, I Chau","doi":"10.1016/j.annonc.2026.08.001","DOIUrl":"10.1016/j.annonc.2026.08.001","url":null,"abstract":"<p><strong>Background: </strong>Both nivolumab plus chemotherapy (P < 0.001) and nivolumab plus ipilimumab (P = 0.001) demonstrated significant overall survival (OS) benefit compared with chemotherapy for patients with previously untreated advanced esophageal squamous-cell carcinoma (ESCC) and programmed death-ligand 1 (PD-L1) ≥1%. We report OS and additional analyses at a minimum follow-up of 5 years.</p><p><strong>Patients and methods: </strong>The open-label, phase III CheckMate 648 trial (NCT03143153) enrolled patients with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomly assigned 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. The primary endpoints were OS and progression-free survival (PFS) by blinded independent central review (BICR) in patients with tumor cell PD-L1 expression ≥1%. Key secondary endpoints included OS and PFS by BICR in all randomly assigned patients.</p><p><strong>Results: </strong>In total, 970 patients were randomly assigned. At the 5-year minimum follow-up, OS improvement continued to be observed with nivolumab plus chemotherapy versus chemotherapy [hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.48-0.79] and nivolumab plus ipilimumab versus chemotherapy (HR 0.62, 95% CI 0.48-0.80) in patients with tumor cell PD-L1 ≥1%. OS benefit was also observed in all randomly assigned patients (HR 0.77, 95% CI 0.65-0.92 for both nivolumab plus chemotherapy and nivolumab plus ipilimumab versus chemotherapy). PFS benefit was observed with nivolumab plus chemotherapy versus chemotherapy in the tumor cell PD-L1 ≥1% (HR 0.67, 95% CI 0.51-0.88) population but not with nivolumab plus ipilimumab versus chemotherapy (HR 1.03, 95% CI 0.78-1.35). Among all treated patients, grade 3-4 treatment-related adverse events were observed in 49% of patients in the nivolumab plus chemotherapy group, 33% in the nivolumab plus ipilimumab group, and 37% in the chemotherapy group.</p><p><strong>Conclusions: </strong>Nivolumab-containing treatment regimens continued to demonstrate clinically meaningful OS benefit versus chemotherapy at the 5-year follow-up, with no new safety signals. These data further support nivolumab in combination with chemotherapy or ipilimumab as first-line treatment for patients with advanced ESCC.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":80.4,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705089","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}

{"title":"SKYSCRAPER-03: a phase III study of tiragolumab plus atezolizumab versus durvalumab in locally advanced, unresectable, stage III NSCLC after platinum-based concurrent chemoradiation.","authors":"H A Wakelee, M-J Ahn, J Bradley, S Popat, K Kelly, A-M Baird, O Ozyilkan, J Yu, S Y Lee, N Yanagitani, M Johnson, A Sánchez-Hernández, A Szczesna, K Cuppens, E Yao, C Parsons, C Matheny, Z Zhang, M N White, J J Hsu, N S Patil, R Dziadziuszko","doi":"10.1016/j.annonc.2026.07.414","DOIUrl":"10.1016/j.annonc.2026.07.414","url":null,"abstract":"<p><strong>Background: </strong>SKYSCRAPER-03 (NCT04513925) was a phase III, open-label, randomized study that evaluated consolidation therapy with tiragolumab plus atezolizumab versus durvalumab in patients with locally advanced, unresectable, stage III, non-small-cell lung cancer (NSCLC) after platinum-based concurrent chemoradiation.</p><p><strong>Patients and methods: </strong>Eligible patients were randomly assigned (1 : 1) to receive either atezolizumab [1680 mg every 4 weeks (Q4W)] plus tiragolumab (840 mg Q4W) on day 1 of each cycle or durvalumab (10 mg/kg every 2 weeks or 1500 mg Q4W for those ≥30 kg body weight) on days 1 and 15 of each cycle for 13 × 28-day cycles. The primary endpoint was Independent Review Facility (IRF)-assessed progression-free survival (PFS) in patients with programmed death-ligand 1 (PD-L1)-positive (tumor cells ≥1%) NSCLC. Key secondary endpoints were overall survival (OS) and safety.</p><p><strong>Results: </strong>The PD-L1 all-comers population included 413 patients randomly assigned to tiragolumab plus atezolizumab and 416 to durvalumab; the PD-L1-positive population included 209 and 210 patients in each arm, respectively. After a median follow-up of 33.0 months, median IRF-assessed PFS in PD-L1-positive patients was 19.4 months with tiragolumab plus atezolizumab compared with 16.6 months with durvalumab [stratified hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.75-1.23, P = 0.76]; median PFS in PD-L1 all-comers was 14.2 compared with 13.8 months, respectively (stratified HR 1.00, 95% CI 0.84-1.19). The median OS in PD-L1-positive patients was not estimable with tiragolumab plus atezolizumab compared with 54.8 months with durvalumab (stratified HR 0.99, 95% CI 0.73-1.34); in PD-L1 all-comers, the median OS was 45.6 compared with 45.8 months, respectively (stratified HR 0.98, 95% CI 0.80-1.20). The safety profile of the combination was consistent with prior observations and there were no new or unexpected findings.</p><p><strong>Conclusions: </strong>The primary endpoint of the SKYSCRAPER-03 study was not met. Tiragolumab plus atezolizumab was tolerated but did not offer additional benefit over durvalumab.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":80.4,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682743","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}

{"title":"Genomic determinants of response to alpelisib plus fulvestrant in the SOLAR-1 trial☆","authors":"D. Juric,&nbsp;H.S. Rugo,&nbsp;A. Reising,&nbsp;K. Vervier,&nbsp;C. Ma,&nbsp;E.M. Ciruelos,&nbsp;S. Loibl,&nbsp;C.F. Singer,&nbsp;J. Sohn,&nbsp;M. Campone,&nbsp;P. Conte,&nbsp;H. Iwata,&nbsp;F. Ghaznawi,&nbsp;M. Miller,&nbsp;T. Taran,&nbsp;F. Su,&nbsp;F. André","doi":"10.1016/j.annonc.2026.04.003","DOIUrl":"10.1016/j.annonc.2026.04.003","url":null,"abstract":"<div><h3>Background</h3><div>Approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) have <em>PIK3CA</em> alterations, which contributes to endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol 3-kinase inhibitor and degrader, given in combination with fulvestrant, is approved for the treatment of <em>PIK3CA</em>-mutated, HR-positive, HER2-negative ABC, based on the results of the SOLAR-1 trial (NCT02437318). Aside from <em>PIK3CA</em>, other gene alterations are associated with poor prognosis and limited response to treatment in this patient population.</div></div><div><h3>Patients and methods</h3><div>In this retrospective analysis, we carried out tissue-based next-generation sequencing of 398 patients (237 <em>PIK3CA</em>-altered, 161 <em>PIK3CA</em>-wild type) from SOLAR-1. Progression-free survival (PFS) correlative analysis was carried out in the <em>PIK3CA</em>-altered cohort.</div></div><div><h3>Results</h3><div><em>PIK3CA</em>-altered and <em>PIK3CA</em>-wild type tumors had distinct genomic profiles. In the <em>PIK3CA</em>-altered cohort, patients who received alpelisib plus fulvestrant had a median PFS of 11.01 months versus 5.55 months for those receiving placebo plus fulvestrant (<em>P</em> = 0.0004). Patients in the lowest tumor mutational burden quartile as well as those with <em>FGFR1</em> or <em>FGFR2</em> alterations derived greater PFS benefit from alpelisib plus fulvestrant versus placebo plus fulvestrant [18.5 versus 3.22 months: hazard ratio (HR) 0.38, 95% confidence interval (CI) 0.21-0.68; <em>FGFR1</em> 12.71 versus 3.75 months: HR 0.38, 95% CI 0.17-0.81, <em>P</em> = 0.32; <em>FGFR2</em> 9.63 versus 2.78 months: HR 0.31, 95% CI 0.1-0.94, <em>P</em> = 0.29]; patients with <em>MYC</em> or <em>RAD21</em> alterations derived limited PFS benefit. Cox and multitask machine learning models identified lower Eastern Cooperative Oncology Group performance status, prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and <em>PTEN</em> or <em>TP53</em> alterations among the most deleterious factors for PFS in the <em>PIK3CA</em>-altered cohort.</div></div><div><h3>Conclusions</h3><div>Alpelisib plus fulvestrant provides clinical benefit for patients with <em>PIK3CA</em>-altered, HR-positive, HER2-negative ABC across a range of concomitant alterations, including those previously implicated in endocrine therapy or CDK4/6i resistance. Machine learning models can identify factors including gene mutations that influenced PFS.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 8","pages":"Pages 1106-1119"},"PeriodicalIF":80.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DART (NCI/SWOG S1609): comprehensive final results from dual checkpoint inhibition with CTLA-4 and PD-1 blockade in rare cancers","authors":"S.P. Patel,&nbsp;M. Othus,&nbsp;Y.K. Chae,&nbsp;T. Azenkot,&nbsp;C. Alviz,&nbsp;S. Threlkel,&nbsp;C. Haymaker,&nbsp;H.Z. Streicher,&nbsp;C.M. Magner,&nbsp;H.X. Chen,&nbsp;E. Sharon,&nbsp;C.W. Ryan,&nbsp;C.D. Blanke,&nbsp;R. Kurzrock","doi":"10.1016/j.annonc.2026.04.004","DOIUrl":"10.1016/j.annonc.2026.04.004","url":null,"abstract":"<div><h3>Background</h3><div>We summarize final results of the NCI/SWOG S1609 trial, the objective of which was to evaluate efficacy signals across 53 refractory rare cancer cohorts treated with dual cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1 inhibition.</div></div><div><h3>Patients and methods</h3><div>A prospective, open-label, multicenter phase II trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) was conducted (<em>N</em> = 53 cohorts). A statistical framework was established to evaluate each cohort in a two-stage design. The primary endpoint was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR, ORR plus stable disease &gt;6 months), immune-related (i)-outcomes, and toxicity as secondary and exploratory endpoints.</div></div><div><h3>Results</h3><div>Overall, 798 previously treated patients were enrolled onto S1609/Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART); 727 eligible patients received treatment; 1083 national (United States) sites opened the trial. Twenty-four of 53 cohorts (45%) demonstrated clinical activity, defined as ≥2 patients with confirmed response. Median (range) ORR was 12% (0%-75%); CBR was 27% (0%-75%). Median (range) 2-year PFS was 10% (0%-75%); 3-year OS was 23% (0%-100%). PFS at 6 months was moderately correlated with 1- and 3-year OS. Patients who attained an iOR versus OR had similar OS. Altogether, 82 patients (11% of the 727 enrolled patients) had an iPFS of ≥2 years. i-toxicity rates were comparable with those reported in prior studies. Adverse events led to treatment discontinuation in 102 patients (14%). The most common adverse events were fever, diarrhea, and rash/pruritus. Patients alive at 6 months who discontinued treatment due to i-toxicity had longer OS than those who discontinued treatment for other reasons.</div></div><div><h3>Conclusion</h3><div>Patients with multiple refractory rare cancer types derived meaningful response to ipilimumab plus nivolumab treatment. More robust characterization of biologically defined subsets is underway to optimize therapeutic selection.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 8","pages":"Pages 1167-1177"},"PeriodicalIF":80.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715643","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}

{"title":"GLP-1 receptor agonist use and cancer risk in obese nondiabetic adults","authors":"A.H.-C. Hsu,&nbsp;P.T. Ramirez,&nbsp;Y.-H. Chang,&nbsp;Y.-C. Chiang,&nbsp;M.C. Santía,&nbsp;T. Meschini,&nbsp;P. Mateo-Kubach,&nbsp;A. Suri,&nbsp;A.A. Kamat","doi":"10.1016/j.annonc.2026.04.013","DOIUrl":"10.1016/j.annonc.2026.04.013","url":null,"abstract":"<div><h3>Background</h3><div>Recent data show that glucagon-like peptide-1 receptor agonist (GLP-1RA) use is associated with decreased cancer incidence in diabetic and obese patients. However, there have been no studies exclusively investigating the association of obesity-associated cancer (OAC) risks and GLP-1RAs in obese, nondiabetic patients.</div></div><div><h3>Patients and methods</h3><div>We conducted a target trial emulation to evaluate the association between GLP-1RA use and risk of 13 OACs. Using TriNetX, a nationwide database of 113 million US patients, we identified obese, nondiabetic adults without prior OAC diagnosis from December 2014 to June 2025. Patients prescribed GLP-1RAs were 1:1 propensity score matched to those receiving diet or exercise counseling and validated using inverse probability of treatment weighting. The primary outcome compared the cumulative incidence of OACs among treatment groups. The secondary outcome analyzed cancer incidence across sex (female, male), body mass index (&lt;40, ≥40 kg/m²), race (white, black), and drug (semaglutide, tirzepatide).</div></div><div><h3>Results</h3><div>The cohort included 229 467 patients; 86 422 (37.7%) received GLP-1RAs, while 143 045 (62.3%) received diet or exercise consultation. After 1:1 propensity score matching, the study cohort included 161 798 patients: 80 899 GLP-1RA users versus 80 899 patients on diet or exercise consultation. Mean age of patients was 47.2 years (standard deviation 14.8). With a median follow-up of 2 years (interquartile range 1-2 years), the propensity score matching analysis showed a significantly lower incidence of any OACs among GLP-1RA users (hazard ratio 0.59, 95% confidence interval 0.53-0.67). Secondary analyses showed that in all subgroups, except for black race, GLP-1RA use was associated with a lower cumulative incidence of OACs. The inverse probability of treatment weighting analysis confirmed the findings.</div></div><div><h3>Conclusions</h3><div>GLP-1RA use was associated with a significantly lower short-term incidence of OACs among obese, nondiabetic patients, with consistent results observed in subgroups, except for race. Prospective trials are needed to confirm causality.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 8","pages":"Pages 1178-1185"},"PeriodicalIF":80.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting regulatory T cells for cancer immunotherapy: promises and pitfalls","authors":"O. Mirallas,&nbsp;G. Pretelli,&nbsp;M. Balsa,&nbsp;P. Jiménez-Labaig,&nbsp;A. Hernando-Calvo,&nbsp;H. Nathan Tan,&nbsp;P.N. Selvadurai,&nbsp;P. Tallón de Lara,&nbsp;M. Vieito,&nbsp;J. Martin-Liberal,&nbsp;K.J. Harrington,&nbsp;S. Champiat,&nbsp;E. Garralda","doi":"10.1016/j.annonc.2026.04.015","DOIUrl":"10.1016/j.annonc.2026.04.015","url":null,"abstract":"<div><h3>Background</h3><div>Regulatory T cells (Tregs) form a distinct subset of CD4⁺ T cells essential for maintaining immune balance and preventing autoimmunity by expressing CD25 and CTLA-4. Tregs, which are defined by the expression of the transcription factor FOXP3 in mice, restrain excessive immune activation through mechanisms such as interleukin 10 (IL-10) expression, transforming growth factor-β expression, metabolic regulation, acting as an IL-2 cytokine sink, and cell-to-cell interaction through co-inhibitory receptors. Although they are indispensable for immune tolerance, Tregs can be co-opted by tumors, where their suppressive activity promotes immune escape. High Treg infiltration within the tumor microenvironment has been linked to variable prognosis depending on the tumor type, highlighting Tregs’ contradictory roles as both guardians of tolerance and enablers of tumor progression.</div></div><div><h3>Design</h3><div>In this review, we summarized Treg biology, Tregs’ contribution to cancer immunity, and emerging therapeutic strategies designed to modulate or deplete Tregs. We conducted a targeted literature review using PubMed/MEDLINE, Web of Science, <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span>, and American Society of Clinical Oncology/European Society of Medical Oncology meeting libraries, complemented by manual reference screening. We also discussed the limitations of existing therapeutic approaches and outlined future directions.</div></div><div><h3>Results</h3><div>Efforts to therapeutically modulate Tregs have focused on three main strategies: depletion (e.g. anti-CD25, anti-CCR4, or anti-CCR8 antibodies), functional blockade (e.g. targeting CTLA-4 or TIGIT), and disruption of metabolic pathways (e.g. adenosine or PI3K signaling) that support Tregs’ biological functions. Although preclinical studies have shown that targeting Tregs has antitumor effects, clinical trials have demonstrated variable efficacy and toxicity , reflecting the fine balance between immune activation and tolerance. Newer approaches aim to selectively impair intratumoral Tregs while preserving peripheral immune control, guided by T-cell subsets such as FOXP3⁺Helios⁺CCR8⁺ cells, which may help predict therapeutic response.</div></div><div><h3>Conclusion</h3><div>A deeper understanding of Treg regulation is needed to unlock their therapeutic potential without compromising immune equilibrium.</div></div>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":"37 8","pages":"Pages 1049-1065"},"PeriodicalIF":80.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}