Clinical Cancer Research最新文献

{"title":"Editor's Note: Antitumor Activity of Suberoylanilide Hydroxamic Acid against Thyroid Cancer Cell Lines In vitro and In vivo.","authors":"Quang T Luong, James O'Kelly, Glenn D Braunstein, Jerome M Hershman, H Phillip Koeffler","doi":"10.1158/1078-0432.CCR-26-1171","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-26-1171","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 9","pages":"1912"},"PeriodicalIF":10.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811923","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":"Urinary Biomarkers Objectively Measure Minimal Residual Disease in Non-Muscle-Invasive Bladder Cancer.","authors":"Andrew B Katims, Charlie White, Syed Muneeb Alam, Mark Farha, Sadra Sepehri, Manuel De Jesus Escano, Neeta D'Souza, Gamze Gokturk Ozcan, Merve Basar, Anthony Martinez Benitez, Melissa McCarter, Morgan Tomberlin, David B Solit, Gopa Iyer, Pan Du, Shidong Jia, Alvin C Goh, Timothy F Donahue, Judy Sarungbam, Bernard H Bochner, Max Kates, Irina Ostrovnaya, Hikmat Al-Ahmadie, Oscar Lin, Eugene J Pietzak","doi":"10.1158/1078-0432.CCR-25-3395","DOIUrl":"10.1158/1078-0432.CCR-25-3395","url":null,"abstract":"<p><strong>Purpose: </strong>To determine whether carcinoma in situ (CIS) is a sufficient measure of minimal residual disease (MRD) in non-muscle-invasive bladder cancer (NMIBC) and evaluate alternative measures of MRD.</p><p><strong>Experimental design: </strong>We evaluated the concordance of CIS on transurethral resection of bladder tumor (TURBT) and radical cystectomy (RC) to determine eradication rates of clinical CIS (cCIS) by TURBT alone and rates of occult pathologic CIS (pCIS) seen only in RC specimens. We studied a prospective cohort of patients with BCG-naïve high-grade NMIBC to evaluate pretreatment urinary cytology and urinary tumor (ut)DNA as alternative biomarkers.</p><p><strong>Results: </strong>Eradication of CIS was seen in 20% of patients (78/383). Positive urinary cytology, but not cCIS, was associated with pCIS. In our prospective cohort (n = 173), abnormal pre-BCG urine cytology, but not pre-BCG cCIS, had worse high-grade recurrence-free survival [HG-RFS; hazard ratio, 3.56; 95% confidence interval (CI), 1.74-7.31, P < 0.001]. The median follow-up was 1.8 years (95% CI, 1.3-2.2). Among those with utDNA available, 84% (56/67) had sufficient DNA for genomic profiling. The 2-year HG-RFS rate in patients without an oncogenic alteration (n = 17) in their pre-BCG urine was 100% versus 60% (95% CI, 46%-78%) in patients with detectable oncogenic alterations (n = 38; P = 0.004). Area under the curve values for predicting 2-year HG-RFS were 0.52 for cCIS, 0.68 for cytology, and 0.74 for utDNA.</p><p><strong>Conclusions: </strong>We found ∼20% eradication of cCIS from TURBT alone. cCIS was a poor metric of MRD, performing worse than abnormal pretreatment urinary cytology and utDNA. These urine biomarkers are more objective MRD measures than cCIS for NMIBC risk stratification and treatment assessment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1755-1765"},"PeriodicalIF":10.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141192","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":"Retraction: Safety and Efficacy of Anlotinib Hydrochloride Plus Temozolomide in Patients with Recurrent Glioblastoma.","authors":"Qingsheng Xu, Kaiyuan Huang, Xiangqi Meng, Yuxiang Weng, Luyuan Zhang, Linghao Bu, Xiujue Zheng, Jinquan Cai, Renya Zhan, Qun Chen","doi":"10.1158/1078-0432.CCR-26-1042","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-26-1042","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 9","pages":"1913"},"PeriodicalIF":10.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811961","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":"Multi-Omic Landscape of Gastrointestinal Stromal Tumors in a Real-World Patient Cohort of 1,427 Cases.","authors":"César Serrano, Andrew Elliott, David Gómez-Peregrina, Mark G Evans, Suzanne George, Margaret von Mehren, Robert G Maki, Sosipatros A Boikos, John A Charlson, Aditi Dhir, Vaia Florou, Daruka Mahadevan, Matthew J Oberley, George W Sledge, Gabriel Tinoco, Richard F Riedel, Jonathan C Trent","doi":"10.1158/1078-0432.CCR-25-4596","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-4596","url":null,"abstract":"<p><strong>Purpose: </strong>Gastrointestinal stromal tumor (GIST) is a genomically-driven neoplasm with a genetic profile that determines the clinical course of the disease. However, currently available molecular data is limited due to the rarity of the disease and does not fully capture GIST clinical and biological heterogeneity.</p><p><strong>Experimental design: </strong>To gain deeper insight into the molecular landscape of GIST, we performed a comprehensive multi-omic analysis (targeted panel, whole exome sequencing, whole transcriptomics) in a large real-world, multicenter cohort including 1,427 cases. Pathological review was undertaken in KIT/PDGFRA-wild type cases. Molecular findings were correlated with clinical data and insurance claims outcomes.</p><p><strong>Results: </strong>There is a complex spectrum of multi-layered genetic events that converge in three GIST molecular subgroups: KIT-mutant, PDGFRA-mutant, and KIT/PDGFRA-wild-type. These alterations can only be captured using next-generation sequencing technologies, and are associated with clinical features, biological aggressiveness, and patient outcomes. Mutations in alternative genes, whether actionable or not, are seldom present and unlikely to contribute to tumor progression. By contrast, the cooperative effect of novel somatic copy number alterations may be required for GIST evolution and progression, in addition to the core set of events involved in the current cytogenetic model of tumorigenesis.</p><p><strong>Conclusions: </strong>This molecular landscape provides a broader molecular understanding of GIST and supports a widespread use of genetic profiling for patients' clinical management.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764223","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":"Early ctDNA stratifies survival in locally advanced and oligometastatic lung cancer treated with radiotherapy.","authors":"Ayesha Hashmi, Jessica Linford, Pradeep S Chauhan, Kaushal Parikh, Malvika Pillai, John Guittar, Rotem Ben-Shachar, Jyoti Patel, Halla Nimeiri, Matteo Bergsagel, Nicholas P Semenkovich, Sean S Park, Kenneth R Olivier, Dawn Owen, David M Routman, Katie N Lee, Alexander D Sherry, Aaron S Mansfield, Daniel Morgensztern, Ramaswamy Govindan, Clifford G Robinson, Carmen Bergom, Saiama N Waqar, Pamela P Samson, Bruna Pellini, Gregory R Vlacich, Aadel A Chaudhuri","doi":"10.1158/1078-0432.CCR-25-4983","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-4983","url":null,"abstract":"<p><strong>Purpose: </strong>Circulating tumor fraction estimate (ctFE) is a machine learning-derived composite metric of circulating tumor DNA (ctDNA) burden. We hypothesized that pre- and early on-treatment ctFE could robustly risk-stratify patients with locally advanced and oligometastatic non-small cell lung cancer (NSCLC) treated with radiotherapy.</p><p><strong>Experimental design: </strong>In a prospective phase II clinical trial (NCT03916419), 26 patients with unresectable stage IIB-III NSCLC received MR-guided hypofractionated chemoradiation (chemoRT) followed by immunotherapy. Plasma ctDNA was profiled at baseline and mid-treatment (day 10-14) to derive ctFE and maximum variant allele frequency (Max VAF). A burden-based ctFE threshold derived from baseline samples was applied unchanged to mid-treatment samples and validated in two external cohorts: locally advanced NSCLC treated with chemoRT (LA-RW; n = 94) and oligometastatic NSCLC treated with radiotherapy (OM-RW; n = 309).</p><p><strong>Results: </strong>Pre- and mid-treatment ctFE burden strongly stratified overall survival (OS) and progression-free survival (PFS), markedly outperforming Max VAF and ctFE detectability. Baseline ctFE was prognostic for OS (HR 5.93, p = 0.005) and PFS (HR 11.08, p < 0.001) and remained significant at mid-treatment (OS: HR 7.08; PFS: HR 12.06; both p < 0.001). Early ctFE dynamics defined three molecular response groups with striking OS separation (median OS 60.8 vs. 13.0 vs. 2.9 months; p < 0.001). ctFE remained associated with survival in both validation cohorts.</p><p><strong>Conclusions: </strong>Early ctFE derived from a clinically available, tumor-naïve ctDNA assay enables noninvasive risk stratification in locally advanced and oligometastatic NSCLC treated with radiotherapy, supporting its use as a practical biomarker for precision treatment adaptation.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764174","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":"Tumor microenvironment gene engineering with LOAd703 in patients with solid malignancies: LOKON002 phase I/IIb clinical trial.","authors":"Amanda Hahn,Sandra Irenaeus,Linda C Sandin,Clara Nordström,Jessica Wenthe,Tanja Lövgren,Emma Eriksson,Salem Alsaqal,Simon Pahnke,Anders Sundin,Justyna Leja Jarblad,Maria Gustafsson Liljefors,Angelica Loskog,Gustav J Ullenhag","doi":"10.1158/1078-0432.ccr-25-4396","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4396","url":null,"abstract":"PURPOSEPatients with advanced cancer have a poor prognosis and need for novel treatments. LOAd703 is a tumor microenvironment (TME) gene engineering viral vector encoding genes targeting the CD40 and 4-1BB pathways. In this study, tolerability (primary endpoint), response activity, and the capacity to inflame the TME were evaluated.PATIENTS AND METHODSIn an open-label, single arm phase I/IIb clinical trial (NCT03225989), maximum eight intratumoral injections of LOAd703 were administered biweekly combined with a gemcitabine-based chemotherapy regimen, either standard-of-care treatment or conditioning gemcitabine if no standard options were available. Dose escalation followed a standard 3+3 design (phase I) and, to optimize dosage, the two highest dose levels were expanded in phase II.RESULTSForty-one patients were enrolled with pancreatic cancer (n=29), colorectal cancer (n=5), ovarian cancer (n=4) and biliary cancer (n=3). The treatment was overall well tolerated with the most common adverse events attributed to LOAd703 being pyrexia (76%), chills (39%) and fatigue (34%), mostly grade 1-2. The overall response rate (ORR) was 0 in the LOAd703 dose cohort 5x1010 viral particles (VP), 25% in 1x1011 VP, and 12% in 5x1011 VP. All patients with an objective response had pancreatic cancer and were treated in first line (ORR 35%). The TME showed a significant upregulation of Th1 immunity biomarkers at week 13 post treatment initiation.CONCLUSIONSTME gene engineering using LOAd703 inflamed immune cold tumors and was followed by long term stabilized disease in several patients. Further evaluation of LOAd703 together with chemotherapy and/or checkpoint inhibitors is warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"21 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754894","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":"Evaluation of Tissue from Patients with Prostate Cancer Identifies B7-H3 as an Androgen-Regulated, Broadly-Expressed, Combinatorial Therapeutic Target.","authors":"Shivang Sharma,Nikita Mundhara,Emirhan Tekoglu,Adrianna Amaral,Pan Gu,Jun Luo,Sean Xie,Morelle Meegane Konchou,Patience Pepra-Ameyaw,Angelo M De Marzo,W Nathaniel Brennen,Ezra G Baraban,Tamara L Lotan,Nathan A Lack,Eugene Shenderov","doi":"10.1158/1078-0432.ccr-26-0642","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-26-0642","url":null,"abstract":"PURPOSEAdvanced Prostate Cancer (PCa) management suffers from therapeutic resistance due to naturally transient or AR-dependent expression of clinically actionable surface targets. We aimed to identify the most promising clinically relevant PCa targets using RNA and protein expression levels across the PCa continuum-hormone-sensitive, castration-resistant, neuroendocrine, and \"double-negative\" prostate cancer (DNPC).EXPERIMENTAL DESIGNWe performed integration of a large single-cell transcriptomics atlas (JHU-PANORAMA, ~1 million cells and 213 patients) and PDX models for systematic investigation of clinically relevant surfaceome, followed by proteomic validation on patient samples and mechanistic investigations on PCa cell lines and patient samples.RESULTSB7-H3 was found to be the most uniformly expressed across the entire PCa continuum. JHU-PANORAMA is made available for interactive visualization as RShiny webapp. Further mitigation of therapeutic resistance is proposed through a systematic framework for bispecific antibody design, where B7-H3 demonstrated high combinatorial scores with TROP-2, NECTIN1, KLK2, and NECTIN4. B7-H3 was also shown to be negatively regulated by AR and synergistically inhibited tumor growth when combined with androgen inhibition.CONCLUSIONSB7-H3 demonstrates low inter-patient and intra-tumoral heterogeneity with significant synergistic effects in combination with AR inhibition. These properties could uniquely place B7-H3 as a broad-spectrum therapeutic target with the potential to combine B7-H3 based therapeutics with standard ADT for synergistic effects to overcome therapeutic resistance across the PCa disease continuum.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"150 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754893","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":"Phase II trial of encapsulated rapamycin to reduce polyp burden associated with familial adenomatous polyposis.","authors":"Joseph C Broderick,Niloy Jewel Samadder,Elena Stoffel,John C Fang,Peter P Stanich,Paul Wise,Randy Wright,Travis Clifton,George Peoples,Carol A Burke","doi":"10.1158/1078-0432.ccr-25-4126","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4126","url":null,"abstract":"PURPOSEFamilial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies.METHODS30 FAP patients enrolled to three dosing regimens of eRapa (0.5 mg): cohort 1 - every other day, cohort 2 - daily every other week, or cohort 3 - daily. The primary endpoints were safety/tolerability, pharmacokinetics, and percentage change from baseline (PCFB) in colorectal polyp burden (CPB) at 6 mos. Secondary endpoints included PCFB total (TPB) and duodenal (DPB) polyp burden, and change in InSiGHT stage and Spigelman score at 6 and 12 mos.RESULTS29/ 30 patients (97%) completed the 12-mos study with predictable bioavailability. Low grade adverse events were frequent, but most pronounced in daily dosing. Two patients discontinued treatment related to toxicity. Cohort 1 had the largest decrease median PCFB CPB, DPB, and TPB at 6 mos: -39.4 % (IQR, 108.9; p = 0.28), -33.33 % (IQR, 90.0; p = 0.04), and -38.6 % (IQR, 88.5; p = 0.26), respectively. At 12 mos, Cohort 2 had the largest decrease median PCFB CPB and TPB: -29.3 % (IQR, 67.6; p = 0.37) and -26.3 % (IQR, 49.5; p = 0.29), respectively. Intermittent dosing cohorts (1 & 2) reduced DPB at 6 mos (p = 0.04), and improved TPB at 12 mos (p = 0.05) compared to daily dosing.CONCLUSIONeRapa was safe, tolerable and showed preliminary efficacy for FAP chemoprevention. The 0.5 mg daily every-other-week schedule will be evaluated in an upcoming phase III trial.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"116 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754629","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":"A Randomized, Phase II Clinical Trial of FLT-PET and FDG-PET for Early Response Assessment of Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer.","authors":"Melek Akay,Jennifer Glendenning,Holly Tovey,Yi-Ting Tsai,Rosalind Graham,Esme Carpenter,Helen Kakkassery,Thanussuyah Alaguthurai,Laura Finneran,Ioannis Roxanis,Angela Swampillai,Mark Harries,Ines Sandri,Ravindran Karthigan,Sally Barrington,Patrycja Gazinska,Gary Cook,Sugama Chicklore,Judith Bliss,Syed Haider,Andrew Tutt,Sheeba Irshad","doi":"10.1158/1078-0432.ccr-26-0041","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-26-0041","url":null,"abstract":"PURPOSEEarly identification of response to neoadjuvant chemotherapy (NACT) in triple negative breast cancer (TNBC) can facilitate timely treatment adjustments. This phase II analytical and clinical validity study (TNPET01) evaluated whether [18F]-fluorodeoxyglucose (FDG) or [18F]-fluorothymidine (FLT) PET/CT can predict response after one NACT cycle Methods: In Part A (analytical validity phase), patients with stage II-III TNBC were randomised to FDG or FLT imaging. Baseline repeat scans assessed test-retest repeatability, followed by a post-cycle-1 scan in week 3. Dynamic imaging preceded static acquisitions at 90-, 120-, and 180-min (FDG) or 90-min (FLT), evaluating SUVmax, SUVmean, SUVpeak and SULpeak. Tracer selection for Part B was based on prespecified repeatability and response criteria. Part B (clinical validity phase) examined associations between changes in SUV (ΔSUV) after one cycle and post-cycle-3 MRI, end-of-treatment MRI, and residual cancer burden (RCB) at surgery. Exploratory analyses assessed relationships between PET response, Ki-67, and tumour-infiltrating lymphocytes (TILs).RESULTSTwenty-two patients enrolled. Both tracers met repeatability thresholds; FDG was selected for Part B owing to superior image quality and availability. Fourteen patients underwent FDG-PET across both parts. ΔSUVmax/mean after one cycle significantly correlated with mid-treatment MRI and final RCB score (p < 0.005). Early post-cycle-1 TIL increases correlated with greater metabolic reduction and lower RCB, while Ki-67 changes were not predictive.CONCLUSIONSFDG-PET after one NACT cycle was associated with histological response and stronger correlations with RCB than MRI. These findings support PET as an early biomarker for treatment response and warrant validation in larger, immunotherapy-era trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"144 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754601","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":"The SOS1 inhibitor BI 1701963 as monotherapy or in combination with trametinib in patients with KRAS mutation-positive solid tumors.","authors":"Pasi A Jänne,Melissa L Johnson,Jin Li,Shubham Pant,Ulrich Dünzinger,Luis Ilia,Kerstin Möldner,Jae Eui Soh,Noboru Yamamoto","doi":"10.1158/1078-0432.ccr-25-3725","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3725","url":null,"abstract":"BACKGROUNDBI 1701963 is a small molecule son of sevenless 1 (SOS1) inhibitor which selectively binds to SOS1, blocking the protein-protein interaction of SOS1 with guanosine diphosphate-bound RAS (rat sarcoma virus) proteins (KRAS, HRAS and NRAS), thus inhibiting the growth of RAS-dependent cancer cells.STUDY DESIGNThree Phase I dose-escalation studies evaluated BI 1701963 as monotherapy (starting dose: 50 mg) or in combination with trametinib (starting dose: 100 mg/1 mg), in patients with KRAS mutation-positive solid tumors (NCT04111458, USA and Europe; NCT04835714, Japan; NCT04627142, China). Primary endpoints were maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs; Part A NCT04111458), and number of patients with DLTs in the MTD evaluation period (Part A NCT04111458 and NCT04835714) or the on-treatment period (Part B NCT04835714).RESULTSNinety-four patients were treated; 75 with monotherapy (50-800 mg), 19 in combination (100 mg/1 mg; 100 mg/1.5 mg; 200 mg/1 mg). Six monotherapy patients (8.0%) and 6 combination patients (31.6%) experienced DLTs in the MTD evaluation period. All patients experienced adverse events; of note, three monotherapy patients had interstitial lung disease during the first treatment cycle leading to death, considered drug-related by the investigator. In the monotherapy group, one patient (1.8%) experienced partial response, and 12 patients (21.8%) had stable disease. In the combination group, four patients (33.3%) had stable disease, carrying different KRAS alleles.CONCLUSIONSBI 1701963 treatment demonstrated limited efficacy as monotherapy. MTD was determined as 800 mg monotherapy (NCT04111458) and 100 mg/1 mg in combination with trametinib (NCT04111458).","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"27 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754628","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}