INTRODUCTIONRecurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is a heterogenous clinical entity with poor prognosis. The molecular and immune landscape of R/M SCCHN is underexplored. To offer a comprehensive view of the tumor microenvironment and molecular profile of R/M SCCHN, we performed an in-depth molecular and immune characterization, evaluating the impact of HPV status, tobacco and alcohol history, primary tumor site, relapse pattern, and treatment history, at the genomic, transcriptomic and immune levels.MATERIAL AND METHODSWe analyzed 253 R/M SCCHN fresh tumor biopsies from the IMMUcan project using RNAseq, whole-exome sequencing, and multiplex immunofluorescence (mIF).RESULTSThe primary clinical factor impacting the immune microenvironment was the number of treatment lines, with significant declines in T cells and B cells observed via mIF and RNAseq as the number of R/M treatment lines progressed. IL-6, IL-13, IL-15, and NRF2 pathways were enriched in HPV-negative R/M SCCHN compared to HPV-positive tumors, while no immune differences were detected between these two clinical groups. Specific genomic alterations were observed in laryngeal cancer (DDR2, FOXP1, KLF5, ROBO2), while non-smokers/non-drinkers exhibited alterations in SPEN, PBRM1, and CYLD. 11q13.3 amplification was linked to HPV-negative metastatic tumors and hypopharyngeal cancer. HPV-negative SCCHN with locoregional recurrence showed elevated EGFR and CXCL12 pathway activity. p-EMT transcriptomic signatures correlated with poor survival, while lymphocyte infiltration, especially in the context of TLS, was associated with improved survival.CONCLUSIONSOur study highlights key molecular and immune differences across R/M SCCHN subgroups, identifies potential biomarkers, and suggests biological rationales for tailored therapeutic strategies.
{"title":"Molecular and immune landscape of recurrent and/or distant metastatic squamous cell carcinoma of the head and neck: an EORTC/IMMUCAN project.","authors":"Athénaïs van der Elst,Daniel Herrero-Saboya,Lucas Michon,Marie Morfouace,Robin Liechti,Preethi Devanand,Daniel Schulz,Maya Persoons,Sylvie Rusakiewicz,Nils Eling,Paul-Antoine Nicolas,Marie-Sophie Robert,Stephanie Tissot,Sophie Déglise,Bruno Palau Fernandez,Bernd Bodenmiller,Henoch S Hong,Rachel Galot,Paolo Bossi,Julio Oliveira,Marc Pracht,Caroline Even,Pierre Saintigny,Céline Lefebvre,Loredana Martignetti,Jean-Pascal Machiels","doi":"10.1158/1078-0432.ccr-25-3377","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3377","url":null,"abstract":"INTRODUCTIONRecurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is a heterogenous clinical entity with poor prognosis. The molecular and immune landscape of R/M SCCHN is underexplored. To offer a comprehensive view of the tumor microenvironment and molecular profile of R/M SCCHN, we performed an in-depth molecular and immune characterization, evaluating the impact of HPV status, tobacco and alcohol history, primary tumor site, relapse pattern, and treatment history, at the genomic, transcriptomic and immune levels.MATERIAL AND METHODSWe analyzed 253 R/M SCCHN fresh tumor biopsies from the IMMUcan project using RNAseq, whole-exome sequencing, and multiplex immunofluorescence (mIF).RESULTSThe primary clinical factor impacting the immune microenvironment was the number of treatment lines, with significant declines in T cells and B cells observed via mIF and RNAseq as the number of R/M treatment lines progressed. IL-6, IL-13, IL-15, and NRF2 pathways were enriched in HPV-negative R/M SCCHN compared to HPV-positive tumors, while no immune differences were detected between these two clinical groups. Specific genomic alterations were observed in laryngeal cancer (DDR2, FOXP1, KLF5, ROBO2), while non-smokers/non-drinkers exhibited alterations in SPEN, PBRM1, and CYLD. 11q13.3 amplification was linked to HPV-negative metastatic tumors and hypopharyngeal cancer. HPV-negative SCCHN with locoregional recurrence showed elevated EGFR and CXCL12 pathway activity. p-EMT transcriptomic signatures correlated with poor survival, while lymphocyte infiltration, especially in the context of TLS, was associated with improved survival.CONCLUSIONSOur study highlights key molecular and immune differences across R/M SCCHN subgroups, identifies potential biomarkers, and suggests biological rationales for tailored therapeutic strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"60 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147495025","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 : 2026-03-23DOI: 10.1158/1078-0432.ccr-25-4158
Keun-Wook Lee,Elena Elimova,Do-Youn Oh,Muralidhar Beeram,Toshihiko Doi,Kay T Yeung,Theresa Samuel Nached,Kavita V Shah,Douglas S Fuller,Diana Shpektor,Emanuele Loro,Funda Meric-Bernstam
PURPOSEHER2 overexpression occurs in various subtypes of salivary gland cancers (SGCs) and can be associated with treatment challenges and poor clinical outcomes. Zanidatamab is a dual HER2-targeted, bispecific antibody that has demonstrated antitumor activity across multiple HER2-positive tumor types. This combined analysis aimed to assess the efficacy and safety of zanidatamab in HER2-positive SGC.PATIENTS AND METHODSAdult patients with previously treated, unresectable locally advanced or metastatic HER2-positive SGC were enrolled in 3 early-phase trials of zanidatamab: a first-in-human phase I study (NCT02892123), a phase I study of patients in Japan (JRCT2031210161), and a phase Ib/II study evaluating zanidatamab plus evorpacept, a high-affinity CD47 inhibitor (NCT05027139). Confirmed objective response rate (cORR) and progression-free survival (PFS) were measured in each study. Outcomes with zanidatamab monotherapy were pooled for summary analysis.RESULTSTen patients with HER2-positive SGC were enrolled across trials; 6 patients were previously treated with HER2-targeted therapy. Among patients who received zanidatamab monotherapy (n = 9), 7 experienced zanidatamab-related adverse events (all grade 1/2), the most common being diarrhea and infusion-related reactions. The cORR (95% CI) was 44% (14%-79%), the median (95% CI) PFS was 10.1 (3.8-not estimable) months, and the median (range) duration of response was not reached (9.4-42.3+) months. All patients experienced a reduction in tumor size. One patient who received zanidatamab plus evorpacept experienced a confirmed partial response and 18.4 months of PFS.CONCLUSIONSAlthough the sample size is small, these findings support the clinical benefit of zanidatamab treatment for HER2-positive SGC.
{"title":"Zanidatamab, a Dual HER2-Targeted Bispecific Antibody, in Patients With Unresectable Locally Advanced or Metastatic HER2-Positive Salivary Gland Cancer: A Combined Analysis of Early-Phase Studies.","authors":"Keun-Wook Lee,Elena Elimova,Do-Youn Oh,Muralidhar Beeram,Toshihiko Doi,Kay T Yeung,Theresa Samuel Nached,Kavita V Shah,Douglas S Fuller,Diana Shpektor,Emanuele Loro,Funda Meric-Bernstam","doi":"10.1158/1078-0432.ccr-25-4158","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4158","url":null,"abstract":"PURPOSEHER2 overexpression occurs in various subtypes of salivary gland cancers (SGCs) and can be associated with treatment challenges and poor clinical outcomes. Zanidatamab is a dual HER2-targeted, bispecific antibody that has demonstrated antitumor activity across multiple HER2-positive tumor types. This combined analysis aimed to assess the efficacy and safety of zanidatamab in HER2-positive SGC.PATIENTS AND METHODSAdult patients with previously treated, unresectable locally advanced or metastatic HER2-positive SGC were enrolled in 3 early-phase trials of zanidatamab: a first-in-human phase I study (NCT02892123), a phase I study of patients in Japan (JRCT2031210161), and a phase Ib/II study evaluating zanidatamab plus evorpacept, a high-affinity CD47 inhibitor (NCT05027139). Confirmed objective response rate (cORR) and progression-free survival (PFS) were measured in each study. Outcomes with zanidatamab monotherapy were pooled for summary analysis.RESULTSTen patients with HER2-positive SGC were enrolled across trials; 6 patients were previously treated with HER2-targeted therapy. Among patients who received zanidatamab monotherapy (n = 9), 7 experienced zanidatamab-related adverse events (all grade 1/2), the most common being diarrhea and infusion-related reactions. The cORR (95% CI) was 44% (14%-79%), the median (95% CI) PFS was 10.1 (3.8-not estimable) months, and the median (range) duration of response was not reached (9.4-42.3+) months. All patients experienced a reduction in tumor size. One patient who received zanidatamab plus evorpacept experienced a confirmed partial response and 18.4 months of PFS.CONCLUSIONSAlthough the sample size is small, these findings support the clinical benefit of zanidatamab treatment for HER2-positive SGC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"15 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147495023","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 : 2026-03-23DOI: 10.1158/1078-0432.ccr-25-4018
Jessica K Lee,Julia C F Quintanilha,Kuei-Ting Chen,Bernard Fendler,Candice Francheska B Tambaoan,Ryon Graf,Nicole Odzer,Lajos Pusztai,Maryam Lustberg,Harshabad Singh,Matthew Strickland,Tess A O'Meara,Sara M Tolaney,Timothy A Yap,Jeffrey Ross,Amaya Gasco Hernandez,Brennan Decker,Richard S P Huang,Samuel J Klempner,Ethan S Sokol,Alexa B Schrock
INTRODUCTIONGene copy number (CN) amplifications and protein overexpression are common drug targets and detection relies on various methodologies, including NGS-based CN, IHC, and ISH. We investigated the pan-tumor landscape of amplifications and developed AmpRatio, a novel method of CN quantitation.METHODSPan-tumor tissue (N=486,340) and liquid (N=85,635) samples underwent hybrid capture-based comprehensive genomic profiling. A genome-wide CN model for each sample was generated to estimate the purity, ploidy, and segment-level CN. AmpRatio was calculated by dividing gene CN/sample ploidy. A US-based de-identified clinico-genomic database was utilized to assess the relationship between ERBB2 AmpRatio and HER2 IHC/FISH and outcomes on anti-HER2 therapies.RESULTSAmplifications with varying degrees of gain were reported in 38.6% of pan-tumor tissue samples, most frequently MYC (5.6%), 11q13 (5.2%), ERBB2 (5.2%), and CCNE1 (3.2%). ERBB2 AmpRatio was associated with HER2 positivity by IHC/FISH in gastroesophageal (overall percent agreement [OPA] 90%) and breast (OPA 95%) cancers. Among patients treated with anti-HER2 therapies, ERBB2 AmpRatio significantly stratified outcomes within the ERBB2-amplified and IHC-defined HER2+ and HER2-low/ultralow populations. High concordance (sensitivity 88%) of amplification detection in liquid biopsy vs tissue was associated with higher AmpRatio and ctDNA tumor fraction ≥20%.CONCLUSIONSCN amplifications are prevalent and diverse biomarkers and AmpRatio is variable across genes and tumor types. ERBB2 AmpRatio is associated with outcomes to HER2-directed therapies and may have utility alongside IHC for clinical decision making. With the increasing number of therapies targeting amplifications/overexpression, it will be important to define harmonized methods for CN quantification for optimal patient selection.
{"title":"The pan-tumor landscape of gene amplifications and copy number amplification ratio for established and emerging clinical targets.","authors":"Jessica K Lee,Julia C F Quintanilha,Kuei-Ting Chen,Bernard Fendler,Candice Francheska B Tambaoan,Ryon Graf,Nicole Odzer,Lajos Pusztai,Maryam Lustberg,Harshabad Singh,Matthew Strickland,Tess A O'Meara,Sara M Tolaney,Timothy A Yap,Jeffrey Ross,Amaya Gasco Hernandez,Brennan Decker,Richard S P Huang,Samuel J Klempner,Ethan S Sokol,Alexa B Schrock","doi":"10.1158/1078-0432.ccr-25-4018","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4018","url":null,"abstract":"INTRODUCTIONGene copy number (CN) amplifications and protein overexpression are common drug targets and detection relies on various methodologies, including NGS-based CN, IHC, and ISH. We investigated the pan-tumor landscape of amplifications and developed AmpRatio, a novel method of CN quantitation.METHODSPan-tumor tissue (N=486,340) and liquid (N=85,635) samples underwent hybrid capture-based comprehensive genomic profiling. A genome-wide CN model for each sample was generated to estimate the purity, ploidy, and segment-level CN. AmpRatio was calculated by dividing gene CN/sample ploidy. A US-based de-identified clinico-genomic database was utilized to assess the relationship between ERBB2 AmpRatio and HER2 IHC/FISH and outcomes on anti-HER2 therapies.RESULTSAmplifications with varying degrees of gain were reported in 38.6% of pan-tumor tissue samples, most frequently MYC (5.6%), 11q13 (5.2%), ERBB2 (5.2%), and CCNE1 (3.2%). ERBB2 AmpRatio was associated with HER2 positivity by IHC/FISH in gastroesophageal (overall percent agreement [OPA] 90%) and breast (OPA 95%) cancers. Among patients treated with anti-HER2 therapies, ERBB2 AmpRatio significantly stratified outcomes within the ERBB2-amplified and IHC-defined HER2+ and HER2-low/ultralow populations. High concordance (sensitivity 88%) of amplification detection in liquid biopsy vs tissue was associated with higher AmpRatio and ctDNA tumor fraction ≥20%.CONCLUSIONSCN amplifications are prevalent and diverse biomarkers and AmpRatio is variable across genes and tumor types. ERBB2 AmpRatio is associated with outcomes to HER2-directed therapies and may have utility alongside IHC for clinical decision making. With the increasing number of therapies targeting amplifications/overexpression, it will be important to define harmonized methods for CN quantification for optimal patient selection.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147495026","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 : 2026-03-23DOI: 10.1158/1078-0432.ccr-25-4061
Ann L. Oberg, William R. Bamlet, Grant Izmirlian, Seetharaman Balasenthil, Surinder K. Batra, Masataka Hayashi, Daniel S. Herman, Michael A. Hollingsworth, Maneesh Jain, Ann M. Killary, Brianna M. Krusen, Suyu Liu, Shounak Majumder, Gopalakrishnan Natarajan, Subrata Sen, Lynette M. Smith, Sudhir Srivastava, Brian M. Wolpin, Kenneth S. Zaret, Michael G. Goggins
Purpose. The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network-defined phase 2 biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel performance, compare the panels’ performance with that of cancer antigen 19-9 (CA19-9) alone, and to evaluate the performance of new combinations of the individual biomarkers. Experimental Design: Ten biomarkers representing eight biomarker panels and CA19-9 were evaluated using plasma, serum and germline DNA from 140 stage I-IV PDAC cases and 140 controls from three tertiary care institutions, with controls frequency-matched to cases on age and sex. LASSO regression was employed to explore new biomarker combinations. The primary metric was area under the receiver operating characteristic curve (AUC). Results: The study population was 51% female, median age 67.3 (minimum: 45.0, maximum: 90.0) years. Biomarker panel AUCs ranged from 89.9 to 96.3; the AUC for serum CA19-9 alone was 91.7 (95% confidence interval: 87.8, 95.6). Two panels had significantly higher AUCs than serum CA19-9 alone, the CA19-9/FUT2/3 panel (AUC=96.3, p=0.002), and the tissue factor pathway inhibitor/tenascin C (TFPI/TNC-FNIII-C) panel (AUC=95, p=0.01). Exploratory models to recombine biomarkers retained all but two biomarkers [optimism-corrected AUC=96.4 (94.0, 98.9)]. Conclusions: The CA19-9/FUT2/3 panel was the best performing panel in this biomarker bakeoff. Its evaluation in larger studies is warranted. Biomarker bakeoffs are an effective strategy for comparing the performance of promising biomarkers for pancreatic cancer early detection, and the PCDC is well poised to conduct such studies. Recommendations for performing such studies are provided.
目的。胰腺癌检测联盟（PCDC）对基于血液的生物标志物面板进行了一项盲法早期检测研究网络定义的2期生物标志物烘烤研究。目的是评估面板的性能，将面板的性能与单独的癌症抗原19-9 （CA19-9）进行比较，并评估单个生物标志物的新组合的性能。实验设计：使用来自三家三级医疗机构的140例I-IV期PDAC病例和140例对照的血浆、血清和种系DNA，对代表8个生物标志物组和CA19-9的10个生物标志物进行了评估，对照的频率与年龄和性别相匹配。LASSO回归用于探索新的生物标志物组合。主要指标为受试者工作特征曲线下面积（AUC）。结果：研究人群51%为女性，中位年龄67.3岁（最小45.0岁，最大90.0岁）。生物标志物面板auc范围为89.9 ~ 96.3；单独检测血清CA19-9的AUC为91.7（95%可信区间：87.8,95.6）。CA19-9/FUT2/3组（AUC=96.3, p=0.002）和组织因子途径抑制剂/tenascin C （TFPI/TNC-FNIII-C）组（AUC=95, p=0.01）的AUC均显著高于单独血清CA19-9。重组生物标志物的探索性模型保留了除两种生物标志物外的所有生物标志物[乐观校正的AUC=96.4(94.0, 98.9)]。结论：CA19-9/FUT2/3组是本次生物标志物检测中表现最好的组。在更大规模的研究中进行评估是有必要的。生物标志物提取是比较胰腺癌早期检测中有前途的生物标志物性能的有效策略，PCDC已经做好了开展此类研究的准备。提出了进行这类研究的建议。
{"title":"Pancreatic Cancer Detection Consortium Biomarker Bakeoff: A Phase 2 blinded biomarker validation and panel discovery study","authors":"Ann L. Oberg, William R. Bamlet, Grant Izmirlian, Seetharaman Balasenthil, Surinder K. Batra, Masataka Hayashi, Daniel S. Herman, Michael A. Hollingsworth, Maneesh Jain, Ann M. Killary, Brianna M. Krusen, Suyu Liu, Shounak Majumder, Gopalakrishnan Natarajan, Subrata Sen, Lynette M. Smith, Sudhir Srivastava, Brian M. Wolpin, Kenneth S. Zaret, Michael G. Goggins","doi":"10.1158/1078-0432.ccr-25-4061","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4061","url":null,"abstract":"Purpose. The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network-defined phase 2 biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel performance, compare the panels’ performance with that of cancer antigen 19-9 (CA19-9) alone, and to evaluate the performance of new combinations of the individual biomarkers. Experimental Design: Ten biomarkers representing eight biomarker panels and CA19-9 were evaluated using plasma, serum and germline DNA from 140 stage I-IV PDAC cases and 140 controls from three tertiary care institutions, with controls frequency-matched to cases on age and sex. LASSO regression was employed to explore new biomarker combinations. The primary metric was area under the receiver operating characteristic curve (AUC). Results: The study population was 51% female, median age 67.3 (minimum: 45.0, maximum: 90.0) years. Biomarker panel AUCs ranged from 89.9 to 96.3; the AUC for serum CA19-9 alone was 91.7 (95% confidence interval: 87.8, 95.6). Two panels had significantly higher AUCs than serum CA19-9 alone, the CA19-9/FUT2/3 panel (AUC=96.3, p=0.002), and the tissue factor pathway inhibitor/tenascin C (TFPI/TNC-FNIII-C) panel (AUC=95, p=0.01). Exploratory models to recombine biomarkers retained all but two biomarkers [optimism-corrected AUC=96.4 (94.0, 98.9)]. Conclusions: The CA19-9/FUT2/3 panel was the best performing panel in this biomarker bakeoff. Its evaluation in larger studies is warranted. Biomarker bakeoffs are an effective strategy for comparing the performance of promising biomarkers for pancreatic cancer early detection, and the PCDC is well poised to conduct such studies. Recommendations for performing such studies are provided.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"15 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147495301","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 : 2026-03-23DOI: 10.1158/1078-0432.ccr-25-3727
Michael Cecchini,Sae-Won Han,Soohyeon Lee,Keun-Wook Lee,Scott Kopetz,Jonathan Mizrahi,Yong Sang Hong,Francois Ghiringhelli,Antoine Italiano,David Tougeron,Brandon Beagle,Mathew Boakye,Tingting Zhao,Vivek Khemka,Zev A Wainberg
PURPOSETargeting the adenosine pathway may enhance the efficacy of chemo/immunotherapy regimens in patients with heavily pretreated advanced metastatic colorectal cancer (mCRC), for whom treatment options are limited.PATIENTS AND METHODSThe phase 2 ARC-9 study, Cohort B (NCT04660812), evaluated the efficacy and safety of etrumadenant (A2a and A2b receptor antagonist), zimberelimab (anti-PD-1 monoclonal antibody), FOLFOX, and bevacizumab (EZFB) vs regorafenib in patients with third-line mCRC who previously progressed on oxaliplatin- and irinotecan-containing regimens.RESULTSFrom September 21, 2021, to September 12, 2022, 112 patients were randomized 2:1 to EZFB (n=75) or regorafenib (n=37). As of November 13, 2023, median survival follow-up was 20.4 months. The primary endpoint of progression-free survival was improved with EZFB (6.2 months) vs regorafenib (2.1 months; HR, 0.27 [95%CI: 0.17, 0.43]; nominal P<.0001), as was the secondary endpoint of overall survival (EZFB, 19.7 months; regorafenib, 9.5 months; HR, 0.37 [95% CI: 0.22, 0.63]; nominal P = .0003). Confirmed overall response rate was 17% (90% CI: 10.6%, 26.1%) with EZFB and 3% (90% CI: 0.1%, 12.2%) with regorafenib. Treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, and TEAEs leading to discontinuation of all study treatments were reported in 99%, 82%, and 5% of the EZFB arm, and in 87%, 49%, and 17% of the regorafenib arm, respectively.CONCLUSIONEZFB significantly improved survival outcomes compared with regorafenib in patients with mCRC as a third-line treatment, with a manageable safety profile. Further investigation is warranted, given the clinically meaningful improvements in progression-free survival and overall survival.
{"title":"The Randomized Phase 2 ARC-9 Study of Etrumadenant-Based Therapy vs Regorafenib in Patients with Previously Treated Metastatic Colorectal Cancer.","authors":"Michael Cecchini,Sae-Won Han,Soohyeon Lee,Keun-Wook Lee,Scott Kopetz,Jonathan Mizrahi,Yong Sang Hong,Francois Ghiringhelli,Antoine Italiano,David Tougeron,Brandon Beagle,Mathew Boakye,Tingting Zhao,Vivek Khemka,Zev A Wainberg","doi":"10.1158/1078-0432.ccr-25-3727","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3727","url":null,"abstract":"PURPOSETargeting the adenosine pathway may enhance the efficacy of chemo/immunotherapy regimens in patients with heavily pretreated advanced metastatic colorectal cancer (mCRC), for whom treatment options are limited.PATIENTS AND METHODSThe phase 2 ARC-9 study, Cohort B (NCT04660812), evaluated the efficacy and safety of etrumadenant (A2a and A2b receptor antagonist), zimberelimab (anti-PD-1 monoclonal antibody), FOLFOX, and bevacizumab (EZFB) vs regorafenib in patients with third-line mCRC who previously progressed on oxaliplatin- and irinotecan-containing regimens.RESULTSFrom September 21, 2021, to September 12, 2022, 112 patients were randomized 2:1 to EZFB (n=75) or regorafenib (n=37). As of November 13, 2023, median survival follow-up was 20.4 months. The primary endpoint of progression-free survival was improved with EZFB (6.2 months) vs regorafenib (2.1 months; HR, 0.27 [95%CI: 0.17, 0.43]; nominal P<.0001), as was the secondary endpoint of overall survival (EZFB, 19.7 months; regorafenib, 9.5 months; HR, 0.37 [95% CI: 0.22, 0.63]; nominal P = .0003). Confirmed overall response rate was 17% (90% CI: 10.6%, 26.1%) with EZFB and 3% (90% CI: 0.1%, 12.2%) with regorafenib. Treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, and TEAEs leading to discontinuation of all study treatments were reported in 99%, 82%, and 5% of the EZFB arm, and in 87%, 49%, and 17% of the regorafenib arm, respectively.CONCLUSIONEZFB significantly improved survival outcomes compared with regorafenib in patients with mCRC as a third-line treatment, with a manageable safety profile. Further investigation is warranted, given the clinically meaningful improvements in progression-free survival and overall survival.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"15 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147495024","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 : 2026-03-19DOI: 10.1158/1078-0432.ccr-26-0064
Tom Wei-Wu Chen
Eribulin was evaluated in angiosarcoma and epithelioid hemangioendothelioma through two prospective international trials. While encouraging activity was observed in EHE, its role in angiosarcoma may depend on further refinement through subgroup selection. These findings underscore the importance of histology-specific interpretation, innovative endpoints, and coordinated strategies for ultra-rare sarcoma drug development.
{"title":"Across borders and histologies: Rethinking endpoints for vascular sarcoma trials.","authors":"Tom Wei-Wu Chen","doi":"10.1158/1078-0432.ccr-26-0064","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-26-0064","url":null,"abstract":"Eribulin was evaluated in angiosarcoma and epithelioid hemangioendothelioma through two prospective international trials. While encouraging activity was observed in EHE, its role in angiosarcoma may depend on further refinement through subgroup selection. These findings underscore the importance of histology-specific interpretation, innovative endpoints, and coordinated strategies for ultra-rare sarcoma drug development.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"95 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483449","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 : 2026-03-19DOI: 10.1158/1078-0432.ccr-25-4035
Roberto Salgado,Marleen Kok
In 390 patients with stage I-III hormone-receptor positive/HER2-negative breast tumors higher number of Tumor Infiltrating Lymphocytes (TILs)-subtypes, regardless of whether they were immunostimulatory or immunosuppressive, including T-regulatory cells and CD8- and non-CD8 T-cells, are associated with improved distant disease free survival and overall survival at 8 years follow-up.
{"title":"Immunity, age, and luminal breast cancer: understanding the Holy Trinity.","authors":"Roberto Salgado,Marleen Kok","doi":"10.1158/1078-0432.ccr-25-4035","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4035","url":null,"abstract":"In 390 patients with stage I-III hormone-receptor positive/HER2-negative breast tumors higher number of Tumor Infiltrating Lymphocytes (TILs)-subtypes, regardless of whether they were immunostimulatory or immunosuppressive, including T-regulatory cells and CD8- and non-CD8 T-cells, are associated with improved distant disease free survival and overall survival at 8 years follow-up.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483448","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 : 2026-03-19DOI: 10.1158/1078-0432.CCR-25-4079
Neil Carleton, Alexander C Chang, Fangyuan Chen, Shannon L Puhalla, Julia Foldi, Hunter Waltermire, Antony Tin, Michael S Cowher, Kristin Lupinacci, Emilia J Diego, Quratulain Sabih, Ronald R Johnson, Monica Malhotra, Amanda Laubenthal, Vikram Gorantla, Marija Balic, Rohit Bhargava, Marion Joy, Tanner Freeman, Catherine Bridges, Ekaterina Kalashnikova, Angel Rodriguez, Minetta C Liu, Steffi Oesterreich, Adrian V Lee, Priscilla F McAuliffe
Purpose: For older patients with competing comorbidities, optimizing oncologic therapies is of paramount importance. Circulating tumor DNA (ctDNA) is a validated prognostic factor across solid tumors and may provide a strategy to identify patients for whom safe de-escalation of certain therapies is possible.
Experimental design: In this prospective, hybrid-decentralized trial (n = 43 patients; NCT05914792) that integrated clinical outcomes, patient- and caregiver-reported outcomes, and correlative tissue analysis, the primary objective was to determine if ctDNA levels were associated with tumor progression in older patients who opted to forgo breast cancer surgery in favor of primary endocrine therapy (pET).
Results: ctDNA levels were highly concordant with imaging findings, and a lack of ctDNA clearance at 6 months was associated with tumor progression. In a competing risk regression adjusted for patient age, tumor stage, tumor grade, and tumor Ki-67, pretreatment ctDNA positivity was associated with a significant risk of tumor progression (HR, 30; 95% confidence interval, 4.4-209; P = 0.0011). No patients with pretreatment ctDNA negativity experienced tumor progression. In correlative analyses examining ctDNA-positive tumors progressing on pET, we identified populations of CD11+ T cell-interacting macrophages that upregulate CD109 and CD89 and secrete immunosuppressive chemokines to create a favorable environment for cancer epithelial cell proliferation.
Conclusions: These findings suggest that ctDNA may be a modality to identify older patients who can safely receive long-term pET, warranting future evaluation in a randomized setting.
{"title":"Use of ctDNA in Older Women with ER+ Breast Cancer to Facilitate Surgical De-escalation: A Prospective, Hybrid-Decentralized Trial with Correlative Studies.","authors":"Neil Carleton, Alexander C Chang, Fangyuan Chen, Shannon L Puhalla, Julia Foldi, Hunter Waltermire, Antony Tin, Michael S Cowher, Kristin Lupinacci, Emilia J Diego, Quratulain Sabih, Ronald R Johnson, Monica Malhotra, Amanda Laubenthal, Vikram Gorantla, Marija Balic, Rohit Bhargava, Marion Joy, Tanner Freeman, Catherine Bridges, Ekaterina Kalashnikova, Angel Rodriguez, Minetta C Liu, Steffi Oesterreich, Adrian V Lee, Priscilla F McAuliffe","doi":"10.1158/1078-0432.CCR-25-4079","DOIUrl":"10.1158/1078-0432.CCR-25-4079","url":null,"abstract":"<p><strong>Purpose: </strong>For older patients with competing comorbidities, optimizing oncologic therapies is of paramount importance. Circulating tumor DNA (ctDNA) is a validated prognostic factor across solid tumors and may provide a strategy to identify patients for whom safe de-escalation of certain therapies is possible.</p><p><strong>Experimental design: </strong>In this prospective, hybrid-decentralized trial (n = 43 patients; NCT05914792) that integrated clinical outcomes, patient- and caregiver-reported outcomes, and correlative tissue analysis, the primary objective was to determine if ctDNA levels were associated with tumor progression in older patients who opted to forgo breast cancer surgery in favor of primary endocrine therapy (pET).</p><p><strong>Results: </strong>ctDNA levels were highly concordant with imaging findings, and a lack of ctDNA clearance at 6 months was associated with tumor progression. In a competing risk regression adjusted for patient age, tumor stage, tumor grade, and tumor Ki-67, pretreatment ctDNA positivity was associated with a significant risk of tumor progression (HR, 30; 95% confidence interval, 4.4-209; P = 0.0011). No patients with pretreatment ctDNA negativity experienced tumor progression. In correlative analyses examining ctDNA-positive tumors progressing on pET, we identified populations of CD11+ T cell-interacting macrophages that upregulate CD109 and CD89 and secrete immunosuppressive chemokines to create a favorable environment for cancer epithelial cell proliferation.</p><p><strong>Conclusions: </strong>These findings suggest that ctDNA may be a modality to identify older patients who can safely receive long-term pET, warranting future evaluation in a randomized setting.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"OF1-OF11"},"PeriodicalIF":10.2,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13004172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484909","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}
Purpose: Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line setting, remains unclear. Experimental Design: This multicenter retrospective and prospective study included mNSCLC patients receiving first- and second-line programmed cell death protein 1 (PD-1) inhibitors along with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified by the mean intestinal radiation dose into <1 Gy, 1-3 Gy, and >3 Gy groups and treatment outcomes were compared. The blood and fecal samples were subjected to multi-omics profiling. Results: g>309 patients were included in the retrospective analysis. Optimal efficacy was observed with a small intestinal mean radiation dose (SIMRD) of 1-3 Gy, showing longer progression-free survival (PFS, 10.2 months) and overall survival (OS, 22.8 months) (P < 0.01), which was consistent across subgroups. Compared with 1-3 Gy, SIMRD >3 Gy (Hazard ratio [HR] = 4.87, P < 0.001) and <1 Gy (HR = 1.85, P < 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (P = 0.041) and PFS (P = 0.046) with SIMRD of 1-3 Gy. Responders were enriched in Bacillota, Clostridia, and indole derivatives, particularly indole-3-carboxylic acid. Moreover, the 1-3 Gy group exhibited increased circulating macrophage inflammatory protein-3α and reduced circulating α4β7+ regulatory T cells. Conclusions: ILDR influences the efficacy of PD-1 blockade in patients with mNSCLC, particularly when SIMRD is maintained within the 1-3 Gy range, likely through modulation of the gut microbiota–metabolite–immune axis.
{"title":"Low-dose intestinal irradiation enhances the efficacy and prognosis of PD-1 blockade in metastatic non-small cell lung cancer","authors":"Baiyang Huang, Jiarui Zhao, Jingyu Zhu, Xingpeng Wang, Min Li, Jing Xu, Kaiyue Wang, Xiaohan Wang, Weiqing Wang, Cong Bo, Jinquan Yao, Menglin Bai, Bo Cheng, Jinming Yu, Guoxin Cai, Xue Meng","doi":"10.1158/1078-0432.ccr-25-4153","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4153","url":null,"abstract":"Purpose: Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line setting, remains unclear. Experimental Design: This multicenter retrospective and prospective study included mNSCLC patients receiving first- and second-line programmed cell death protein 1 (PD-1) inhibitors along with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified by the mean intestinal radiation dose into &lt;1 Gy, 1-3 Gy, and &gt;3 Gy groups and treatment outcomes were compared. The blood and fecal samples were subjected to multi-omics profiling. Results: g&gt;309 patients were included in the retrospective analysis. Optimal efficacy was observed with a small intestinal mean radiation dose (SIMRD) of 1-3 Gy, showing longer progression-free survival (PFS, 10.2 months) and overall survival (OS, 22.8 months) (P &lt; 0.01), which was consistent across subgroups. Compared with 1-3 Gy, SIMRD &gt;3 Gy (Hazard ratio [HR] = 4.87, P &lt; 0.001) and &lt;1 Gy (HR = 1.85, P &lt; 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (P = 0.041) and PFS (P = 0.046) with SIMRD of 1-3 Gy. Responders were enriched in Bacillota, Clostridia, and indole derivatives, particularly indole-3-carboxylic acid. Moreover, the 1-3 Gy group exhibited increased circulating macrophage inflammatory protein-3α and reduced circulating α4β7+ regulatory T cells. Conclusions: ILDR influences the efficacy of PD-1 blockade in patients with mNSCLC, particularly when SIMRD is maintained within the 1-3 Gy range, likely through modulation of the gut microbiota–metabolite–immune axis.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"197 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478068","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 : 2026-03-18DOI: 10.1158/1078-0432.ccr-25-2565
Jeanna M. Arbesfeld-Qiu, Jae-Won Cho, Phuong T.T. Nguyen, Nicole A. Lester, Jennifer Su, Carina Shiau, Jimmy A. Guo, Hannah Hoffman, Nicholas Caldwell, Shugo Muratani, Miranda Galvan, Jessica E. Proctor, Zackery Ely, Steven Wang, Maria Ganci, Ruben Dries, Theodore Hong, Jennifer Wo, Genevieve Boland, Carlos Fernandez-del Castillo, Cristina R. Ferrone, Christopher M. Heaphy, M. Lisa Zhang, Mari Mino-Kenudson, Martin Hemberg, William L. Hwang
Purpose: Pancreatic neuroendocrine tumors (PNET) are rare malignancies of the endocrine pancreas with diverse clinical outcomes. While some PNETs are indolent, others are aggressive and metastasize quickly. However, clinically-relevant molecular stratification for PNET to predict outcomes and guide therapeutic decision-making is limited. Thus, there is an urgent need to understand the molecular heterogeneity of PNETs to refine prognostication and discover novel therapeutic vulnerabilities. Experimental Design: We performed single-nucleus RNA sequencing on untreated, resected primary and metastatic PNETs (n = 18). We inferred gene expression programs (GEPs) of malignant and non-malignant cells and investigated associations with clinical outcomes. Next, we inferred interactions in the tumor microenvironment (TME) and performed transwell migration assays for functional validation. Finally, we explored genomic and transcriptomic evolution in a unique case study of an untreated primary PNET with two asynchronous hepatic metastases. Results: A malignant GEP enriched for neural/synaptic signaling genes was associated with worse overall survival, broad chromosomal loss of heterozygosity, and alternative lengthening of telomeres. Another malignant GEP enriched for VEGF signaling increased throughout metastatic progression in our case study. We found that macrophage-derived glutamate drives polarization towards an immunosuppressive phenotype and activates the MAPK/ERK pathway in malignant cells to increase migratory capacity. Conclusions: This study provides a detailed single-nucleus transcriptomic classification of malignant, stromal, and immune cell types and states in PNETs, their interactions in the TME, and associations with clinical outcomes. The refined molecular taxonomy of PNET may guide the development of more efficacious biomarkers and therapeutic strategies.
{"title":"Distinct malignant cell states and myeloid glutamate signaling associated with aggressive pancreatic neuroendocrine tumors","authors":"Jeanna M. Arbesfeld-Qiu, Jae-Won Cho, Phuong T.T. Nguyen, Nicole A. Lester, Jennifer Su, Carina Shiau, Jimmy A. Guo, Hannah Hoffman, Nicholas Caldwell, Shugo Muratani, Miranda Galvan, Jessica E. Proctor, Zackery Ely, Steven Wang, Maria Ganci, Ruben Dries, Theodore Hong, Jennifer Wo, Genevieve Boland, Carlos Fernandez-del Castillo, Cristina R. Ferrone, Christopher M. Heaphy, M. Lisa Zhang, Mari Mino-Kenudson, Martin Hemberg, William L. Hwang","doi":"10.1158/1078-0432.ccr-25-2565","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2565","url":null,"abstract":"Purpose: Pancreatic neuroendocrine tumors (PNET) are rare malignancies of the endocrine pancreas with diverse clinical outcomes. While some PNETs are indolent, others are aggressive and metastasize quickly. However, clinically-relevant molecular stratification for PNET to predict outcomes and guide therapeutic decision-making is limited. Thus, there is an urgent need to understand the molecular heterogeneity of PNETs to refine prognostication and discover novel therapeutic vulnerabilities. Experimental Design: We performed single-nucleus RNA sequencing on untreated, resected primary and metastatic PNETs (n = 18). We inferred gene expression programs (GEPs) of malignant and non-malignant cells and investigated associations with clinical outcomes. Next, we inferred interactions in the tumor microenvironment (TME) and performed transwell migration assays for functional validation. Finally, we explored genomic and transcriptomic evolution in a unique case study of an untreated primary PNET with two asynchronous hepatic metastases. Results: A malignant GEP enriched for neural/synaptic signaling genes was associated with worse overall survival, broad chromosomal loss of heterozygosity, and alternative lengthening of telomeres. Another malignant GEP enriched for VEGF signaling increased throughout metastatic progression in our case study. We found that macrophage-derived glutamate drives polarization towards an immunosuppressive phenotype and activates the MAPK/ERK pathway in malignant cells to increase migratory capacity. Conclusions: This study provides a detailed single-nucleus transcriptomic classification of malignant, stromal, and immune cell types and states in PNETs, their interactions in the TME, and associations with clinical outcomes. The refined molecular taxonomy of PNET may guide the development of more efficacious biomarkers and therapeutic strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"58 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478067","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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