Pub Date : 2025-12-22DOI: 10.1158/1078-0432.ccr-25-3103
Nicholas J. McNamee, Jia Liu, Rebecca C. Poulos, Adel T. Aref, Roger R. Reddel
Antibody-drug conjugate (ADC) development is progressing rapidly with significant impacts on the treatment landscape of clinical oncology. However, the development of predictive biomarkers to guide ADC selection has not kept pace, and to date has been mostly limited to immunohistochemistry, hampering patient selection and personalized treatment recommendations. Here, we review the current state of ADC target protein assessment, and the association between target expression levels and therapeutic efficacy. We discuss the limitations and challenges of existing protein assessment technology and highlight the potential clinical role of quantitative mass spectrometry-based proteomics for rapid, comprehensive and accurate protein quantification. We propose that integrating multiplexed proteomic assays early in ADC development and clinical trial design can improve therapeutic targeting, enhance clinical trial design and ultimately lead to more personalized ADC-based treatment strategies.
{"title":"Predictive Biomarkers of Antibody-Drug Conjugate Efficacy for Solid Tumors: Current Challenges and the Potential Role of Quantitative Proteomics","authors":"Nicholas J. McNamee, Jia Liu, Rebecca C. Poulos, Adel T. Aref, Roger R. Reddel","doi":"10.1158/1078-0432.ccr-25-3103","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3103","url":null,"abstract":"Antibody-drug conjugate (ADC) development is progressing rapidly with significant impacts on the treatment landscape of clinical oncology. However, the development of predictive biomarkers to guide ADC selection has not kept pace, and to date has been mostly limited to immunohistochemistry, hampering patient selection and personalized treatment recommendations. Here, we review the current state of ADC target protein assessment, and the association between target expression levels and therapeutic efficacy. We discuss the limitations and challenges of existing protein assessment technology and highlight the potential clinical role of quantitative mass spectrometry-based proteomics for rapid, comprehensive and accurate protein quantification. We propose that integrating multiplexed proteomic assays early in ADC development and clinical trial design can improve therapeutic targeting, enhance clinical trial design and ultimately lead to more personalized ADC-based treatment strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"46 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801083","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 : 2025-12-22DOI: 10.1158/1078-0432.ccr-25-2773
Paolo Manca, Marta Paoli, Francesca Galardi, Federica Morano, Samantha Di Donato, Laura Biganzoli, Luca Malorni, Agostina Nardone, Margherita Ambrosini, Carolina Sciortino, Simone Oldani, Filippo Ghelardi, Vincenzo Nasca, Camilla Damonte, Cecilia Villa, Roberta Fazio, Salsabil Mohamed, Francesca Demichelis, Isacco Montroni, Sara Pusceddu, Chiara Cremolini, Sara Lonardi, Matteo Benelli, Filippo Pietrantonio
Purpose: Longitudinal measuring of circulating tumor DNA (ctDNA) during systemic treatment of metastatic colorectal cancer (mCRC) is promising for disease monitoring, but it is hampered by high costs and lacks formal demonstration of clinical usefulness. Patients and Methods: We leveraged METER, a novel, highly reproducible, computational workflow that infers ctDNA presence and fraction from low-pass whole genome bisulfite sequencing to investigate baseline and 8-week ctDNA dynamics in patients with RAS wild-type mCRC undergoing first-line treatment with panitumumab/FOLFOX in the VALENTINO randomized phase 2 trial. IchorCNA was used to provide a benchmark for METER. Results: A total of 154 patients were evaluable. Baseline ctDNA was detected in 72.7% of patients and was associated with significantly higher risk of progression (1.65, 95%CI: 1.13-2.42; p=0.010) and death (HR: 2.24, 95%CI: 1.37-3.66; p<0.001). CtDNA clearance at 8 weeks was observed in 80.2% of patients with baseline detectable ctDNA; persistence of ctDNA was associated with significantly higher risk of progression (2.70, 95%CI: 1.63-4.49; p<0.001) and death (HR: 3.37, 95%CI: 2.00-5.69; p<0.001). CtDNA clearance was associated with a more profound depth of response (DoR) (median -48.4% vs -41.2%; p=0.023) but not with a higher frequency of early tumor shrinkage (72.0% vs 73.7%, p=1.00). METER expanded the number of ctDNA-positive patients relative to a copy number alteration– and a variant allele frequency–based methods. Conclusion: CtDNA detection and quantification with METER is a promising tool for cost-effective treatment monitoring in mCRC and can complement radiological assessment of response dynamics.
目的：在转移性结直肠癌（mCRC）全身治疗期间，循环肿瘤DNA （ctDNA）的纵向测量有望用于疾病监测，但由于成本高且缺乏正式的临床有效性证明。患者和方法：在VALENTINO随机2期试验中，我们利用METER（一种新颖的、高度可重复的计算工作流程，从低通全基因组亚硫酸氢盐测序中推断ctDNA的存在和比例）来研究接受帕尼单抗/FOLFOX一线治疗的RAS野生型mCRC患者的基线和8周ctDNA动态。IchorCNA为METER提供了一个基准。结果：154例患者可评估。基线ctDNA在72.7%的患者中被检测到，并且与更高的进展风险（1.65,95%CI: 1.13-2.42; p=0.010）和死亡风险（HR: 2.24, 95%CI: 1.37-3.66; p<0.001）相关。在基线CtDNA可检测的患者中，80.2%的患者在8周时观察到CtDNA清除；ctDNA的持续存在与更高的进展风险（2.70,95%CI: 1.63-4.49; p<0.001）和死亡风险（HR: 3.37, 95%CI: 2.00-5.69; p<0.001）相关。CtDNA清除率与更深刻的反应深度（DoR）相关（中位数为-48.4% vs -41.2%, p=0.023），但与更高的早期肿瘤缩小频率无关（72.0% vs 73.7%, p=1.00）。相对于基于拷贝数改变和基于变异等位基因频率的方法，METER扩大了ctdna阳性患者的数量。结论：利用METER进行CtDNA检测和定量是一种具有成本效益的mCRC治疗监测工具，可以补充放射学评估反应动力学。
{"title":"CtDNA detection with low-pass whole genome bisulfite sequencing in RAS wild-type metastatic colorectal cancer: an exploratory objective of the VALENTINO trial","authors":"Paolo Manca, Marta Paoli, Francesca Galardi, Federica Morano, Samantha Di Donato, Laura Biganzoli, Luca Malorni, Agostina Nardone, Margherita Ambrosini, Carolina Sciortino, Simone Oldani, Filippo Ghelardi, Vincenzo Nasca, Camilla Damonte, Cecilia Villa, Roberta Fazio, Salsabil Mohamed, Francesca Demichelis, Isacco Montroni, Sara Pusceddu, Chiara Cremolini, Sara Lonardi, Matteo Benelli, Filippo Pietrantonio","doi":"10.1158/1078-0432.ccr-25-2773","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2773","url":null,"abstract":"Purpose: Longitudinal measuring of circulating tumor DNA (ctDNA) during systemic treatment of metastatic colorectal cancer (mCRC) is promising for disease monitoring, but it is hampered by high costs and lacks formal demonstration of clinical usefulness. Patients and Methods: We leveraged METER, a novel, highly reproducible, computational workflow that infers ctDNA presence and fraction from low-pass whole genome bisulfite sequencing to investigate baseline and 8-week ctDNA dynamics in patients with RAS wild-type mCRC undergoing first-line treatment with panitumumab/FOLFOX in the VALENTINO randomized phase 2 trial. IchorCNA was used to provide a benchmark for METER. Results: A total of 154 patients were evaluable. Baseline ctDNA was detected in 72.7% of patients and was associated with significantly higher risk of progression (1.65, 95%CI: 1.13-2.42; p=0.010) and death (HR: 2.24, 95%CI: 1.37-3.66; p&lt;0.001). CtDNA clearance at 8 weeks was observed in 80.2% of patients with baseline detectable ctDNA; persistence of ctDNA was associated with significantly higher risk of progression (2.70, 95%CI: 1.63-4.49; p&lt;0.001) and death (HR: 3.37, 95%CI: 2.00-5.69; p&lt;0.001). CtDNA clearance was associated with a more profound depth of response (DoR) (median -48.4% vs -41.2%; p=0.023) but not with a higher frequency of early tumor shrinkage (72.0% vs 73.7%, p=1.00). METER expanded the number of ctDNA-positive patients relative to a copy number alteration– and a variant allele frequency–based methods. Conclusion: CtDNA detection and quantification with METER is a promising tool for cost-effective treatment monitoring in mCRC and can complement radiological assessment of response dynamics.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801121","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 : 2025-12-22DOI: 10.1158/1078-0432.ccr-25-2239
Daniel J. Hodson, Geoffrey Shouse, Ho-Jin Shin, Antonio Salar, Sabela Bobillo, Vincent Ribrag, Nicol A. Macpherson, Raul Cordoba, Jin Seok Kim, Stephanie Guidez, Alex F. Herrera, Franck Morschhauser, Dachelle Colton, Macarena Izuzquiza, Nisha Sambamurthy, Veerendra Munugalavadla, Sergio Vicente, Gullu Gorgun, Robert Chen, Anas Younes, Michael L. Wang
Purpose: An unmet treatment need remains for relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), including the follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) subtypes. The PI3K/AKT/mTOR pathway is dysregulated and associated with poor prognosis in NHL. The AKT inhibitor capivasertib has preclinical activity in hematologic malignancy models. Methods: NCT05008055 was a modular, open-label, multicenter phase II study that examined oral capivasertib monotherapy in patients with R/R B-cell NHL who had received ≥2 prior lines of therapy. Patients had R/R FL (Cohort 1A), MZL (Cohort 1B), or MCL (Cohort 1C). Capivasertib 480 mg twice daily was administered orally 4 days on/3 days off. The primary objective was to determine the objective response rate (ORR) by blinded independent central review. Results: 30 patients were enrolled (of 272 planned). The ORRs for patients with R/R FL, MZL, and MCL were 18.8% (3/16), 33.3% (1/3), and 30% (3/10), respectively; 62.5% (10/16) of patients with R/R FL had stable disease. Baseline tumor PTEN expression was deficient/undetectable in the two patients who had a complete response and three of five patients who had a partial response. The most common capivasertib-related adverse events (AEs) were diarrhea (63.3%), nausea (20%), vomiting (13.3%), and hyperglycemia (10%). Capivasertib-related grade ≥3 AEs or serious AEs were observed in 9 and 3 patients, respectively. Conclusion: The study was terminated early with a small sample size, limiting interpretation, although antitumor activity was limited. Future studies of capivasertib in hematologic malignancies would likely require biomarker-directed patient selection and/or combination therapy.
{"title":"Efficacy and Safety of Capivasertib (AZD5363), a Potent, Oral Pan-AKT Inhibitor, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma (CAPITAL)","authors":"Daniel J. Hodson, Geoffrey Shouse, Ho-Jin Shin, Antonio Salar, Sabela Bobillo, Vincent Ribrag, Nicol A. Macpherson, Raul Cordoba, Jin Seok Kim, Stephanie Guidez, Alex F. Herrera, Franck Morschhauser, Dachelle Colton, Macarena Izuzquiza, Nisha Sambamurthy, Veerendra Munugalavadla, Sergio Vicente, Gullu Gorgun, Robert Chen, Anas Younes, Michael L. Wang","doi":"10.1158/1078-0432.ccr-25-2239","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2239","url":null,"abstract":"Purpose: An unmet treatment need remains for relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), including the follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) subtypes. The PI3K/AKT/mTOR pathway is dysregulated and associated with poor prognosis in NHL. The AKT inhibitor capivasertib has preclinical activity in hematologic malignancy models. Methods: NCT05008055 was a modular, open-label, multicenter phase II study that examined oral capivasertib monotherapy in patients with R/R B-cell NHL who had received ≥2 prior lines of therapy. Patients had R/R FL (Cohort 1A), MZL (Cohort 1B), or MCL (Cohort 1C). Capivasertib 480 mg twice daily was administered orally 4 days on/3 days off. The primary objective was to determine the objective response rate (ORR) by blinded independent central review. Results: 30 patients were enrolled (of 272 planned). The ORRs for patients with R/R FL, MZL, and MCL were 18.8% (3/16), 33.3% (1/3), and 30% (3/10), respectively; 62.5% (10/16) of patients with R/R FL had stable disease. Baseline tumor PTEN expression was deficient/undetectable in the two patients who had a complete response and three of five patients who had a partial response. The most common capivasertib-related adverse events (AEs) were diarrhea (63.3%), nausea (20%), vomiting (13.3%), and hyperglycemia (10%). Capivasertib-related grade ≥3 AEs or serious AEs were observed in 9 and 3 patients, respectively. Conclusion: The study was terminated early with a small sample size, limiting interpretation, although antitumor activity was limited. Future studies of capivasertib in hematologic malignancies would likely require biomarker-directed patient selection and/or combination therapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"21 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801122","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 : 2025-12-19DOI: 10.1158/1078-0432.ccr-25-2581
Felix John, Lea Ruge, Malte Verheyen, Heather Scharpenseel, Sebastian Yves Friedrich. Michels, Richard Riedel, Rieke Fischer, Carolin Jakob, Janna Siemanowski-Hrach, Jana Fassunke, Carina Heydt, Michaela Angelika. Ihle, Su Ir. Lyu, Anna Rasokat, Wolfgang Schulte, Karl-Josef Franke, Ullrich Graeven, Jutta Kappes, Anna Kron, Udo Siebolts, Sabine Merkelbach-Bruse, Alexander Quaas, Reinhard Büttner, Jürgen Wolf, Matthias Scheffler
Purpose: KRAS G12V is among the most frequent KRAS mutations in non-small cell lung cancer (NSCLC), yet its clinical and molecular features remain poorly understood. Experimental Design: In this retrospective study, we analyzed 636 patients with KRAS G12V-mutated NSCLC diagnosed between 2018 and 2023. Clinical, pathological, and molecular characteristics, including co-mutations, smoking history, PD-L1 expression, CD8+ T-cell infiltration, and treatment outcomes, were assessed. Results: The majority of patients (94.2%) were current or former smokers, with a median tobacco exposure of 40 pack-years. Co-mutations were frequent, most commonly in TP53 (40.2%), STK11 (30.2%), and KEAP1 (29.3%). Heavy smokers exhibited significantly higher PD-L1 expression and more frequent TP53, KEAP1, and NTRK1–3mutations than light smokers. CD8+ T-cell infiltration showed a non-significant trend toward higher values in G12V compared to non-G12V KRAS subtypes. Among 151 patients with advanced disease, those treated with immune checkpoint blockade (ICB) alone or in combination with chemotherapy had significantly higher response rates and improved real-world progression-free (rwPFS) and overall survival (rwOS) compared to chemotherapy alone. In patients with PD-L1 TPS ≥50%, ICB-based treatment achieved a median rwOS of 30 months. Conclusions: KRAS G12V-mutated NSCLC is characterized by a strong association with tobacco use, high co-mutation rates in clinically relevant genes, and a favorable response to PD-L1-based immunotherapy. The observed mutation landscape supports the potential for dual checkpoint blockade in a significant subset.
{"title":"Molecular and clinical characteristics of patients with non-small cell lung cancer (NSCLC) harboring KRAS G12V mutations","authors":"Felix John, Lea Ruge, Malte Verheyen, Heather Scharpenseel, Sebastian Yves Friedrich. Michels, Richard Riedel, Rieke Fischer, Carolin Jakob, Janna Siemanowski-Hrach, Jana Fassunke, Carina Heydt, Michaela Angelika. Ihle, Su Ir. Lyu, Anna Rasokat, Wolfgang Schulte, Karl-Josef Franke, Ullrich Graeven, Jutta Kappes, Anna Kron, Udo Siebolts, Sabine Merkelbach-Bruse, Alexander Quaas, Reinhard Büttner, Jürgen Wolf, Matthias Scheffler","doi":"10.1158/1078-0432.ccr-25-2581","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2581","url":null,"abstract":"Purpose: KRAS G12V is among the most frequent KRAS mutations in non-small cell lung cancer (NSCLC), yet its clinical and molecular features remain poorly understood. Experimental Design: In this retrospective study, we analyzed 636 patients with KRAS G12V-mutated NSCLC diagnosed between 2018 and 2023. Clinical, pathological, and molecular characteristics, including co-mutations, smoking history, PD-L1 expression, CD8+ T-cell infiltration, and treatment outcomes, were assessed. Results: The majority of patients (94.2%) were current or former smokers, with a median tobacco exposure of 40 pack-years. Co-mutations were frequent, most commonly in TP53 (40.2%), STK11 (30.2%), and KEAP1 (29.3%). Heavy smokers exhibited significantly higher PD-L1 expression and more frequent TP53, KEAP1, and NTRK1–3mutations than light smokers. CD8+ T-cell infiltration showed a non-significant trend toward higher values in G12V compared to non-G12V KRAS subtypes. Among 151 patients with advanced disease, those treated with immune checkpoint blockade (ICB) alone or in combination with chemotherapy had significantly higher response rates and improved real-world progression-free (rwPFS) and overall survival (rwOS) compared to chemotherapy alone. In patients with PD-L1 TPS ≥50%, ICB-based treatment achieved a median rwOS of 30 months. Conclusions: KRAS G12V-mutated NSCLC is characterized by a strong association with tobacco use, high co-mutation rates in clinically relevant genes, and a favorable response to PD-L1-based immunotherapy. The observed mutation landscape supports the potential for dual checkpoint blockade in a significant subset.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785833","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 : 2025-12-19DOI: 10.1158/1078-0432.ccr-25-3541
Enrique Sanz-Garcia, Shirin Soleimani, Jeff P. Bruce, Stephanie Pedersen, Marian Tang, Lisa Avery, Jenna Eagles, Anna Spreafico, Aaron R. Hansen, Lawson Eng, George Laliotis, Michael Krainock, Minetta Liu, Prabhjit Basra, Celeste Yu, Sam Felicen, Pamela S. Ohashi, Scott V. Bratman, Trevor J. Pugh, Lillian L. Siu
Purpose: Immune checkpoint blockade (ICB) therapies targeting the PD-1 axis have significantly improved survival in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Circulating tumor DNA (ctDNA) and peripheral T cell receptor (TCR) repertoires are emerging as promising biomarkers for predicting ICB response. Early characterization of ctDNA and TCR dynamics may enable timely treatment adjustments before clinical or radiological progression. Patients and Methods: The IO-KIN study (NCT04606940) is a single-center, prospective trial involving 15 patients with R/M HNSCC treated with nivolumab or pembrolizumab. Blood samples (n=104) were collected across seven timepoints from baseline to day 29. ctDNA was analyzed using a personalized assay (Signatera), and peripheral TCR repertoires were profiled using CapTCR-seq in eight patients. Results: A decline in ctDNA after day 8 was associated with radiological response, longer progression-free survival, and a trend toward improved overall survival. TCR repertoires transiently diversified between days 8-22, with longer diversification windows in patients showing sustained ctDNA decline. Using the GLIPHII algorithm, an EBV-specific TCR signature was identified and persisted in patients with clinical benefit. Additional TCR signatures, potentially recognizing tumor-associated antigens, emerged as early as day 3 and were linked to positive outcomes. Conclusions: Simultaneous early monitoring of ctDNA and TCR dynamics reveals key determinants of ICB outcomes in R/M HNSCC. The transient nature of TCR diversification emphasizes the importance of precise sample timing to guide early therapeutic decisions and improve patient outcomes.
{"title":"Investigating Early Kinetics in Plasma ctDNA and Peripheral T Cell Receptor Repertoire to Predict Treatment Outcomes to PD-1 Inhibitors in Head and Neck Cancer","authors":"Enrique Sanz-Garcia, Shirin Soleimani, Jeff P. Bruce, Stephanie Pedersen, Marian Tang, Lisa Avery, Jenna Eagles, Anna Spreafico, Aaron R. Hansen, Lawson Eng, George Laliotis, Michael Krainock, Minetta Liu, Prabhjit Basra, Celeste Yu, Sam Felicen, Pamela S. Ohashi, Scott V. Bratman, Trevor J. Pugh, Lillian L. Siu","doi":"10.1158/1078-0432.ccr-25-3541","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3541","url":null,"abstract":"Purpose: Immune checkpoint blockade (ICB) therapies targeting the PD-1 axis have significantly improved survival in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Circulating tumor DNA (ctDNA) and peripheral T cell receptor (TCR) repertoires are emerging as promising biomarkers for predicting ICB response. Early characterization of ctDNA and TCR dynamics may enable timely treatment adjustments before clinical or radiological progression. Patients and Methods: The IO-KIN study (NCT04606940) is a single-center, prospective trial involving 15 patients with R/M HNSCC treated with nivolumab or pembrolizumab. Blood samples (n=104) were collected across seven timepoints from baseline to day 29. ctDNA was analyzed using a personalized assay (Signatera), and peripheral TCR repertoires were profiled using CapTCR-seq in eight patients. Results: A decline in ctDNA after day 8 was associated with radiological response, longer progression-free survival, and a trend toward improved overall survival. TCR repertoires transiently diversified between days 8-22, with longer diversification windows in patients showing sustained ctDNA decline. Using the GLIPHII algorithm, an EBV-specific TCR signature was identified and persisted in patients with clinical benefit. Additional TCR signatures, potentially recognizing tumor-associated antigens, emerged as early as day 3 and were linked to positive outcomes. Conclusions: Simultaneous early monitoring of ctDNA and TCR dynamics reveals key determinants of ICB outcomes in R/M HNSCC. The transient nature of TCR diversification emphasizes the importance of precise sample timing to guide early therapeutic decisions and improve patient outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"29 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785832","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}
Purpose: Germline pathogenic variants (GPVs) are frequently identified as secondary findings in cancer gene panel testing. Due to limited data on germline conversion rates (GCRs) in the Japanese population, clinical decisions have relied on ESMO criteria. We aimed to develop a variant-level GCR prediction algorithm using Japanese tumor-normal matched panel database and compare its utility with existing standards. Patients and Methods: We analyzed 7,078 Japanese cases from the NCC Oncopanel dataset, focusing on 32 hereditary cancer genes. Clinical features, sample information, sequence results, and minor allele frequency (MAF) in healthy populations were incorporated int a machine learning model and nomogram. Clinical utility was assessed via decision curve analysis and validated using GenMineTOP dataset. Results: Among 3,372 cases (mean age 61; 51% male), 4,905 pathogenic variants were identified, including 491 GPVs (GCR: 10%). High disease-specific GCRs were observed in BAP1 (11% in ocular tumors), BRCA1 and/or BRCA2 (13–16% in ovarian/peritoneal cancers), and NF1 (16% in peripheral nerve tumors). Genes with >50% GCRs included RAD51C, BRCA1, PALB2, CHEK2, RET, BRCA2, and PMS2. Significant predictors included age <30, multiple cancers, gene type, cancer type, MAF, relative variant allele frequency to tumor purity, and tumor allele ratio (TAR). The model achieved a c-index of 0.96–0.97, outperforming ESMO (0.88), with a 1.2% net benefit at a 5% threshold. The results were confirmed using GenMineTOP dataset. Conclusions: Variant-level prediction models for Japanese cancer patients incorporating TAR and MAF offer improved GPV prediction over gene-level approaches and support clinical decision-making and personalized medicine.
{"title":"Germline pathogenic variant prediction model for tumor-only sequencing based on Japanese clinicogenomic database","authors":"Masachika Ikegami, Liuzhe Zhang, Makoto Hirata, Tatsuro Yamaguchi, Shinya Oda, Shinji Kohsaka, Hiroyuki Mano, Toshihide Hirai, Hiroshi Kobayashi","doi":"10.1158/1078-0432.ccr-25-2985","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2985","url":null,"abstract":"Purpose: Germline pathogenic variants (GPVs) are frequently identified as secondary findings in cancer gene panel testing. Due to limited data on germline conversion rates (GCRs) in the Japanese population, clinical decisions have relied on ESMO criteria. We aimed to develop a variant-level GCR prediction algorithm using Japanese tumor-normal matched panel database and compare its utility with existing standards. Patients and Methods: We analyzed 7,078 Japanese cases from the NCC Oncopanel dataset, focusing on 32 hereditary cancer genes. Clinical features, sample information, sequence results, and minor allele frequency (MAF) in healthy populations were incorporated int a machine learning model and nomogram. Clinical utility was assessed via decision curve analysis and validated using GenMineTOP dataset. Results: Among 3,372 cases (mean age 61; 51% male), 4,905 pathogenic variants were identified, including 491 GPVs (GCR: 10%). High disease-specific GCRs were observed in BAP1 (11% in ocular tumors), BRCA1 and/or BRCA2 (13–16% in ovarian/peritoneal cancers), and NF1 (16% in peripheral nerve tumors). Genes with &gt;50% GCRs included RAD51C, BRCA1, PALB2, CHEK2, RET, BRCA2, and PMS2. Significant predictors included age &lt;30, multiple cancers, gene type, cancer type, MAF, relative variant allele frequency to tumor purity, and tumor allele ratio (TAR). The model achieved a c-index of 0.96–0.97, outperforming ESMO (0.88), with a 1.2% net benefit at a 5% threshold. The results were confirmed using GenMineTOP dataset. Conclusions: Variant-level prediction models for Japanese cancer patients incorporating TAR and MAF offer improved GPV prediction over gene-level approaches and support clinical decision-making and personalized medicine.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765239","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 : 2025-12-17DOI: 10.1158/1078-0432.ccr-25-1818
Hope S. Rugo, David W. Cescon, Mark E. Robson, Seock-Ah Im, Florence Dalenc, Eduardo Yañez Ruiz, Felipe Reyes-Cosmelli, Janice M. Walshe, Young-Hyuck Im, Sergii Kulyk, Oleksandr Dudnichenko, Néstor Llinás-Quintero, Shigehira Saji, Yasuo Miyoshi, Aditya Bardia, Nadia Harbeck, Amin Haiderali, Li Fan, Jaime A. Mejia, Vassiliki Karantza, Antonio Llombart-Cussac
Purpose: Pembrolizumab plus olaparib versus pembrolizumab plus chemotherapy was evaluated as post-induction therapy for patients with PD-L1‒unselected locally recurrent inoperable/metastatic triple-negative breast cancer (TNBC) who derived clinical benefit from first-line pembrolizumab plus platinum-based chemotherapy induction therapy. Methods: In this phase 2 study (NCT04191135), participants with previously untreated locally recurrent inoperable/metastatic TNBC received first-line pembrolizumab 200 mg Q3W plus platinum-based chemotherapy. Participants with complete/partial response or stable disease (per RECIST v1.1) were randomized 1:1 to pembrolizumab 200 mg Q3W plus olaparib 300 mg BID or pembrolizumab plus chemotherapy. PFS and OS were primary endpoints. Results: Of 460 participants receiving induction treatment, 271 were randomized to post-induction therapy. Median PFS was 5.5 months in the pembrolizumab plus olaparib group versus 5.6 months in the pembrolizumab plus chemotherapy group (HR, 0.98; 95% CI, 0.72‒1.33; P=0.4556). Median OS was 25.1 versus 23.4 months, respectively (HR, 0.95; 95% CI, 0.64‒1.40). In participants with tumor BRCA1/BRCA2 mutations (tBRCAm), HRs for PFS (HR, 0.70; 95% CI, 0.33‒1.48) and OS (0.81; 95% CI, 0.28‒2.37) favored pembrolizumab plus olaparib. Treatment-related adverse events occurred in 84.4% and 96.2% of participants receiving pembrolizumab plus olaparib and pembrolizumab plus chemotherapy, respectively. Conclusion: Although the primary endpoint was not met, post-induction pembrolizumab plus olaparib therapy resulted in similar PFS and OS compared with pembrolizumab plus chemotherapy in this setting. The positive trend for PFS and OS in participants with tBRCAm suggests a potential non-chemotherapy strategy for maintaining clinical benefit attained with first-line pembrolizumab plus chemotherapy induction treatment. No new safety signals were identified.
{"title":"KEYLYNK-009: Pembrolizumab Plus Olaparib in Locally Recurrent Inoperable or Metastatic Triple-Negative Breast Cancer and Clinical Benefit From First-Line Pembrolizumab Plus Chemotherapy","authors":"Hope S. Rugo, David W. Cescon, Mark E. Robson, Seock-Ah Im, Florence Dalenc, Eduardo Yañez Ruiz, Felipe Reyes-Cosmelli, Janice M. Walshe, Young-Hyuck Im, Sergii Kulyk, Oleksandr Dudnichenko, Néstor Llinás-Quintero, Shigehira Saji, Yasuo Miyoshi, Aditya Bardia, Nadia Harbeck, Amin Haiderali, Li Fan, Jaime A. Mejia, Vassiliki Karantza, Antonio Llombart-Cussac","doi":"10.1158/1078-0432.ccr-25-1818","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1818","url":null,"abstract":"Purpose: Pembrolizumab plus olaparib versus pembrolizumab plus chemotherapy was evaluated as post-induction therapy for patients with PD-L1‒unselected locally recurrent inoperable/metastatic triple-negative breast cancer (TNBC) who derived clinical benefit from first-line pembrolizumab plus platinum-based chemotherapy induction therapy. Methods: In this phase 2 study (NCT04191135), participants with previously untreated locally recurrent inoperable/metastatic TNBC received first-line pembrolizumab 200 mg Q3W plus platinum-based chemotherapy. Participants with complete/partial response or stable disease (per RECIST v1.1) were randomized 1:1 to pembrolizumab 200 mg Q3W plus olaparib 300 mg BID or pembrolizumab plus chemotherapy. PFS and OS were primary endpoints. Results: Of 460 participants receiving induction treatment, 271 were randomized to post-induction therapy. Median PFS was 5.5 months in the pembrolizumab plus olaparib group versus 5.6 months in the pembrolizumab plus chemotherapy group (HR, 0.98; 95% CI, 0.72‒1.33; P=0.4556). Median OS was 25.1 versus 23.4 months, respectively (HR, 0.95; 95% CI, 0.64‒1.40). In participants with tumor BRCA1/BRCA2 mutations (tBRCAm), HRs for PFS (HR, 0.70; 95% CI, 0.33‒1.48) and OS (0.81; 95% CI, 0.28‒2.37) favored pembrolizumab plus olaparib. Treatment-related adverse events occurred in 84.4% and 96.2% of participants receiving pembrolizumab plus olaparib and pembrolizumab plus chemotherapy, respectively. Conclusion: Although the primary endpoint was not met, post-induction pembrolizumab plus olaparib therapy resulted in similar PFS and OS compared with pembrolizumab plus chemotherapy in this setting. The positive trend for PFS and OS in participants with tBRCAm suggests a potential non-chemotherapy strategy for maintaining clinical benefit attained with first-line pembrolizumab plus chemotherapy induction treatment. No new safety signals were identified.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"21 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765235","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 : 2025-12-16DOI: 10.1158/1078-0432.ccr-25-2312
Elena Garralda, Charles Abbott, Alma Calahorro, Oriol Mirallas, Jason Pugh, Ana Belén Moreno-Cárdenas, Kathleen Keough, Vladimir Galvao, Guzman Alonso, Armando Mel Olano, María Vieito Villar, Arjun Oberoi, Julia Lostes Bardaji, Alberto Hernando-Calvo, Irene Braña, Giulia Pretelli, Belen Ortega, Carlota Arenillas, Natalia Czerniak, Fábio C.P. Navarro, Bailiang Li, Rachel Marty Pyke, Neeraja Ravi, Christina Zatse, Francesco Grussu, Marta Sanz, Cristina Viaplana, Kira Raskina, Jose Jimenez, Roberta Fasani, Patricia Casbas-Hernandez, Ezoglin Oflazoglu, Darren Hodgson, Jorge Reis-Filho, Enriqueta Felip, Elena Élez, Eva Muñoz, Rodrigo Dienstmann, Josep Tabernero, Raquel Lopez-Perez, Paolo Nuciforo, Richard O. Chen, Sean M. Boyle, Rodrigo A. Toledo
Purpose: Prior studies have suggested the biomarker potential of plasma-derived ctDNA in patients with cancer treated with immune checkpoint inhibitors. This study investigated the ability of ctDNA to predict progression-free and overall survival in a cohort of patients with advanced cancer treated with immunotherapies. Experimental Design: In order to characterize the potential role of ultrasensitive ctDNA detection in the management of these patients, we have performed tumor whole-genome sequencing–informed, ultrasensitive ctDNA analysis—tracking approximately 1,800 tumor-specific mutations per patient—in a retrospective cohort (n = 136) and a prospective validation cohort (n = 66) across 24 cancer types treated with immune checkpoint inhibitors alone or in combination with bispecific antibodies or immune cell engagers. Results: Analyzing 1,455 longitudinal samples, we found that ctDNA molecular response measured as early as 3 weeks after treatment initiation correlated with improved progression-free and overall survival, whereas ctDNA clearance at any time strongly correlated with radiologic response and prolonged survival. Additionally, ctDNA dynamics distinguished true progression from pseudoprogression and predicted outcomes in patients receiving continued immunotherapy beyond initial progression. Conclusions: This study highlights the broader applicability of ultrasensitive ctDNA as a biomarker across cancer types and immunotherapy modalities.
{"title":"Broad Utility of Ultrasensitive Analysis of ctDNA Dynamics across Solid Tumors Treated with Immunotherapy","authors":"Elena Garralda, Charles Abbott, Alma Calahorro, Oriol Mirallas, Jason Pugh, Ana Belén Moreno-Cárdenas, Kathleen Keough, Vladimir Galvao, Guzman Alonso, Armando Mel Olano, María Vieito Villar, Arjun Oberoi, Julia Lostes Bardaji, Alberto Hernando-Calvo, Irene Braña, Giulia Pretelli, Belen Ortega, Carlota Arenillas, Natalia Czerniak, Fábio C.P. Navarro, Bailiang Li, Rachel Marty Pyke, Neeraja Ravi, Christina Zatse, Francesco Grussu, Marta Sanz, Cristina Viaplana, Kira Raskina, Jose Jimenez, Roberta Fasani, Patricia Casbas-Hernandez, Ezoglin Oflazoglu, Darren Hodgson, Jorge Reis-Filho, Enriqueta Felip, Elena Élez, Eva Muñoz, Rodrigo Dienstmann, Josep Tabernero, Raquel Lopez-Perez, Paolo Nuciforo, Richard O. Chen, Sean M. Boyle, Rodrigo A. Toledo","doi":"10.1158/1078-0432.ccr-25-2312","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2312","url":null,"abstract":"Purpose: Prior studies have suggested the biomarker potential of plasma-derived ctDNA in patients with cancer treated with immune checkpoint inhibitors. This study investigated the ability of ctDNA to predict progression-free and overall survival in a cohort of patients with advanced cancer treated with immunotherapies. Experimental Design: In order to characterize the potential role of ultrasensitive ctDNA detection in the management of these patients, we have performed tumor whole-genome sequencing–informed, ultrasensitive ctDNA analysis—tracking approximately 1,800 tumor-specific mutations per patient—in a retrospective cohort (n = 136) and a prospective validation cohort (n = 66) across 24 cancer types treated with immune checkpoint inhibitors alone or in combination with bispecific antibodies or immune cell engagers. Results: Analyzing 1,455 longitudinal samples, we found that ctDNA molecular response measured as early as 3 weeks after treatment initiation correlated with improved progression-free and overall survival, whereas ctDNA clearance at any time strongly correlated with radiologic response and prolonged survival. Additionally, ctDNA dynamics distinguished true progression from pseudoprogression and predicted outcomes in patients receiving continued immunotherapy beyond initial progression. Conclusions: This study highlights the broader applicability of ultrasensitive ctDNA as a biomarker across cancer types and immunotherapy modalities.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"158 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759712","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 : 2025-12-15DOI: 10.1158/1078-0432.CCR-25-4106
Eric S Christenson, Won Jin Ho, Daniel Shu, Jennifer N Durham, Madelena Brancati, Heather Davis Bruning, Susan Petrie, Hao Wang, Jiayun Lu, Katherine M Bever, Daniel Laheru, Ana de Jesus-Acosta, Ilene Browner, Ross Donehower, Michael J Pishvaian, Nilofer Azad, Qingfeng Zhu, Alens Valentin, Jayalaxmi Suresh Babu, Alexei Hernandez, George Apostol, Yiyang Gao, Nicolas Llosa, Franck Housseau, Drew Pardoll, Elizabeth M Jaffee, Robert Anders, Dung T Le
{"title":"Correction: Nivolumab and Relatlimab for the Treatment of Patients with Unresectable or Metastatic Mismatch Repair-Proficient Colorectal Cancer.","authors":"Eric S Christenson, Won Jin Ho, Daniel Shu, Jennifer N Durham, Madelena Brancati, Heather Davis Bruning, Susan Petrie, Hao Wang, Jiayun Lu, Katherine M Bever, Daniel Laheru, Ana de Jesus-Acosta, Ilene Browner, Ross Donehower, Michael J Pishvaian, Nilofer Azad, Qingfeng Zhu, Alens Valentin, Jayalaxmi Suresh Babu, Alexei Hernandez, George Apostol, Yiyang Gao, Nicolas Llosa, Franck Housseau, Drew Pardoll, Elizabeth M Jaffee, Robert Anders, Dung T Le","doi":"10.1158/1078-0432.CCR-25-4106","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-4106","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 24","pages":"5317"},"PeriodicalIF":10.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145755423","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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