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}
Pub Date : 2025-12-12DOI: 10.1158/1078-0432.ccr-25-2274
Egle Ramelyte, Julian Kött, Aleigha R. Lawless, Amélie Ciernik, Isabel Heidrich, Caroline Zellweger, Kamaneh Montazeri, Johanna Mangana, Daniel J. Smit, Sandra N. Freiberger, Stephany Orjuela, Reinhard Dummer, Ryan J. Sullivan, Mitchell P. Levesque, Christoffer Gebhardt
Background: Circulating tumor DNA (ctDNA) refers to small DNA-fragments, shed from tumor cells into the bloodstream. Measuring ctDNA provides a non-invasive tool for real-time disease monitoring. While ctDNA predicted overall survival (OS) in metastatic uveal melanoma (mUM) treated with tebentafusp, its broader prognostic value across treatment modalities remains unclear. Here, we assess the prognostic relevance of longitudinal ctDNA detection and mutant allele fraction (MAF) in patients with mUM treated with different modalities. Objective: To assess ctDNA monitoring as a tool in evaluating therapy response and clinical outcomes in patients with mUM, using an IVDR-certified digital PCR assay targeting GNAQQ209 and GNA11Q209 mutations. Results: We analyzed 655 samples from 75 patients with mUM. Absence of detectable ctDNA in baseline samples prior to first-line therapy was associated with improved OS (HR=0.13, p=0.02) and progression-free survival (PFS) (HR=0.31, p=0.008). Similar associations were observed in patients treated with any-line of therapy (OS: HR=0.19, p=0.002; PFS: HR=0.27, p=0.02). Detection of ctDNA within 3months of therapy initiation was associated with worse outcomes, independent of baseline detection. Furthermore, patients with MAF >5% any timepoint had a significantly poorer prognosis compared to patients with MAF <5% (median OS 4months vs 21months, p<0.001; median PFS 2.5months vs 3.6months, p=0.004), emphasizing the added value of quantitative assessment. Conclusion: Both the presence and level of ctDNA at baseline, along with persistence of ctDNA within 3months of treatment-start, are strong negative prognostic markers in mUM. These findings support the clinical utility of ctDNA as a non-invasive tool for disease monitoring.
{"title":"Circulating tumor DNA is prognostic of patient outcome and enables therapy monitoring in metastatic uveal melanoma","authors":"Egle Ramelyte, Julian Kött, Aleigha R. Lawless, Amélie Ciernik, Isabel Heidrich, Caroline Zellweger, Kamaneh Montazeri, Johanna Mangana, Daniel J. Smit, Sandra N. Freiberger, Stephany Orjuela, Reinhard Dummer, Ryan J. Sullivan, Mitchell P. Levesque, Christoffer Gebhardt","doi":"10.1158/1078-0432.ccr-25-2274","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2274","url":null,"abstract":"Background: Circulating tumor DNA (ctDNA) refers to small DNA-fragments, shed from tumor cells into the bloodstream. Measuring ctDNA provides a non-invasive tool for real-time disease monitoring. While ctDNA predicted overall survival (OS) in metastatic uveal melanoma (mUM) treated with tebentafusp, its broader prognostic value across treatment modalities remains unclear. Here, we assess the prognostic relevance of longitudinal ctDNA detection and mutant allele fraction (MAF) in patients with mUM treated with different modalities. Objective: To assess ctDNA monitoring as a tool in evaluating therapy response and clinical outcomes in patients with mUM, using an IVDR-certified digital PCR assay targeting GNAQQ209 and GNA11Q209 mutations. Results: We analyzed 655 samples from 75 patients with mUM. Absence of detectable ctDNA in baseline samples prior to first-line therapy was associated with improved OS (HR=0.13, p=0.02) and progression-free survival (PFS) (HR=0.31, p=0.008). Similar associations were observed in patients treated with any-line of therapy (OS: HR=0.19, p=0.002; PFS: HR=0.27, p=0.02). Detection of ctDNA within 3months of therapy initiation was associated with worse outcomes, independent of baseline detection. Furthermore, patients with MAF &gt;5% any timepoint had a significantly poorer prognosis compared to patients with MAF &lt;5% (median OS 4months vs 21months, p&lt;0.001; median PFS 2.5months vs 3.6months, p=0.004), emphasizing the added value of quantitative assessment. Conclusion: Both the presence and level of ctDNA at baseline, along with persistence of ctDNA within 3months of treatment-start, are strong negative prognostic markers in mUM. These findings support the clinical utility of ctDNA as a non-invasive tool for disease monitoring.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"66 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731030","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 : 2025-12-12DOI: 10.1158/1078-0432.ccr-25-2807
Ralph G. Zinner, Eric V. Mastrolonardo, Jennifer M. Johnson, Kathryn Nunes, Pablo Llerena, Zachary Elliott, Madalina Tuluc, Joseph M. Curry, Christopher E. Fundakowski, Andrew Yampolsky, Richard Goldman, Charalambos C. Solomides, Stacey M. Gargano, Haresh Naringrekar, Larry Harshyne, Dawn Poller, Benjamin E. Leiby, Voichita Bar-Ad, Rita Axelrod, Athanassios Argiris, Adam J. Luginbuhl, David M. Cognetti
Background: In locally-advanced resectable squamous cell carcinoma of the head and neck (SCCHN), patients treated with neoadjuvant chemotherapy with major pathologic response (MPR) or pathologic complete response (pCR) have overall survival (OS) rates superior to those of patients with poorer pathologic responses. To improve efficacy, we added the PD-1 inhibitor, nivolumab, to neoadjuvant chemotherapy and evaluated the combination. Methods: In this single-arm, open-label phase II trial, patients with newly-diagnosed stage III–IV HPV-negative SCCHN in the oral cavity, oropharynx, hypopharynx, and larynx or stage II–III HPV-positive oropharyngeal SCCHN received neoadjuvant carboplatin and paclitaxel (6 weeks) plus nivolumab (every other week) followed by surgery and adjuvant radiotherapy+/-chemotherapy. Primary endpoint was pCR at the primary site. Results: Thirty-four patients were enrolled and received neoadjuvant therapy. Thirty-three patients received surgery (R0 resection=100%). Disease sites included the oral cavity (79%), oropharynx (12%), hypopharynx (6%), and larynx (3%). Twenty-eight (85%) patients had stage IVA disease. Median postsurgical follow-up was 35.3 months. Fourteen (41%) patients experienced Grade 3/ 4 treatment-related adverse events. Twenty-seven (82%) patients completed all cycles of neoadjuvant therapy. Twenty-four (73%) patients had at least an MPR at the primary site, and 15(45%) had a pCR. In an unplanned analysis at 3-years, recurrence-free survival and OS were 74% and 83%, respectively. Conclusions: This phase II trial of neoadjuvant nivolumab plus carboplatin and paclitaxel in previously untreated, locally-advanced, resectable SCCHN was well tolerated and reached its primary endpoint of pCR at the primary site. A phase III confirmatory study is warranted in advanced-stage, resectable HPV-negative SCCHN.
{"title":"Neoadjuvant nivolumab plus carboplatin and paclitaxel in patients with locally advanced resectable squamous cell carcinoma of the head and neck: a phase II, single-arm trial","authors":"Ralph G. Zinner, Eric V. Mastrolonardo, Jennifer M. Johnson, Kathryn Nunes, Pablo Llerena, Zachary Elliott, Madalina Tuluc, Joseph M. Curry, Christopher E. Fundakowski, Andrew Yampolsky, Richard Goldman, Charalambos C. Solomides, Stacey M. Gargano, Haresh Naringrekar, Larry Harshyne, Dawn Poller, Benjamin E. Leiby, Voichita Bar-Ad, Rita Axelrod, Athanassios Argiris, Adam J. Luginbuhl, David M. Cognetti","doi":"10.1158/1078-0432.ccr-25-2807","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2807","url":null,"abstract":"Background: In locally-advanced resectable squamous cell carcinoma of the head and neck (SCCHN), patients treated with neoadjuvant chemotherapy with major pathologic response (MPR) or pathologic complete response (pCR) have overall survival (OS) rates superior to those of patients with poorer pathologic responses. To improve efficacy, we added the PD-1 inhibitor, nivolumab, to neoadjuvant chemotherapy and evaluated the combination. Methods: In this single-arm, open-label phase II trial, patients with newly-diagnosed stage III–IV HPV-negative SCCHN in the oral cavity, oropharynx, hypopharynx, and larynx or stage II–III HPV-positive oropharyngeal SCCHN received neoadjuvant carboplatin and paclitaxel (6 weeks) plus nivolumab (every other week) followed by surgery and adjuvant radiotherapy+/-chemotherapy. Primary endpoint was pCR at the primary site. Results: Thirty-four patients were enrolled and received neoadjuvant therapy. Thirty-three patients received surgery (R0 resection=100%). Disease sites included the oral cavity (79%), oropharynx (12%), hypopharynx (6%), and larynx (3%). Twenty-eight (85%) patients had stage IVA disease. Median postsurgical follow-up was 35.3 months. Fourteen (41%) patients experienced Grade 3/ 4 treatment-related adverse events. Twenty-seven (82%) patients completed all cycles of neoadjuvant therapy. Twenty-four (73%) patients had at least an MPR at the primary site, and 15(45%) had a pCR. In an unplanned analysis at 3-years, recurrence-free survival and OS were 74% and 83%, respectively. Conclusions: This phase II trial of neoadjuvant nivolumab plus carboplatin and paclitaxel in previously untreated, locally-advanced, resectable SCCHN was well tolerated and reached its primary endpoint of pCR at the primary site. A phase III confirmatory study is warranted in advanced-stage, resectable HPV-negative SCCHN.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"61 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731029","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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