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}
Pub Date : 2025-12-12DOI: 10.1158/1078-0432.ccr-25-2435
Miguel Martín, Angel L. Guerrero-Zotano, María E. Pérez-López, Manuel Ruiz-Borrego, Noelia Martinez Jañez, José I. Chacón, Miguel Gil-Gil, Raquel Andrés, Begoña Bermejo, Pedro Sánchez-Rovira, Sonia del Barco, José J. Ponce, Isaura Fernandez, Eduardo Martínez de Dueñas, Carmen Hinojo-Gonzále, Marta González, Elisa García-Garre, Blanca Hernando, Juan de la Haba-Rodriguez, Isabel M. Álvarez, Santiago González-Santiago, Jose A. Garcia-Saenz, Ana Santaballa, Maribel Casas, Susana Bezares, Rosalía Caballero, Federico Rojo, Emilio Alba
Purpose: Neoadjuvant chemotherapy is standard for high-risk HR+/HER2–breast cancer (BC). This study evaluates whether 12 months of letrozole plus abemaciclib could be an alternative. Patients and Methods: The phase II, open-label CARABELA trial randomized HR+/HER2− stage II-III BC patients with Ki-67 ≥20% to receive letrozole/abemaciclib for 12 months or chemotherapy for 6 months. Patients were stratified by menopausal status, TNM stage, and Ki-67 index (<30% vs. ≥30%). The primary endpoint was the rate of residual cancer burden (RCB) 0–I. Secondary endpoints included clinical response rate (CRR) and correlations of Ki-67 and Recurrence Score® (RS) with tumor response. A Bayesian design aimed to assess treatment similarity. Results: 200 patients (median age 53 years, 57% postmenopausal, 79% stage II, 77% Ki-67 ≥30%, 58% RS ≥26) were randomized. RCB 0-I was achieved in 13% (letrozole/abemaciclib, 95% Credible Intervals (CrI): 7.4% − 20.5%) vs. 18% (chemotherapy, 95% CrI: 11.5% − 26.4%), failing to show similarity between treatment arms. The CRRs were 78% (letrozole/abemaciclib) vs. 71% (chemotherapy) (P=0.26). Tumors with Ki-67 ≥30% and/or RS results ≥26 showed a trend toward higher RCB 0–I rates with chemotherapy (23% vs. 17%, P=0.52). RCB 0-I rates were similar between treatments for tumors with Ki-67 <30% or RS <26. Conclusions: CARABELA trial results suggest that 12 months of letrozole/abemaciclib may not offer similar efficacy to that of chemotherapy in achieving RCB 0–I. However, in less proliferative tumors (RS <26 or Ki-67 <30%), outcomes were comparable, suggesting that letrozole/abemaciclib could replace (neo)adjuvant chemotherapy in selected patients.
{"title":"Neoadjuvant Abemaciclib plus Letrozole vs. Chemotherapy in patients with HR+/HER2– Highly Proliferative Breast Cancer","authors":"Miguel Martín, Angel L. Guerrero-Zotano, María E. Pérez-López, Manuel Ruiz-Borrego, Noelia Martinez Jañez, José I. Chacón, Miguel Gil-Gil, Raquel Andrés, Begoña Bermejo, Pedro Sánchez-Rovira, Sonia del Barco, José J. Ponce, Isaura Fernandez, Eduardo Martínez de Dueñas, Carmen Hinojo-Gonzále, Marta González, Elisa García-Garre, Blanca Hernando, Juan de la Haba-Rodriguez, Isabel M. Álvarez, Santiago González-Santiago, Jose A. Garcia-Saenz, Ana Santaballa, Maribel Casas, Susana Bezares, Rosalía Caballero, Federico Rojo, Emilio Alba","doi":"10.1158/1078-0432.ccr-25-2435","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2435","url":null,"abstract":"Purpose: Neoadjuvant chemotherapy is standard for high-risk HR+/HER2–breast cancer (BC). This study evaluates whether 12 months of letrozole plus abemaciclib could be an alternative. Patients and Methods: The phase II, open-label CARABELA trial randomized HR+/HER2− stage II-III BC patients with Ki-67 ≥20% to receive letrozole/abemaciclib for 12 months or chemotherapy for 6 months. Patients were stratified by menopausal status, TNM stage, and Ki-67 index (&lt;30% vs. ≥30%). The primary endpoint was the rate of residual cancer burden (RCB) 0–I. Secondary endpoints included clinical response rate (CRR) and correlations of Ki-67 and Recurrence Score® (RS) with tumor response. A Bayesian design aimed to assess treatment similarity. Results: 200 patients (median age 53 years, 57% postmenopausal, 79% stage II, 77% Ki-67 ≥30%, 58% RS ≥26) were randomized. RCB 0-I was achieved in 13% (letrozole/abemaciclib, 95% Credible Intervals (CrI): 7.4% − 20.5%) vs. 18% (chemotherapy, 95% CrI: 11.5% − 26.4%), failing to show similarity between treatment arms. The CRRs were 78% (letrozole/abemaciclib) vs. 71% (chemotherapy) (P=0.26). Tumors with Ki-67 ≥30% and/or RS results ≥26 showed a trend toward higher RCB 0–I rates with chemotherapy (23% vs. 17%, P=0.52). RCB 0-I rates were similar between treatments for tumors with Ki-67 &lt;30% or RS &lt;26. Conclusions: CARABELA trial results suggest that 12 months of letrozole/abemaciclib may not offer similar efficacy to that of chemotherapy in achieving RCB 0–I. However, in less proliferative tumors (RS &lt;26 or Ki-67 &lt;30%), outcomes were comparable, suggesting that letrozole/abemaciclib could replace (neo)adjuvant chemotherapy in selected patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"6 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731033","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-25-2820
Michelle Mierzwa, Benjamin Rosen, Krithika Suresh, Arjun Dinesh, Sam Regan, Collin Brummel, Kakit Wong, Keith Casper, Mark Prince, Kelly Malloy, Andrew Shuman, Steven Chinn, Yue Cao, Madhava Aryal, Molly Heft-Neal, Chaz Stucken, Marisa Buchakjian, David Forner, Pratyusha Yalamanchi, Paul Swiecicki, Theodore S. Lawrence, Rawan Akhdar, Muneesh Tewari, Chandan Bhambhani, Heather Walline, J. Chad. Brenner, Jennifer Shah, Francis Worden
Purpose: We conducted a phase II multicenter clinical trial to test the hypothesis that FDG-PET based chemoradiation (CRT) dose de-escalation would provide non-inferior loco-regional control compared to historical controls among patients with early-stage p16+ oropharyngeal cancer. We also hypothesized that HPVctDNA changes during treatment predict loco-regional recurrence (LRR). Patients and Methods: Patients with Stage I/II p16+ oropharyngeal squamous cell carcinoma were planned to receive radiation 70Gy in 35 fractions with concurrent weekly carboplatin and paclitaxel. All patients underwent FDG-PET at baseline and at RT fraction 10. Patients with ≥50% decrease from baseline to mid-treatment metabolic tumor volume (MTV)2.5 had treatment deescalated to 54Gy in 27 fractions. The primary endpoint was LRR. Plasma HPVctDNA was evaluated weekly and in surveillance. Results: Of 84 evaluable patients, 43% met de-escalation criteria. With a median follow-up of 37.8 months, 24-month LRR for the entire cohort was 7.8% (90% CI: 2.6% - 12.6%), which was less than the 25% rate specified for assessing non-inferiority, thereby meeting the primary endpoint. At 1 month post RT, the mean of multiple quality of life measures between the two groups were improved in the 54Gy cohort, exceeding the minimal clinically important difference (MCID) threshold. During CRT, week 1 percentage increase in ctDNA relative to baseline was significantly associated with worse LRC (HR=1.052 per 10 percentage points increase in ctDNA, 95% CI: 1.007-1.099; p=0.023) and LRPFS (HR=1.038, 95% CI: 1.002-1.076; p=0.035). Conclusion: FDG-PET-based RT dose personalization resulted in promising LRR outcomes in early stage oropharynx cancer with improved short- term PROs. Furthermore, HPVctDNA changes early in treatment may predict LRC.
{"title":"FDG-PET-based Selective De-escalation of Chemoradiation in Human Papillomavirus-related Oropharyngeal Squamous Cell Carcinoma: a Multi-center Phase II Trial","authors":"Michelle Mierzwa, Benjamin Rosen, Krithika Suresh, Arjun Dinesh, Sam Regan, Collin Brummel, Kakit Wong, Keith Casper, Mark Prince, Kelly Malloy, Andrew Shuman, Steven Chinn, Yue Cao, Madhava Aryal, Molly Heft-Neal, Chaz Stucken, Marisa Buchakjian, David Forner, Pratyusha Yalamanchi, Paul Swiecicki, Theodore S. Lawrence, Rawan Akhdar, Muneesh Tewari, Chandan Bhambhani, Heather Walline, J. Chad. Brenner, Jennifer Shah, Francis Worden","doi":"10.1158/1078-0432.ccr-25-2820","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2820","url":null,"abstract":"Purpose: We conducted a phase II multicenter clinical trial to test the hypothesis that FDG-PET based chemoradiation (CRT) dose de-escalation would provide non-inferior loco-regional control compared to historical controls among patients with early-stage p16+ oropharyngeal cancer. We also hypothesized that HPVctDNA changes during treatment predict loco-regional recurrence (LRR). Patients and Methods: Patients with Stage I/II p16+ oropharyngeal squamous cell carcinoma were planned to receive radiation 70Gy in 35 fractions with concurrent weekly carboplatin and paclitaxel. All patients underwent FDG-PET at baseline and at RT fraction 10. Patients with ≥50% decrease from baseline to mid-treatment metabolic tumor volume (MTV)2.5 had treatment deescalated to 54Gy in 27 fractions. The primary endpoint was LRR. Plasma HPVctDNA was evaluated weekly and in surveillance. Results: Of 84 evaluable patients, 43% met de-escalation criteria. With a median follow-up of 37.8 months, 24-month LRR for the entire cohort was 7.8% (90% CI: 2.6% - 12.6%), which was less than the 25% rate specified for assessing non-inferiority, thereby meeting the primary endpoint. At 1 month post RT, the mean of multiple quality of life measures between the two groups were improved in the 54Gy cohort, exceeding the minimal clinically important difference (MCID) threshold. During CRT, week 1 percentage increase in ctDNA relative to baseline was significantly associated with worse LRC (HR=1.052 per 10 percentage points increase in ctDNA, 95% CI: 1.007-1.099; p=0.023) and LRPFS (HR=1.038, 95% CI: 1.002-1.076; p=0.035). Conclusion: FDG-PET-based RT dose personalization resulted in promising LRR outcomes in early stage oropharynx cancer with improved short- term PROs. Furthermore, HPVctDNA changes early in treatment may predict LRC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"227 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731032","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 : 2025-12-11DOI: 10.1158/1078-0432.ccr-25-2054
Dongchen Sun, Gang Chen, Yu Chen, Song Qu, Lei Liu, Kunyu Yang, Jingao Li, Lisha Chen, Xiaoming Huang, Haisheng Zhu, Wenjun Tang, Rensheng Wang, Yaqian Han, Dengsheng Hu, Jin Gao, Xiaozhong Chen, Hailin Xiong, Wu Chen, Bin Fan, Shengli Cai, Xiaoqiang Kang, Li Zhang, Yunpeng Yang
Purpose: Prior studies reported synergistic antitumor activity by dual inhibition of lymphocyte activation gene-3 (LAG-3) and PD-1. This study investigated activity, safety and biomarker of LAG-3/PD-1 co-blockade plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). Patients and Methods: Previously untreated RM-NPC patients received LBL-007 (anti-LAG-3), tislelizumab (anti-PD-1), and gemcitabine-cisplatin for 4 to 6 cycles, followed by maintenance therapy with LBL-007 and tislelizumab. Primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), duration of response (DoR), time to response (TTR), disease control rate (DCR), overall survival (OS) and safety. Biomarker analysis included LAG-3 and PD-L1 expression. Results: Forty-two patients were enrolled from 15 centers in China. With a median follow-up of 19.0 months, ORR was 83.3% (95% CI, 68.6%-93.0%), and DCR was 97.6% (95% CI, 87.4%-99.9%). Median PFS reached 15.8 months (95% CI, 9.9-not estimable); 12-month PFS rate was 55.1% (95% CI, 41.7%-72.9%). Median DoR was 14.6 months (95% CI, 10.3-not estimable); median OS was not reached. Grade 3 or higher treatment-related adverse events occurred in 37 patients (98.1%). No new safety signals were identified. In biomarker analysis, patients with dual-positive LAG-3/PD-L1 expression demonstrated more favorable outcomes than those lacking either biomarker, including 12-month PFS rate of 65.0% versus 40.2%, and median PFS of 16.0 versus 10.3 months. Conclusions: LBL-007 plus tislelizumab and chemotherapy shows promising clinical benefits and manageable toxicity as first-line therapy for RM-NPC. Dual-positive LAG-3/PD-L1 expression was associated with improved outcomes, supporting further exploration of this biomarker-defined subpopulation in randomized trials.
{"title":"Anti-LAG-3 Antibody LBL-007 Plus Tislelizumab and Chemotherapy as First-Line Therapy for Advanced Nasopharyngeal Carcinoma: A Multicenter Phase 2 Trial","authors":"Dongchen Sun, Gang Chen, Yu Chen, Song Qu, Lei Liu, Kunyu Yang, Jingao Li, Lisha Chen, Xiaoming Huang, Haisheng Zhu, Wenjun Tang, Rensheng Wang, Yaqian Han, Dengsheng Hu, Jin Gao, Xiaozhong Chen, Hailin Xiong, Wu Chen, Bin Fan, Shengli Cai, Xiaoqiang Kang, Li Zhang, Yunpeng Yang","doi":"10.1158/1078-0432.ccr-25-2054","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2054","url":null,"abstract":"Purpose: Prior studies reported synergistic antitumor activity by dual inhibition of lymphocyte activation gene-3 (LAG-3) and PD-1. This study investigated activity, safety and biomarker of LAG-3/PD-1 co-blockade plus chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). Patients and Methods: Previously untreated RM-NPC patients received LBL-007 (anti-LAG-3), tislelizumab (anti-PD-1), and gemcitabine-cisplatin for 4 to 6 cycles, followed by maintenance therapy with LBL-007 and tislelizumab. Primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), duration of response (DoR), time to response (TTR), disease control rate (DCR), overall survival (OS) and safety. Biomarker analysis included LAG-3 and PD-L1 expression. Results: Forty-two patients were enrolled from 15 centers in China. With a median follow-up of 19.0 months, ORR was 83.3% (95% CI, 68.6%-93.0%), and DCR was 97.6% (95% CI, 87.4%-99.9%). Median PFS reached 15.8 months (95% CI, 9.9-not estimable); 12-month PFS rate was 55.1% (95% CI, 41.7%-72.9%). Median DoR was 14.6 months (95% CI, 10.3-not estimable); median OS was not reached. Grade 3 or higher treatment-related adverse events occurred in 37 patients (98.1%). No new safety signals were identified. In biomarker analysis, patients with dual-positive LAG-3/PD-L1 expression demonstrated more favorable outcomes than those lacking either biomarker, including 12-month PFS rate of 65.0% versus 40.2%, and median PFS of 16.0 versus 10.3 months. Conclusions: LBL-007 plus tislelizumab and chemotherapy shows promising clinical benefits and manageable toxicity as first-line therapy for RM-NPC. Dual-positive LAG-3/PD-L1 expression was associated with improved outcomes, supporting further exploration of this biomarker-defined subpopulation in randomized trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"13 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717271","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 : 2025-12-11DOI: 10.1158/1078-0432.ccr-25-3042
Robert L. Hollis, Austin Miller, Heather A. Lankes, Kwong-Kwok Wong, William Rodgers, David Millan, Karen Carty, Robert L. Coleman, Kathleen N. Moore, Angeles Alvarez Secord, David M. O'Malley, John K. Chan, Andrea R. Hagemann, Stephanie Gaillard, Saketh R. Guntupalli, Mitchell Edelson, Peter G. Rose, Oliver Dorigo, Susana Banerjee, Ailith Ewing, Michael Churchman, Anil K. Sood, C. Simon. Herrington, Charlie Gourley, David M. Gershenson
Purpose:Low-grade serous ovarian carcinoma(LGSOC) is a distinct form of ovarian cancer characterised by younger patient age and relative chemoresistance. The GOG281/LOGS trial(NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared to physician’s choice standard of care(SOC) in LGSOC patients with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival(PFS) in the trametinib-treated arm. Experimental Design:260 patients with recurrent/persistent LGSOC were enrolled and randomised in GOG281. We performed molecular analysis of 170 patients with available tumour specimens, comprising whole exome sequencing and phospho-ERK immunohistochemistry, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort(n=170) were comparable to the total trial cohort. Results:High tumour pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs 5.6 months, log-rank P<0.0001; test for interaction P=0.023). Tumours harbouring canonical RAS-RAF-MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs 8.3%; Barnard's P=0.0004; test for interaction P=0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P=0.719). KRAS amplification (n=5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n=25 without KRAS/NRAS/BRAF mutation or KRAS copy-number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss(49% cases) was associated with lower pERK expression(P=0.021). Conclusion:This exploratory analysis suggests pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.
目的：低级别浆液性卵巢癌（LGSOC）是一种独特的卵巢癌形式，其特征是患者年龄较轻和相对耐药。GOG281/LOGS试验（NCT02101788）研究了MEK抑制剂曲美替尼（trametinib）与医生选择的标准护理（SOC）在持续/复发性LGSOC患者中的疗效。该研究显示，曲美替尼治疗组的无进展生存期（PFS）显著改善。实验设计：260例复发/持续性LGSOC患者入组并随机分为GOG281组。我们对170例患者的肿瘤标本进行了分子分析，包括全外显子组测序和磷酸化erk免疫组织化学，以确定曲美替尼临床获益的生物标志物。翻译队列（n=170）的人口统计学数据与总试验队列相当。结果：高肿瘤pERK表达（高于中位组织评分140）与曲美替尼治疗与SOC相比显著延长PFS相关（中位20.1 vs 5.6个月，log-rank P<0.0001；相互作用检验P=0.023）。具有典型RAS-RAF-MAPK突变的肿瘤（KRAS/BRAF/NRAS: 44/134, 32.8%的病例）对曲美替尼有更高的应答率（50.0% vs 8.3%; Barnard’s P=0.0004；相互作用检验P=0.054），但KRAS/BRAF/NRAS状态不能预测PFS延长（相互作用检验P=0.719）。KRAS扩增（n=5，无KRAS/NRAS/BRAF突变）和MAPK相关基因突变（n=25，无KRAS/NRAS/BRAF突变或KRAS拷贝数增加）将可识别的MAPK缺陷病例数量扩大到55.2%，但考虑这些事件并没有提高对曲美替尼应答者的区分。Chr1p缺失（49%）与较低的pERK表达相关（P=0.021）。结论：该探索性分析提示pERK表达和KRAS/BRAF/NRAS突变分别是PFS改善和曲美替尼应答的候选生物标志物。
{"title":"Molecular profiling and tumour biomarker analysis of GOG281/LOGS: a positive late-phase trial of trametinib for recurrent/persistent low grade-serous ovarian cancer","authors":"Robert L. Hollis, Austin Miller, Heather A. Lankes, Kwong-Kwok Wong, William Rodgers, David Millan, Karen Carty, Robert L. Coleman, Kathleen N. Moore, Angeles Alvarez Secord, David M. O'Malley, John K. Chan, Andrea R. Hagemann, Stephanie Gaillard, Saketh R. Guntupalli, Mitchell Edelson, Peter G. Rose, Oliver Dorigo, Susana Banerjee, Ailith Ewing, Michael Churchman, Anil K. Sood, C. Simon. Herrington, Charlie Gourley, David M. Gershenson","doi":"10.1158/1078-0432.ccr-25-3042","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3042","url":null,"abstract":"Purpose:Low-grade serous ovarian carcinoma(LGSOC) is a distinct form of ovarian cancer characterised by younger patient age and relative chemoresistance. The GOG281/LOGS trial(NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared to physician’s choice standard of care(SOC) in LGSOC patients with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival(PFS) in the trametinib-treated arm. Experimental Design:260 patients with recurrent/persistent LGSOC were enrolled and randomised in GOG281. We performed molecular analysis of 170 patients with available tumour specimens, comprising whole exome sequencing and phospho-ERK immunohistochemistry, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort(n=170) were comparable to the total trial cohort. Results:High tumour pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs 5.6 months, log-rank P&lt;0.0001; test for interaction P=0.023). Tumours harbouring canonical RAS-RAF-MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs 8.3%; Barnard's P=0.0004; test for interaction P=0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P=0.719). KRAS amplification (n=5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n=25 without KRAS/NRAS/BRAF mutation or KRAS copy-number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss(49% cases) was associated with lower pERK expression(P=0.021). Conclusion:This exploratory analysis suggests pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"365 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717269","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 : 2025-12-11DOI: 10.1158/1078-0432.ccr-25-2900
Manmeet S. Ahluwalia, Sophie Solomon, Sandip P. Patel, Zouina Sarfraz, Megan Othus, Young K. Chae, Razelle Kurzrock
Purpose: To evaluate the efficacy and safety of dual immune checkpoint inhibitors (ICI) in patients with brain metastases (BM) from rare cancers. Patients and Methods: Patients with and without BM received nivolumab (240 mg every two weeks) and ipilimumab (1 mg/kg every six weeks) (NCI/SWOG S1609 DART trial, NCT02834013) across >1,000 sites. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method; hazard ratios (HR) with 95% confidence intervals (CI) were derived from Cox models. Systemic ORR was assessed by RECIST v1.1, and adverse events were graded using CTCAE v5.0. Intracranial outcomes were assessed in a subset of patients with BM to evaluate best intracranial response. Results: Among 727 patients, the systemic ORR was 11.5% in those without BM (n=707) and 10% in those with BM (n=20) (p=0.76). PFS and OS were similar between groups (PFS: HR=1.29, 95% CI 0.81-2.07, p=0.28; OS: HR=1.36, 95% CI 0.81-2.27, p=0.24). Intracranial response was evaluable in 12 patients with BM (60%). No intracranial complete or partial responses were observed, and six patients (50%) achieved intracranial stable disease as their best intracranial response. Grade ≥3 CNS toxicities occurred in 3% of patients without BM and 5% of those with BM (p=0.43). Conclusions: Dual-ICI therapy showed comparable efficacy and safety in patients with and without BM.
{"title":"Efficacy and CNS Toxicity of Nivolumab and Ipilimumab in Rare Cancer Brain Metastases: A Multi-Center Basket Trial Analysis (NCI/SWOG S1609)","authors":"Manmeet S. Ahluwalia, Sophie Solomon, Sandip P. Patel, Zouina Sarfraz, Megan Othus, Young K. Chae, Razelle Kurzrock","doi":"10.1158/1078-0432.ccr-25-2900","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2900","url":null,"abstract":"Purpose: To evaluate the efficacy and safety of dual immune checkpoint inhibitors (ICI) in patients with brain metastases (BM) from rare cancers. Patients and Methods: Patients with and without BM received nivolumab (240 mg every two weeks) and ipilimumab (1 mg/kg every six weeks) (NCI/SWOG S1609 DART trial, NCT02834013) across &gt;1,000 sites. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method; hazard ratios (HR) with 95% confidence intervals (CI) were derived from Cox models. Systemic ORR was assessed by RECIST v1.1, and adverse events were graded using CTCAE v5.0. Intracranial outcomes were assessed in a subset of patients with BM to evaluate best intracranial response. Results: Among 727 patients, the systemic ORR was 11.5% in those without BM (n=707) and 10% in those with BM (n=20) (p=0.76). PFS and OS were similar between groups (PFS: HR=1.29, 95% CI 0.81-2.07, p=0.28; OS: HR=1.36, 95% CI 0.81-2.27, p=0.24). Intracranial response was evaluable in 12 patients with BM (60%). No intracranial complete or partial responses were observed, and six patients (50%) achieved intracranial stable disease as their best intracranial response. Grade ≥3 CNS toxicities occurred in 3% of patients without BM and 5% of those with BM (p=0.43). Conclusions: Dual-ICI therapy showed comparable efficacy and safety in patients with and without BM.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"38 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717270","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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