Pub Date : 2026-01-15DOI: 10.1158/1078-0432.ccr-25-4382
Sarah Waliany, Alissa J. Cooper, Stephen V. Liu, Oliver Gautschi, Julia K. Rotow, Katherine Emilie Rhoades. Smith, Urs M. Weber, Dae Ho Lee, Herbert H. F. Loong, Jyoti D. Patel, Nathan A. Pennell, Misako Nagasaka, Shetal A. Patel, Daniel S. W. Tan, Benjamin J. Solomon, Tae Min Kim, Georg Pall, Jonathan W. Riess, Lova Sun, Martin Früh, Natalie F. Uy, Shirish Gadgeel, Jamie Feng, Andrew Do, Christina Falcon, Natasha B. Leighl, Christina S. Baik, Gillianne G. Y. Lai, S. Ignatius. Ou, Kingsley S. Y. Cheung, Tejas Patil, Aaron S. Mansfield, Daniela Weiler, Beow Y. Yeap, Lori J. Wirth, Justin F. Gainor, Alexander Drilon, Jessica J. Lin
Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRIs) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRIs. Experimental Design: We established 'RETgistry,' a global consortium of patients with advanced RET-altered solid tumors who received SRIs and underwent post-progression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with Kaplan-Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung: n=94; thyroid: n=15) who underwent 143 post-SRI progression biopsies (tissue: 91; plasma: 52). Median PFS and TTD were 13.9 months (95% confidence interval [CI] 10.1-16.6) and 17.3 months (95% CI 14.0-20.2), respectively. Secondary RET mutations were detected in 20 (14.0%) biopsies (lung cancer: 15 [12.4%], thyroid carcinoma: 5 [22.7%]). Common acquired off-target alterations involved MET (18.2%; amplification: 15.0%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort: 17.6% vs 2.0%, p=0.022; lung cancer: 19.1% vs 2.1%, p=0.022). Conclusions: Prevalence of secondary RET mutations after SRIs was low, underscoring greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide development of novel therapeutic strategies.
目的:转染过程中的重排(RET)改变是实体肿瘤的致癌驱动因素。选择性RET抑制剂(SRIs) selpercatinib和pralsetinib已经改变了RET改变恶性肿瘤患者的预后。对SRIs耐药的基因组机制了解有限。实验设计:我们建立了“registry”,这是一个全球性的晚期ret改变实体瘤患者联盟,这些患者接受了SRIs,并通过下一代测序进行了进展后组织或血浆活检。确定继发性RET耐药突变和获得性非RET基因改变的频率。用Kaplan-Meier法估计首次SRI的无进展生存期(PFS)和停药时间(TTD)。结果:登记包括109例ret改变的晚期实体瘤患者(肺:n=94;甲状腺:n=15),他们接受了143次sri后进展活检(组织:91;血浆:52)。中位PFS和TTD分别为13.9个月(95%可信区间[CI] 10.1-16.6)和17.3个月(95% CI 14.0-20.2)。20例(14.0%)活检检出继发性RET突变(肺癌15例(12.4%),甲状腺癌5例(22.7%))。常见的获得性脱靶改变包括MET(18.2%;扩增:15.0%)、TP53(8.2%)、APC(7.6%)、KRAS(7.1%)、KEAP1(5.9%)和CDKN2A/B(5.3%)。在sri后与前标本中,MET改变丰富(全队列:17.6% vs 2.0%, p=0.022;肺癌:19.1% vs 2.1%, p=0.022)。结论:SRIs后继发性RET突变的发生率较低,强调脱靶耐药的作用更大。发现了涉及肿瘤抑制基因或MAPK和PI3K途径上游调控因子的复发性获得性改变,最常见的是MET扩增。继续努力表征SRI耐药生物学对指导新治疗策略的发展至关重要。
{"title":"Landscape of Genomic Mechanisms of Resistance to Selective RET Inhibitors in RET -Altered Solid Tumors: Analysis of the RETgistry Global Consortium","authors":"Sarah Waliany, Alissa J. Cooper, Stephen V. Liu, Oliver Gautschi, Julia K. Rotow, Katherine Emilie Rhoades. Smith, Urs M. Weber, Dae Ho Lee, Herbert H. F. Loong, Jyoti D. Patel, Nathan A. Pennell, Misako Nagasaka, Shetal A. Patel, Daniel S. W. Tan, Benjamin J. Solomon, Tae Min Kim, Georg Pall, Jonathan W. Riess, Lova Sun, Martin Früh, Natalie F. Uy, Shirish Gadgeel, Jamie Feng, Andrew Do, Christina Falcon, Natasha B. Leighl, Christina S. Baik, Gillianne G. Y. Lai, S. Ignatius. Ou, Kingsley S. Y. Cheung, Tejas Patil, Aaron S. Mansfield, Daniela Weiler, Beow Y. Yeap, Lori J. Wirth, Justin F. Gainor, Alexander Drilon, Jessica J. Lin","doi":"10.1158/1078-0432.ccr-25-4382","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4382","url":null,"abstract":"Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRIs) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRIs. Experimental Design: We established 'RETgistry,' a global consortium of patients with advanced RET-altered solid tumors who received SRIs and underwent post-progression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with Kaplan-Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung: n=94; thyroid: n=15) who underwent 143 post-SRI progression biopsies (tissue: 91; plasma: 52). Median PFS and TTD were 13.9 months (95% confidence interval [CI] 10.1-16.6) and 17.3 months (95% CI 14.0-20.2), respectively. Secondary RET mutations were detected in 20 (14.0%) biopsies (lung cancer: 15 [12.4%], thyroid carcinoma: 5 [22.7%]). Common acquired off-target alterations involved MET (18.2%; amplification: 15.0%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort: 17.6% vs 2.0%, p=0.022; lung cancer: 19.1% vs 2.1%, p=0.022). Conclusions: Prevalence of secondary RET mutations after SRIs was low, underscoring greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide development of novel therapeutic strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"219 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1158/1078-0432.ccr-25-2958
Mariano Provencio, Roberto Serna-Blasco, Ernest Nadal, José Luis González Larriba, Alex Martinez-Marti, Reyes Bernabé Caro, Joaquim Bosch-Barrera, Virginia Calvo, Amelia Insa Molla, Noemí Reguart, Javier de Castro Carpeño, Carlos Aguado de la Rosa, Ramon Palmero Sanchez, Florentino Hernando Trancho, Javier Martín-López, Alejandro Rodríguez-Festa, Pilar Mediavilla-Medel, Martín Lázaro, Jim Hayes, Alberto Cruz-Bermúdez, Bartomeu Massutí, Atocha Romero
Purpose: Perioperative chemoimmunotherapy is the standard of care for resectable, locally advanced non-small cell lung cancer (NSCLC). While pathological complete response (pCR) correlates with excellent survival outcomes, some patients without pCR still exhibit long-term survival. Here we evaluate the added value of minimal residual disease (MRD). Experimental Design: MRD was assessed in 60 patients from the NADIM II trial (NCT03838159) using Guardant Reveal assay. In NADIM II, NSCLC patients without EGFR or ALK alterations were randomized to receive neoadjuvant nivolumab plus chemotherapy (experimental arm) or chemotherapy alone, followed by surgery. Patients in the experimental arm with R0 resection received adjuvant nivolumab. Results: MRD detection rate was 9.6%. MRD after surgery or during adjuvant treatment was associated with inferior EFS and OS (HR: 10.2; 95%CI: 3.7-28.3 and HR: 10.0; 95%CI: 2.0-49.9, respectively). All patients with MRD-negative plasma samples in at least two time points were alive (HR: not estimable [NE], p < 0.001), with only one relapse (HR: 41.6; 95%CI: 5.0–348.8), corresponding to a patient relapsing with a single brain metastasis. MRD enhanced the prognostic value of pCR for both EFS (p<0.001) and OS (p=0.015). Among non-pCR patients, MRD remained a significant prognostic marker (HR: 6.2; 95%CI: 2.2-17.1 and HR: 6.5; 95%CI: 1.3-32.5, for EFS and OS respectively). All non-pCR patients with MRD-negative results in at least two time points were alive (HR: NE, p=0.025), with one relapse (HR: 19.9; 95%CI: 2.4–165.6), corresponding to the aforementioned case. Conclusions: MRD may refine prognostic evaluation beyond pCR in resectable NSCLC undergoing perioperative chemoimmunotherapy.
{"title":"Minimal Residual Disease Enhances Prognostic Stratification Beyond Pathological Response in Resectable Non-Small Cell Lung Cancer","authors":"Mariano Provencio, Roberto Serna-Blasco, Ernest Nadal, José Luis González Larriba, Alex Martinez-Marti, Reyes Bernabé Caro, Joaquim Bosch-Barrera, Virginia Calvo, Amelia Insa Molla, Noemí Reguart, Javier de Castro Carpeño, Carlos Aguado de la Rosa, Ramon Palmero Sanchez, Florentino Hernando Trancho, Javier Martín-López, Alejandro Rodríguez-Festa, Pilar Mediavilla-Medel, Martín Lázaro, Jim Hayes, Alberto Cruz-Bermúdez, Bartomeu Massutí, Atocha Romero","doi":"10.1158/1078-0432.ccr-25-2958","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2958","url":null,"abstract":"Purpose: Perioperative chemoimmunotherapy is the standard of care for resectable, locally advanced non-small cell lung cancer (NSCLC). While pathological complete response (pCR) correlates with excellent survival outcomes, some patients without pCR still exhibit long-term survival. Here we evaluate the added value of minimal residual disease (MRD). Experimental Design: MRD was assessed in 60 patients from the NADIM II trial (NCT03838159) using Guardant Reveal assay. In NADIM II, NSCLC patients without EGFR or ALK alterations were randomized to receive neoadjuvant nivolumab plus chemotherapy (experimental arm) or chemotherapy alone, followed by surgery. Patients in the experimental arm with R0 resection received adjuvant nivolumab. Results: MRD detection rate was 9.6%. MRD after surgery or during adjuvant treatment was associated with inferior EFS and OS (HR: 10.2; 95%CI: 3.7-28.3 and HR: 10.0; 95%CI: 2.0-49.9, respectively). All patients with MRD-negative plasma samples in at least two time points were alive (HR: not estimable [NE], p &lt; 0.001), with only one relapse (HR: 41.6; 95%CI: 5.0–348.8), corresponding to a patient relapsing with a single brain metastasis. MRD enhanced the prognostic value of pCR for both EFS (p&lt;0.001) and OS (p=0.015). Among non-pCR patients, MRD remained a significant prognostic marker (HR: 6.2; 95%CI: 2.2-17.1 and HR: 6.5; 95%CI: 1.3-32.5, for EFS and OS respectively). All non-pCR patients with MRD-negative results in at least two time points were alive (HR: NE, p=0.025), with one relapse (HR: 19.9; 95%CI: 2.4–165.6), corresponding to the aforementioned case. Conclusions: MRD may refine prognostic evaluation beyond pCR in resectable NSCLC undergoing perioperative chemoimmunotherapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"58 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1158/1078-0432.ccr-25-3189
Brinda Alagesan,Anna M Varghese,Celina Ang,Martin Gutierrez,Moshe Kamar,Maria Passhak,Ravit Geva,Nirit Yarom,Maor Lahav,Rosario Ligresti,Iyad Khamaysi,Manoop S Bhutani,Adam Phillips,Shay Matalon,Orit Pollack-Shragai,Dror Rom,Mitchell Shirvan,Milind M Javle,Wungki Park,Kenneth Yu,Carly Schwartz,Talia Golan,Mark Schattner,Eileen M O'Reilly
PURPOSELocally advanced pancreatic cancer (LAPC) accounts for 30% of pancreatic cancers. We assessed the efficacy and safety of a novel extended-release siRNA targeting KRAS G12D/V mutations (siG12D-LODER) combined with chemotherapy in LAPC.PATIENTS AND METHODSThis two-cohort, phase 2 multicenter, open-label study (NCT01676259) evaluated siG12D-LODER with chemotherapy in patients with LAPC, irrespective of KRAS status. In cohort 1, patients were randomized to siG12D-LODER plus gemcitabine/nab-paclitaxel (Arm 1) or gemcitabine/nab-paclitaxel alone (Arm 2). In cohort 2, patients with LAPC or borderline resectable disease received siG12D-LODER plus standard chemotherapy (modified FOLFIRINOX or gemcitabine/nab-paclitaxel) in a single-arm, non-randomized design. Primary endpoints were overall survival (OS) for cohort 1 and objective response rate (ORR) for cohort 2. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), OS (cohort 2), and ORR (cohort 1).RESULTSFifty-nine patients were enrolled across two cohorts. In cohort 1, median OS in the modified intent-to-treat (mITT) population unselected for KRAS status was 22.7 months for siG12D-LODER + gemcitabine/nab-paclitaxel versus 21.9 months for chemotherapy alone (p>0.05). Among patients with KRAS G12D/V mutations, OS was 22.7 vs 13.4 months (HR 0.59, 95% CI 0.18-1.96, p=0.36). In cohort 2, ORR was 31.6% (95% CI 0.13-0.57) in the mITT (unselected for KRAS); in the G12D/V subgroup, ORR was 57.1%, similar to 63.6% in cohort 1. TEAEs were mainly procedure-related, including grade 1/2 gastrointestinal events and higher infection rates in the intervention arm.CONCLUSIONSsiG12D-LODER plus chemotherapy is safe, tolerable, and warrants further investigation in KRAS G12D/V-mutant LAPC.
目的局部晚期胰腺癌(LAPC)占胰腺癌的30%。我们评估了一种靶向KRAS G12D/V突变的新型缓释siRNA (siG12D-LODER)联合化疗治疗LAPC的疗效和安全性。患者和方法:这项双队列、多中心、开放标签的2期研究(NCT01676259)评估了siG12D-LODER在LAPC患者化疗中的应用,无论KRAS状态如何。在队列1中,患者被随机分配到siG12D-LODER联合吉西他滨/nab-紫杉醇组(第1组)或单独使用吉西他滨/nab-紫杉醇组(第2组)。在队列2中,患有LAPC或边缘性可切除疾病的患者在单组非随机设计中接受siG12D-LODER加标准化疗(改良的FOLFIRINOX或吉西他滨/nab-紫杉醇)。主要终点是队列1的总生存期(OS)和队列2的客观缓解率(ORR)。次要终点包括无进展生存期(PFS)、反应持续时间(DoR)、OS(队列2)和ORR(队列1)。结果两组共入组59例患者。在队列1中,未选择KRAS状态的改良意向治疗(mITT)人群中,siG12D-LODER +吉西他滨/nab-紫杉醇组的中位OS为22.7个月,而单独化疗组为21.9个月(p < 0.05)。KRAS G12D/V突变患者的OS为22.7个月vs 13.4个月(HR 0.59, 95% CI 0.18-1.96, p=0.36)。在队列2中,mITT(未选择KRAS)的ORR为31.6% (95% CI 0.13-0.57);在G12D/V亚组中,ORR为57.1%,与队列1的63.6%相似。teae主要与手术相关,包括1/2级胃肠道事件和干预组较高的感染率。结论ssig12d - loder联合化疗在KRAS G12D/ v突变型LAPC中是安全、耐受的,值得进一步研究。
{"title":"A Phase 2 Trial of an Extended-release siRNA Implant Targeting KRAS G12D/V in Locally Advanced Pancreatic Cancer.","authors":"Brinda Alagesan,Anna M Varghese,Celina Ang,Martin Gutierrez,Moshe Kamar,Maria Passhak,Ravit Geva,Nirit Yarom,Maor Lahav,Rosario Ligresti,Iyad Khamaysi,Manoop S Bhutani,Adam Phillips,Shay Matalon,Orit Pollack-Shragai,Dror Rom,Mitchell Shirvan,Milind M Javle,Wungki Park,Kenneth Yu,Carly Schwartz,Talia Golan,Mark Schattner,Eileen M O'Reilly","doi":"10.1158/1078-0432.ccr-25-3189","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3189","url":null,"abstract":"PURPOSELocally advanced pancreatic cancer (LAPC) accounts for 30% of pancreatic cancers. We assessed the efficacy and safety of a novel extended-release siRNA targeting KRAS G12D/V mutations (siG12D-LODER) combined with chemotherapy in LAPC.PATIENTS AND METHODSThis two-cohort, phase 2 multicenter, open-label study (NCT01676259) evaluated siG12D-LODER with chemotherapy in patients with LAPC, irrespective of KRAS status. In cohort 1, patients were randomized to siG12D-LODER plus gemcitabine/nab-paclitaxel (Arm 1) or gemcitabine/nab-paclitaxel alone (Arm 2). In cohort 2, patients with LAPC or borderline resectable disease received siG12D-LODER plus standard chemotherapy (modified FOLFIRINOX or gemcitabine/nab-paclitaxel) in a single-arm, non-randomized design. Primary endpoints were overall survival (OS) for cohort 1 and objective response rate (ORR) for cohort 2. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), OS (cohort 2), and ORR (cohort 1).RESULTSFifty-nine patients were enrolled across two cohorts. In cohort 1, median OS in the modified intent-to-treat (mITT) population unselected for KRAS status was 22.7 months for siG12D-LODER + gemcitabine/nab-paclitaxel versus 21.9 months for chemotherapy alone (p>0.05). Among patients with KRAS G12D/V mutations, OS was 22.7 vs 13.4 months (HR 0.59, 95% CI 0.18-1.96, p=0.36). In cohort 2, ORR was 31.6% (95% CI 0.13-0.57) in the mITT (unselected for KRAS); in the G12D/V subgroup, ORR was 57.1%, similar to 63.6% in cohort 1. TEAEs were mainly procedure-related, including grade 1/2 gastrointestinal events and higher infection rates in the intervention arm.CONCLUSIONSsiG12D-LODER plus chemotherapy is safe, tolerable, and warrants further investigation in KRAS G12D/V-mutant LAPC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1158/1078-0432.ccr-25-1616
Allison L Brodsky,Amma Asare,Bryan Fellman,Kristin Anderson,Jun Yao,Sanghoon Lee,Hai Tran,Xun Xu,Jinsong Liu,Joseph Celestino,Richard A Hajek,Margaret B Morgan,Mohammad Mohammad,Pamela Soliman,Aaron Shafer,Anil K Sood,Diane Bodurka,Nicole D Fleming,Michaela Onstad Grinsfelder,Ljiljana Milojevic,Amir A Jazaeri,Gordon B Mills,Robert L Coleman,Shannon N Westin
PURPOSEPatients with recurrent endometrial or ovarian cancer have poor survival outcomes. We evaluated clinical efficacy and toxicity of copanlisib (a PI3K inhibitor) and niraparib in this patient population with translational insights.PATIENTS AND METHODSThis was a phase 1b trial. Copanlisib was administered IV on days 1, 8, and 15 of a 28-day cycle, and niraparib was given orally once daily. Four dose levels were explored over a dose-limiting toxicity (DLT) window of 28 days. The primary objective was to determine the recommended phase 2 dose (RP2D) of this combination. Secondary objectives included safety, objective response rate (ORR), and pharmacokinetics. Tumor biopsies were analyzed using Reverse Phase Protein Array (RPPA) to identify molecular correlates of response.RESULTSThirty patients were enrolled. A RP2D was not established due to DLTs, most commonly grade 3 maculopapular rash attributed to copanlisib. The ORR was 12.5% (95% CI: 2.8-33.6%). RPPA was performed on tumors from 8 patients. PI3K pathway activity did not correlate with PI3K mutational status. Nineteen proteins were differentially expressed between patients with stable disease and those with progressive disease; many were substrates of Akt (protein kinase B), implicating downstream PI3K signaling in response.CONCLUSIONSThe combination of copanlisib and niraparib demonstrated limited tolerability, and the objective response rate was modest. However, functional proteomic analyses identified candidate biomarkers-particularly Akt pathway substrates-which may inform future strategies to optimize PI3K and PARP inhibitor combinations.
{"title":"Combination Therapy with Copanlisib and Niraparib in Patients with Recurrent Endometrial and Ovarian Cancer (COPANIRA): Efficacy, Toxicity, and Translational Insights.","authors":"Allison L Brodsky,Amma Asare,Bryan Fellman,Kristin Anderson,Jun Yao,Sanghoon Lee,Hai Tran,Xun Xu,Jinsong Liu,Joseph Celestino,Richard A Hajek,Margaret B Morgan,Mohammad Mohammad,Pamela Soliman,Aaron Shafer,Anil K Sood,Diane Bodurka,Nicole D Fleming,Michaela Onstad Grinsfelder,Ljiljana Milojevic,Amir A Jazaeri,Gordon B Mills,Robert L Coleman,Shannon N Westin","doi":"10.1158/1078-0432.ccr-25-1616","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1616","url":null,"abstract":"PURPOSEPatients with recurrent endometrial or ovarian cancer have poor survival outcomes. We evaluated clinical efficacy and toxicity of copanlisib (a PI3K inhibitor) and niraparib in this patient population with translational insights.PATIENTS AND METHODSThis was a phase 1b trial. Copanlisib was administered IV on days 1, 8, and 15 of a 28-day cycle, and niraparib was given orally once daily. Four dose levels were explored over a dose-limiting toxicity (DLT) window of 28 days. The primary objective was to determine the recommended phase 2 dose (RP2D) of this combination. Secondary objectives included safety, objective response rate (ORR), and pharmacokinetics. Tumor biopsies were analyzed using Reverse Phase Protein Array (RPPA) to identify molecular correlates of response.RESULTSThirty patients were enrolled. A RP2D was not established due to DLTs, most commonly grade 3 maculopapular rash attributed to copanlisib. The ORR was 12.5% (95% CI: 2.8-33.6%). RPPA was performed on tumors from 8 patients. PI3K pathway activity did not correlate with PI3K mutational status. Nineteen proteins were differentially expressed between patients with stable disease and those with progressive disease; many were substrates of Akt (protein kinase B), implicating downstream PI3K signaling in response.CONCLUSIONSThe combination of copanlisib and niraparib demonstrated limited tolerability, and the objective response rate was modest. However, functional proteomic analyses identified candidate biomarkers-particularly Akt pathway substrates-which may inform future strategies to optimize PI3K and PARP inhibitor combinations.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"52 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961402","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}
PURPOSEImmune Checkpoint Blockers (ICB) have revolutionized oncology by achieving durable tumor responses in advanced cancers. Nevertheless, currently approved biomarkers (PD-L1, MSI, TMB) have suboptimal positive and negative predictive values for tumor response and survival.EXPERIMENTAL DESIGNWe aimed to assess the value of RNA sequencing from whole blood to predict responses to ICB. We performed total paired-end RNA sequencing at 20 million reads and analyzed differential gene expression, signaling pathway activation, and immune cell abundances according to cancer outcomes. The analysis was conducted on baseline frozen whole blood samples from 164 patients prospectively enrolled in the IOPREDI study.RESULTSWe found that some immune-related genes and signaling pathways were highly expressed in patients who achieved a durable clinical benefit. Furthermore, analyses of both progression-free survival (PFS) and overall survival (OS) confirmed significantly higher expression levels of immune-related signaling pathways in long-term survivors. Gene expression signatures capable of classifying patients based on clinical response or PFS were also identified. Interestingly, deconvolution analysis revealed a significant higher abundance of resting NK cells in patients with prolonged PFS or OS, in contrast to other cytotoxic cell types. Finally, high expression of the CST7 gene and increased abundance of naïve B lymphocytes were associated with immune-related adverse events (irAEs).CONCLUSIONSTotal RNA sequencing from whole blood provides high-quality data to predict clinical response, survival, and occurrence of irAEs. The use of this type of samples prior to immune checkpoint blockage could improve treatment efficacy and irAEs management.
{"title":"Circulating transcriptome analysis finds gene signatures and immune cell activation and abundance predict response to immunotherapy in bladder cancer.","authors":"Sandy Chevrier,Corentin Richard,Olivier Adotévi,Maha Ayyoub,Nathalie Chaput,Diane Damotte,François Ghiringhelli,Salima Hacein-Bey-Abina,Eric Tartour,Laurence Zitvogel,Aurélien Marabelle,Romain Boidot","doi":"10.1158/1078-0432.ccr-25-2306","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2306","url":null,"abstract":"PURPOSEImmune Checkpoint Blockers (ICB) have revolutionized oncology by achieving durable tumor responses in advanced cancers. Nevertheless, currently approved biomarkers (PD-L1, MSI, TMB) have suboptimal positive and negative predictive values for tumor response and survival.EXPERIMENTAL DESIGNWe aimed to assess the value of RNA sequencing from whole blood to predict responses to ICB. We performed total paired-end RNA sequencing at 20 million reads and analyzed differential gene expression, signaling pathway activation, and immune cell abundances according to cancer outcomes. The analysis was conducted on baseline frozen whole blood samples from 164 patients prospectively enrolled in the IOPREDI study.RESULTSWe found that some immune-related genes and signaling pathways were highly expressed in patients who achieved a durable clinical benefit. Furthermore, analyses of both progression-free survival (PFS) and overall survival (OS) confirmed significantly higher expression levels of immune-related signaling pathways in long-term survivors. Gene expression signatures capable of classifying patients based on clinical response or PFS were also identified. Interestingly, deconvolution analysis revealed a significant higher abundance of resting NK cells in patients with prolonged PFS or OS, in contrast to other cytotoxic cell types. Finally, high expression of the CST7 gene and increased abundance of naïve B lymphocytes were associated with immune-related adverse events (irAEs).CONCLUSIONSTotal RNA sequencing from whole blood provides high-quality data to predict clinical response, survival, and occurrence of irAEs. The use of this type of samples prior to immune checkpoint blockage could improve treatment efficacy and irAEs management.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"35 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1158/1078-0432.ccr-25-4251
Christine M Parseghian,Madhulika Eluri
Colorectal cancers treated with targeted therapies frequently acquire numerous subclonal genomic alterations. Tumor mutation burden (TMB) is under investigation as a biomarker for predicting response to immunotherapy in microsatellite-stable metastatic colorectal cancer. Here, we contextualize a recent study evaluating high plasma TMB post-targeted therapy and its implications for immunotherapy.
{"title":"Beyond the Burden: Elevating Immunotherapy in Colorectal Cancer.","authors":"Christine M Parseghian,Madhulika Eluri","doi":"10.1158/1078-0432.ccr-25-4251","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4251","url":null,"abstract":"Colorectal cancers treated with targeted therapies frequently acquire numerous subclonal genomic alterations. Tumor mutation burden (TMB) is under investigation as a biomarker for predicting response to immunotherapy in microsatellite-stable metastatic colorectal cancer. Here, we contextualize a recent study evaluating high plasma TMB post-targeted therapy and its implications for immunotherapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"29 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1158/1078-0432.ccr-25-2871
Emre Yekedüz,Weiwei Bian,Stephanie E Siegmund,Marc Machaalani,Jad El Masri,Mustafa Saleh,Eddy Saad,Liliana Ascione,Razane El Hajj Chehade,Clara Steiner,Pablo Moura Barrios,Stephanie A Berg,Bradley McGregor,Charlene Mantia,Praful Ravi,Wenxin Xu,Michelle S Hirsch,Toni K Choueiri,Michael Serzan
PURPOSEIn renal cell carcinoma (RCC), loss of the NF2 tumor suppressor gene encoding the merlin protein is associated with aggressive clinical behavior. However, data regarding the clinical course and additional molecular features in the context of contemporary systemic therapies remains limited.METHODSClinical outcomes were evaluated in patients with RCC exhibiting merlin loss by immunohistochemistry in one academic cohort. Integrative genomic analyses were performed, including targeted DNA sequencing via the institutional OncoPanel assay and RNA sequencing data from The Cancer Genome Atlas (TCGA).RESULTSIn the institutional cohort (n=33), most patients had biphasic hyalinizing psammomatous RCC (66.6%) and metastatic disease (78.8%). Among 23 patients receiving systemic therapy, those treated with non-immunotherapy (IO)-based regimens (n=5) had numerically longer overall survival (24.5 vs 16.5 months, p=0.2) and progression-free survival (9.8 vs 5 months, p=0.5) compared to IO-based therapies (n=18), though differences were not statistically significant. Genomic analysis (n=17) revealed frequent truncating mutations of NF2 (82.3%) and recurrent alterations in chromatin remodeling and DNA damage-response signaling genes with prominent deletions in tumor suppressor genes such as CDKN2A/B. Transcriptomic profiling of NF2-inactivated tumors from TCGA (n=13) demonstrated enrichment of cellular proliferation and concurrent suppression of metabolic and immune pathways, suggesting an aggressive phenotype compared to clear cell RCC without NF2 inactivation (n=529).CONCLUSIONSBiallelic NF2 inactivation and merlin protein deficiency drives an aggressive RCC phenotype marked by immune dysfunction, high proliferation, and frequent cell cycle and DNA damage-response signaling alterations. Limited treatment response to immunotherapy highlights the need for molecularly tailored therapies.
目的:在肾细胞癌(RCC)中,编码merlin蛋白的NF2肿瘤抑制基因的缺失与侵袭性临床行为有关。然而,关于临床过程和其他分子特征的数据在当代全身治疗的背景下仍然有限。方法采用免疫组化方法对一个学术队列中表现为梅林丢失的肾细胞癌患者的临床结果进行评估。进行了综合基因组分析,包括通过机构OncoPanel测定的靶向DNA测序和来自癌症基因组图谱(TCGA)的RNA测序数据。结果在机构队列中(33例),大多数患者患有双期透明性沙质癌(66.6%)和转移性疾病(78.8%)。在接受全身治疗的23例患者中,与基于免疫治疗的治疗(n=18)相比,接受非免疫治疗(IO)方案治疗的患者(n=5)的总生存期(24.5 vs 16.5个月,p=0.2)和无进展生存期(9.8 vs 5个月,p=0.5)更长,但差异无统计学意义。基因组分析(n=17)显示NF2频繁截断突变(82.3%),染色质重塑和DNA损伤反应信号基因复发性改变,肿瘤抑制基因如CDKN2A/B显著缺失。来自TCGA的NF2失活肿瘤的转录组学分析(n=13)显示细胞增殖富集,代谢和免疫途径同时受到抑制,表明与未NF2失活的透明细胞RCC相比,其表型具有侵袭性(n=529)。结论双等位基因NF2失活和merlin蛋白缺乏驱动侵袭性RCC表型,其特征是免疫功能障碍、高增殖、频繁的细胞周期和DNA损伤反应信号改变。有限的治疗反应免疫疗法突出需要分子定制治疗。
{"title":"Integrative Clinical and Molecular Evaluation of Renal Cell Carcinoma with Merlin Protein Deficiency and Biallelic Loss of NF2.","authors":"Emre Yekedüz,Weiwei Bian,Stephanie E Siegmund,Marc Machaalani,Jad El Masri,Mustafa Saleh,Eddy Saad,Liliana Ascione,Razane El Hajj Chehade,Clara Steiner,Pablo Moura Barrios,Stephanie A Berg,Bradley McGregor,Charlene Mantia,Praful Ravi,Wenxin Xu,Michelle S Hirsch,Toni K Choueiri,Michael Serzan","doi":"10.1158/1078-0432.ccr-25-2871","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2871","url":null,"abstract":"PURPOSEIn renal cell carcinoma (RCC), loss of the NF2 tumor suppressor gene encoding the merlin protein is associated with aggressive clinical behavior. However, data regarding the clinical course and additional molecular features in the context of contemporary systemic therapies remains limited.METHODSClinical outcomes were evaluated in patients with RCC exhibiting merlin loss by immunohistochemistry in one academic cohort. Integrative genomic analyses were performed, including targeted DNA sequencing via the institutional OncoPanel assay and RNA sequencing data from The Cancer Genome Atlas (TCGA).RESULTSIn the institutional cohort (n=33), most patients had biphasic hyalinizing psammomatous RCC (66.6%) and metastatic disease (78.8%). Among 23 patients receiving systemic therapy, those treated with non-immunotherapy (IO)-based regimens (n=5) had numerically longer overall survival (24.5 vs 16.5 months, p=0.2) and progression-free survival (9.8 vs 5 months, p=0.5) compared to IO-based therapies (n=18), though differences were not statistically significant. Genomic analysis (n=17) revealed frequent truncating mutations of NF2 (82.3%) and recurrent alterations in chromatin remodeling and DNA damage-response signaling genes with prominent deletions in tumor suppressor genes such as CDKN2A/B. Transcriptomic profiling of NF2-inactivated tumors from TCGA (n=13) demonstrated enrichment of cellular proliferation and concurrent suppression of metabolic and immune pathways, suggesting an aggressive phenotype compared to clear cell RCC without NF2 inactivation (n=529).CONCLUSIONSBiallelic NF2 inactivation and merlin protein deficiency drives an aggressive RCC phenotype marked by immune dysfunction, high proliferation, and frequent cell cycle and DNA damage-response signaling alterations. Limited treatment response to immunotherapy highlights the need for molecularly tailored therapies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"39 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1158/1078-0432.CCR-25-2406
Janus S Jakobsen, Michael M Grandal, Randi W Hansen, Harsh Bansia, Emily Armbruster, Isabelle Theret, Niels Jørgen Ø Skartved, Rikke Hald, Maria C Melander, Anne Worsaae, Matteo Riva, Kristian Reckzeh, Laurent Vuillard, Johan Lantto, Amedee des Georges, Camilla Fröhlich
Purpose: Adenosine signaling may be a central immune suppressive mechanism in several cancers, and blockade of the rate-limiting CD73 AMP-to-adenosine enzyme has been demonstrated to improve clinical efficacy of PD(L)-1 immune therapy. However, deep inhibition of CD73 activity could prove difficult in tumor environments with a constant AMP supply and high CD73 levels. Here, we sought to identify, characterize, and benchmark a novel antagonistic anti-CD73 antibody, Sym024 (S95024), and to structurally decode its mode of action.
Experimental design: Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic activity, and T cell activation assays. Its in vivo tumor growth inhibition was examined in transplanted human or mouse tumors in immunocompetent or immunodeficient mice, and intra-tumoral enzymatic inhibition and immune cell recruitment were assessed. We investigated Sym024-CD73 interaction using surface plasmon resonance, cryo-electron microscopy, site-directed mutagenesis, and population level complex formation through size-exclusion-chromatography with light scatter mass detection. Preclinical safety and pharmacokinetics were assessed in monkeys.
Results: Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably to benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro as well as in vivo. Our structural data indicate that a unique one-to-one Sym024-CD73 interaction engenders this comprehensive inhibition. No pre-clinical safety flags were observed, and the pharmacokinetics profile of Sym024 supported a standard clinical dosing regimen.
Conclusions: The comprehensive CD73 inhibition exhibited by Sym024 may improve the efficacy of anti-PD(L)-1/anti-CD73 combination treatment.
{"title":"Sym024 interacts with a unique epitope on the CD73 homodimer, favoring effective bivalent binding to improve anti-PD1 therapy.","authors":"Janus S Jakobsen, Michael M Grandal, Randi W Hansen, Harsh Bansia, Emily Armbruster, Isabelle Theret, Niels Jørgen Ø Skartved, Rikke Hald, Maria C Melander, Anne Worsaae, Matteo Riva, Kristian Reckzeh, Laurent Vuillard, Johan Lantto, Amedee des Georges, Camilla Fröhlich","doi":"10.1158/1078-0432.CCR-25-2406","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-2406","url":null,"abstract":"<p><strong>Purpose: </strong>Adenosine signaling may be a central immune suppressive mechanism in several cancers, and blockade of the rate-limiting CD73 AMP-to-adenosine enzyme has been demonstrated to improve clinical efficacy of PD(L)-1 immune therapy. However, deep inhibition of CD73 activity could prove difficult in tumor environments with a constant AMP supply and high CD73 levels. Here, we sought to identify, characterize, and benchmark a novel antagonistic anti-CD73 antibody, Sym024 (S95024), and to structurally decode its mode of action.</p><p><strong>Experimental design: </strong>Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic activity, and T cell activation assays. Its in vivo tumor growth inhibition was examined in transplanted human or mouse tumors in immunocompetent or immunodeficient mice, and intra-tumoral enzymatic inhibition and immune cell recruitment were assessed. We investigated Sym024-CD73 interaction using surface plasmon resonance, cryo-electron microscopy, site-directed mutagenesis, and population level complex formation through size-exclusion-chromatography with light scatter mass detection. Preclinical safety and pharmacokinetics were assessed in monkeys.</p><p><strong>Results: </strong>Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably to benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro as well as in vivo. Our structural data indicate that a unique one-to-one Sym024-CD73 interaction engenders this comprehensive inhibition. No pre-clinical safety flags were observed, and the pharmacokinetics profile of Sym024 supported a standard clinical dosing regimen.</p><p><strong>Conclusions: </strong>The comprehensive CD73 inhibition exhibited by Sym024 may improve the efficacy of anti-PD(L)-1/anti-CD73 combination treatment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1158/1078-0432.CCR-25-3336
David M Thomas, Jeong Eun Kim, Fabrice Barlesi, Uwe M Martens, Maciej Krzakowski, Rafal Dziadziuszko, Jae Ho Jeong, Gennaro Daniele, Timothy R Wilson, Felice Wu, Brian P Simmons, Sid Patel, Maria Sbirnac, Monika Kaul, Shirish M Gadgeel
Purpose: Patients with tumor mutational burden (TMB)-high tumors can derive benefit from atezolizumab, though previous studies have used inconsistent TMB cutoffs. We report data for atezolizumab in patients with TMB-high solid tumors from the phase II, TAPISTRY multicohort trial, using TMB cutoffs of ≥13 and ≥16 mutations/megabase (mut/Mb).
Methods: Patients with PD-L1 inhibitor-naïve,TMB-high (≥13 mut/Mb) advanced/metastatic solid tumors received atezolizumab every 21 days (1200 mg adults, 15 mg/kg [up to 1200 mg/kg] children).
Primary endpoint: independent review committee (IRC)-assessed objective response rate (ORR) for TMB ≥16 mut/Mb. Secondary endpoints (using TMB ≥13 mut/Mb) included IRC-assessed ORR, duration of response (DOR), progression-free survival (PFS), and safety.
Results: As of November 9, 2023 (median survival follow-up: 9.8 months), 148 patients received treatment. Median age was 63 years, 31.8% of patients had >2 prior therapy lines, and the most common tumor types were colorectal (29.1%), breast (8.8%), and gastroesophageal (8.8%). IRC-assessed ORR was 22.3% (95% CI, 15.0-31.2) with TMB ≥16 mut/Mb (n=112), and 20.2% (95% CI, 13.6-28.1) with TMB ≥13 mut/Mb (n=129). Median IRC-assessed DOR was not estimable. Median IRC-assessed PFS was 2.8 (95% CI, 1.7-5.4) and 2.7 (95% CI, 1.5-4.2) months using TMB ≥16 and ≥13 mut/Mb, respectively. Adverse events (AEs) were reported in 93.2% of patients, of which 53.4% were treatment-related (no grade 5) and 40.5% were grade ≥3.
Conclusion: Atezolizumab led to moderate antitumor activity in various TMB-high solid tumors. Safety was consistent with previous reports.
{"title":"TAPISTRY: A Phase II Study of Atezolizumab in Patients with Tumor Mutational Burden-High Tumors.","authors":"David M Thomas, Jeong Eun Kim, Fabrice Barlesi, Uwe M Martens, Maciej Krzakowski, Rafal Dziadziuszko, Jae Ho Jeong, Gennaro Daniele, Timothy R Wilson, Felice Wu, Brian P Simmons, Sid Patel, Maria Sbirnac, Monika Kaul, Shirish M Gadgeel","doi":"10.1158/1078-0432.CCR-25-3336","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-3336","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with tumor mutational burden (TMB)-high tumors can derive benefit from atezolizumab, though previous studies have used inconsistent TMB cutoffs. We report data for atezolizumab in patients with TMB-high solid tumors from the phase II, TAPISTRY multicohort trial, using TMB cutoffs of ≥13 and ≥16 mutations/megabase (mut/Mb).</p><p><strong>Methods: </strong>Patients with PD-L1 inhibitor-naïve,TMB-high (≥13 mut/Mb) advanced/metastatic solid tumors received atezolizumab every 21 days (1200 mg adults, 15 mg/kg [up to 1200 mg/kg] children).</p><p><strong>Primary endpoint: </strong>independent review committee (IRC)-assessed objective response rate (ORR) for TMB ≥16 mut/Mb. Secondary endpoints (using TMB ≥13 mut/Mb) included IRC-assessed ORR, duration of response (DOR), progression-free survival (PFS), and safety.</p><p><strong>Results: </strong>As of November 9, 2023 (median survival follow-up: 9.8 months), 148 patients received treatment. Median age was 63 years, 31.8% of patients had >2 prior therapy lines, and the most common tumor types were colorectal (29.1%), breast (8.8%), and gastroesophageal (8.8%). IRC-assessed ORR was 22.3% (95% CI, 15.0-31.2) with TMB ≥16 mut/Mb (n=112), and 20.2% (95% CI, 13.6-28.1) with TMB ≥13 mut/Mb (n=129). Median IRC-assessed DOR was not estimable. Median IRC-assessed PFS was 2.8 (95% CI, 1.7-5.4) and 2.7 (95% CI, 1.5-4.2) months using TMB ≥16 and ≥13 mut/Mb, respectively. Adverse events (AEs) were reported in 93.2% of patients, of which 53.4% were treatment-related (no grade 5) and 40.5% were grade ≥3.</p><p><strong>Conclusion: </strong>Atezolizumab led to moderate antitumor activity in various TMB-high solid tumors. Safety was consistent with previous reports.</p><p><strong>Clinical trial number: </strong>NCT04589845.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1158/1078-0432.CCR-25-2733
Lily V S Hillson, Ross K McMahon, Norman J Galbraith, Ashley K McCulloch, Chia Yew Kong, Walaiphorn Woraharn, Lydia Melissourgou-Syka, Kathryn A F Pennel, Jean A Quinn, Leia Jones, Raheleh Amirkhah, Natalie Fisher, Noori Maka, Aula Ammar, Phimmada Hatthakarnkul, Liang Tang, Annabelle Smith, Simon Milling, Alec C McDonald, Harikrishnan Nair, Paul G Horgan, Colin W Steele, Janet S Graham, Philip D Dunne, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh
Purpose: Two dominant neoadjuvant radiotherapy (RT) regimens are in common use for locally advanced rectal cancer (LARC): long-course radiotherapy (LCRT;25x1.8Gy) with concomitant chemotherapy and short-course radiotherapy (SCRT;5x5Gy) typically followed by systemic chemotherapy. This study uses serial sampling to investigate the evolution of systemic and local immune responses to different radiotherapy regimens in LARC.
Experimental design: We conducted a serial sampling study involving patients receiving radiotherapy for LARC, in which longitudinal blood and tumor biospecimens were collected at baseline, and at 2, 6, and 12 weeks after treatment initiation. Leukocyte concentrations via full blood count and a multiplex cytokine ELISA of plasma samples measured systemic changes. Multiplex immunofluorescence (CD8 and FOXP3) and RNA-sequencing of tumor biopsies were used to assess local changes.
Results: Circulating lymphocyte concentrations tended to increase in SCRT patients and decrease in LCRT patients between week 2 and week 6 and were significantly lower in LCRT patients compared to SCRT patients at week 6 (p<0.0001) and week 12 (p=0.019). Additionally, we report higher densities of CD8+ and FOXP3+ tumoral lymphocytes from SCRT patients compared to LCRT patients at week 2 (CD8 p=0.053, FOXP3 p=0.023) and week 6 (CD8 p=0.035, FOXP3 p=0.0016).
Conclusions: SCRT is less lympho-depleting and induces more frequent increases in intra-tumoral T cell infiltration compared to LCRT. These results are relevant to the field of radiation-immune-oncology combination studies in LARC. Furthermore, these findings may underpin early trial results, where higher rates of response to radiotherapy-immune checkpoint inhibitor combinations have been reported with SCRT-based regimens.
{"title":"Differential Immunological Effects of Short-Course and Long-Course Radiotherapy in Locally Advanced Rectal Cancer.","authors":"Lily V S Hillson, Ross K McMahon, Norman J Galbraith, Ashley K McCulloch, Chia Yew Kong, Walaiphorn Woraharn, Lydia Melissourgou-Syka, Kathryn A F Pennel, Jean A Quinn, Leia Jones, Raheleh Amirkhah, Natalie Fisher, Noori Maka, Aula Ammar, Phimmada Hatthakarnkul, Liang Tang, Annabelle Smith, Simon Milling, Alec C McDonald, Harikrishnan Nair, Paul G Horgan, Colin W Steele, Janet S Graham, Philip D Dunne, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh","doi":"10.1158/1078-0432.CCR-25-2733","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-2733","url":null,"abstract":"<p><strong>Purpose: </strong>Two dominant neoadjuvant radiotherapy (RT) regimens are in common use for locally advanced rectal cancer (LARC): long-course radiotherapy (LCRT;25x1.8Gy) with concomitant chemotherapy and short-course radiotherapy (SCRT;5x5Gy) typically followed by systemic chemotherapy. This study uses serial sampling to investigate the evolution of systemic and local immune responses to different radiotherapy regimens in LARC.</p><p><strong>Experimental design: </strong>We conducted a serial sampling study involving patients receiving radiotherapy for LARC, in which longitudinal blood and tumor biospecimens were collected at baseline, and at 2, 6, and 12 weeks after treatment initiation. Leukocyte concentrations via full blood count and a multiplex cytokine ELISA of plasma samples measured systemic changes. Multiplex immunofluorescence (CD8 and FOXP3) and RNA-sequencing of tumor biopsies were used to assess local changes.</p><p><strong>Results: </strong>Circulating lymphocyte concentrations tended to increase in SCRT patients and decrease in LCRT patients between week 2 and week 6 and were significantly lower in LCRT patients compared to SCRT patients at week 6 (p<0.0001) and week 12 (p=0.019). Additionally, we report higher densities of CD8+ and FOXP3+ tumoral lymphocytes from SCRT patients compared to LCRT patients at week 2 (CD8 p=0.053, FOXP3 p=0.023) and week 6 (CD8 p=0.035, FOXP3 p=0.0016).</p><p><strong>Conclusions: </strong>SCRT is less lympho-depleting and induces more frequent increases in intra-tumoral T cell infiltration compared to LCRT. These results are relevant to the field of radiation-immune-oncology combination studies in LARC. Furthermore, these findings may underpin early trial results, where higher rates of response to radiotherapy-immune checkpoint inhibitor combinations have been reported with SCRT-based regimens.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931526","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}