Purpose: To evaluate the safety and efficacy of combining intra-tumoral IL-12 gene therapy with docetaxel and pembrolizumab in high-risk patients with early stage triple-negative breast cancer (TNBC) refractory to anthracycline-based neoadjuvant chemotherapy.
Methods: In this single-arm, open-label phase II trial, patients with stage I-III TNBC and residual disease after anthracycline therapy received neoadjuvant docetaxel (100 mg/m2 IV) and pembrolizumab (200 mg IV) every three weeks for four cycles. Intra-tumoral injections of adenoviral-mediated interleukin-12 (ADV/IL-12) gene therapy were administered three days prior to cycles 2-4. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were safety and toxicity assessments. Correlative analyses included immune profiling and cytokine measurement.
Results: Eight patients were enrolled; half received ADV/IL-12 at a starting dose of 5 x 1011 viral particles (VP) in 2mL volume, injected into the breast tumor. Owing to adverse events (AE's), the remaining 4 patients received 3 x 1011 viral particles. The trial was terminated early due to toxicity, with 87.5% of patients experiencing grade ≥3 AE's, including two treatment-related deaths. Only one patient (12.5%) who received a lower dose of ADV/IL-12 achieved a pCR. Elevation of CCL4 levels was observed exclusively in the patient who achieved pCR.
Conclusions: The combination of docetaxel, pembrolizumab, and intratumoral ADV/IL-12 is associated with high systemic toxicity and minimal efficacy. These results underscore the need for cautious dose optimization and patient selection when integrating immuno-potentiating cytokines into neoadjuvant regimens. Translational insights from this study inform safer design of future IL-12-based strategies in immune-refractory TNBC.
{"title":"A phase II study of docetaxel and pembrolizumab plus Interleukin-12 gene therapy in non-metastatic, anthracycline-refractory triple negative breast cancer (INTEGRAL).","authors":"Polly Niravath, Ivonne Uzair, Kai Sun, Hanh Mai, Jian Guan, Mailin Li, Jenying Deng, Wei Qian, Jianying Zhou, Liliana Guzman, Kelsey Banaglorioso, Rabia Hashmani, Sunil Mathur, Jenny Chang","doi":"10.1158/1078-0432.CCR-25-2649","DOIUrl":"10.1158/1078-0432.CCR-25-2649","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the safety and efficacy of combining intra-tumoral IL-12 gene therapy with docetaxel and pembrolizumab in high-risk patients with early stage triple-negative breast cancer (TNBC) refractory to anthracycline-based neoadjuvant chemotherapy.</p><p><strong>Methods: </strong>In this single-arm, open-label phase II trial, patients with stage I-III TNBC and residual disease after anthracycline therapy received neoadjuvant docetaxel (100 mg/m2 IV) and pembrolizumab (200 mg IV) every three weeks for four cycles. Intra-tumoral injections of adenoviral-mediated interleukin-12 (ADV/IL-12) gene therapy were administered three days prior to cycles 2-4. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were safety and toxicity assessments. Correlative analyses included immune profiling and cytokine measurement.</p><p><strong>Results: </strong>Eight patients were enrolled; half received ADV/IL-12 at a starting dose of 5 x 1011 viral particles (VP) in 2mL volume, injected into the breast tumor. Owing to adverse events (AE's), the remaining 4 patients received 3 x 1011 viral particles. The trial was terminated early due to toxicity, with 87.5% of patients experiencing grade ≥3 AE's, including two treatment-related deaths. Only one patient (12.5%) who received a lower dose of ADV/IL-12 achieved a pCR. Elevation of CCL4 levels was observed exclusively in the patient who achieved pCR.</p><p><strong>Conclusions: </strong>The combination of docetaxel, pembrolizumab, and intratumoral ADV/IL-12 is associated with high systemic toxicity and minimal efficacy. These results underscore the need for cautious dose optimization and patient selection when integrating immuno-potentiating cytokines into neoadjuvant regimens. Translational insights from this study inform safer design of future IL-12-based strategies in immune-refractory TNBC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141184","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 : 2026-02-09DOI: 10.1158/1078-0432.CCR-25-3395
Andrew B Katims, Charlie White, Syed Muneeb Alam, Mark Farha, Sadra Sepehri, Manuel De Jesus Escano, Neeta D'Souza, Gamze Gokturk Ozcan, Merve Basar, Anthony Martinez Benitez, Melissa McCarter, Morgan Tomberlin, David B Solit, Gopa Iyer, Pan Du, Shidong Jia, Alvin C Goh, Timothy F Donahue, Judy Sarungbam, Bernard H Bochner, Max Kates, Irina Ostrovnaya, Hikmat Al-Ahmadie, Oscar Lin, Eugene J Pietzak
Purpose: To determine if carcinoma in situ (CIS) is a sufficient measure of minimal residual disease (MRD) in non-muscle-invasive bladder cancer (NMIBC) and to evaluate alternative measures of MRD.
Experimental design: We evaluated concordance of CIS on TURBT and radical cystectomy (RC) to determine eradication rates of clinical CIS (cCIS) by TURBT alone and rates of occult pathologic CIS (pCIS) seen only in RC specimens. We studied a prospective cohort of patients with BCG-naive high-grade NMIBC to evaluate pretreatment urinary cytology and urinary tumor (ut)DNA as alternative biomarkers.
Results: Eradication of CIS was seen in 20% of patients (78/383). Positive urinary cytology, but not cCIS, was associated with pCIS. In our prospective cohort (n=173), abnormal pre-BCG urine cytology, but not pre-BCG cCIS, had worse high-grade recurrence-free survival (HG-RFS) (hazard ratio [HR] 3.56 95%, confidence interval [CI] 1.74 - 7.31, p<0.001). Median follow-up was 1.8 years (95% CI: 1.3-2.2). Among those with utDNA available, 84% (56/67) had sufficient DNA for genomic profiling. The 2-year HG-RFS rate in patients without an oncogenic alteration (n=17) in their pre-BCG urine was 100% versus 60% (95% CI: 46%-78%) in patients with detectable oncogenic alterations (n=38) (p=0.004). Area under the curve values for predicting 2-year HG-RFS were 0.52 for cCIS, 0.68 for cytology, and 0.74 for utDNA.
Conclusions: We found ~20% eradication of cCIS from TURBT alone. cCIS was a poor metric of MRD, performing worse than abnormal pretreatment urinary cytology and utDNA. These urine biomarkers are more objective MRD measures than cCIS for NMIBC risk stratification and treatment assessment.
{"title":"Urinary Biomarkers Objectively Measure Minimal Residual Disease in Non-Muscle-Invasive Bladder Cancer.","authors":"Andrew B Katims, Charlie White, Syed Muneeb Alam, Mark Farha, Sadra Sepehri, Manuel De Jesus Escano, Neeta D'Souza, Gamze Gokturk Ozcan, Merve Basar, Anthony Martinez Benitez, Melissa McCarter, Morgan Tomberlin, David B Solit, Gopa Iyer, Pan Du, Shidong Jia, Alvin C Goh, Timothy F Donahue, Judy Sarungbam, Bernard H Bochner, Max Kates, Irina Ostrovnaya, Hikmat Al-Ahmadie, Oscar Lin, Eugene J Pietzak","doi":"10.1158/1078-0432.CCR-25-3395","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-3395","url":null,"abstract":"<p><strong>Purpose: </strong>To determine if carcinoma in situ (CIS) is a sufficient measure of minimal residual disease (MRD) in non-muscle-invasive bladder cancer (NMIBC) and to evaluate alternative measures of MRD.</p><p><strong>Experimental design: </strong>We evaluated concordance of CIS on TURBT and radical cystectomy (RC) to determine eradication rates of clinical CIS (cCIS) by TURBT alone and rates of occult pathologic CIS (pCIS) seen only in RC specimens. We studied a prospective cohort of patients with BCG-naive high-grade NMIBC to evaluate pretreatment urinary cytology and urinary tumor (ut)DNA as alternative biomarkers.</p><p><strong>Results: </strong>Eradication of CIS was seen in 20% of patients (78/383). Positive urinary cytology, but not cCIS, was associated with pCIS. In our prospective cohort (n=173), abnormal pre-BCG urine cytology, but not pre-BCG cCIS, had worse high-grade recurrence-free survival (HG-RFS) (hazard ratio [HR] 3.56 95%, confidence interval [CI] 1.74 - 7.31, p<0.001). Median follow-up was 1.8 years (95% CI: 1.3-2.2). Among those with utDNA available, 84% (56/67) had sufficient DNA for genomic profiling. The 2-year HG-RFS rate in patients without an oncogenic alteration (n=17) in their pre-BCG urine was 100% versus 60% (95% CI: 46%-78%) in patients with detectable oncogenic alterations (n=38) (p=0.004). Area under the curve values for predicting 2-year HG-RFS were 0.52 for cCIS, 0.68 for cytology, and 0.74 for utDNA.</p><p><strong>Conclusions: </strong>We found ~20% eradication of cCIS from TURBT alone. cCIS was a poor metric of MRD, performing worse than abnormal pretreatment urinary cytology and utDNA. These urine biomarkers are more objective MRD measures than cCIS for NMIBC risk stratification and treatment assessment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141192","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 : 2026-02-06DOI: 10.1158/1078-0432.ccr-25-4001
Aslı D. Munzur, Cameron Herberts, Edmond M. Kwan, Louise Emmett, Shahneen Sandhu, James P. Buteau, Amir Iravani, Anthony M. Joshua, Roslyn J. Francis, Sze-Ting Lee, Andrew M. Scott, Andrew J. Martin, Martin R. Stockler, Alison Y. Zhang, Scott G. Williams, Cecily Q. Bernales, Gráinne Donnellan, Melissa Koudjanian, Karan Parekh, Jack V. W. Bacon, Aly Karsan, Arun A. Azad, Ian D. Davis, Michael S. Hofman, Alexander W. Wyatt
Background: Clonal hematopoiesis (CH) is a precursor state linked to risk of hematological neoplasms, and may be exacerbated by radiation exposure. We aimed to compare CH prevalence after the new radioligand therapy 177Lu-PSMA-617 versus the alternative standard-of-care cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). Methods: This post hoc correlative analysis used serial blood samples from TheraP (ANZUP 1603), a randomized phase II trial in docetaxel-refractory mCRPC. Cell-free DNA and leukocyte DNA underwent deep error-corrected targeted sequencing. CH mutations were called at variant allele frequency (VAF)≥0.25%. Variants detected at progression but undetected at baseline were defined as treatment-emergent CH. 178 patients had a baseline sample; 107 (60 177Lu-PSMA-617; 47 cabazitaxel) had paired baseline–progression samples (median interval 29 versus 27 weeks). Results: Baseline CH was detected in 77% (138/178) of patients, with similar prevalence and gene distribution between arms. Treatment-emergent CH occurred more often after 177Lu-PSMA-617 than cabazitaxel (62% [37/60] vs 40% [19/47]; P=0.03), and 83% (121/146) of all emergent mutations were detected after 177Lu-PSMA-617. The DNA damage response gene PPM1D accounted for 42% (51/121) of 177Lu-PSMA-617-emergent mutations; with odds ratios of 3.2 for any treatment-emergent CH and 5.4 for PPM1D, relative to cabazitaxel. CH clones expanded more frequently and to a greater magnitude with 177Lu-PSMA-617 (proportion expanding, 70.9% vs 29.5%; P=7.5×10-5), and increases in maximal CH VAF correlated with number of 177Lu-PSMA-617 cycles received (+2.9% per cycle; P=0.002). Conclusion: 177Lu-PSMA-617 strongly promotes CH, supporting integration of longitudinal monitoring for long-term hematologic sequelae as radioligand therapy is implemented earlier in prostate cancer care.
{"title":"Clonal hematopoiesis after 177Lu-PSMA-617 radioligand therapy in prostate cancer","authors":"Aslı D. Munzur, Cameron Herberts, Edmond M. Kwan, Louise Emmett, Shahneen Sandhu, James P. Buteau, Amir Iravani, Anthony M. Joshua, Roslyn J. Francis, Sze-Ting Lee, Andrew M. Scott, Andrew J. Martin, Martin R. Stockler, Alison Y. Zhang, Scott G. Williams, Cecily Q. Bernales, Gráinne Donnellan, Melissa Koudjanian, Karan Parekh, Jack V. W. Bacon, Aly Karsan, Arun A. Azad, Ian D. Davis, Michael S. Hofman, Alexander W. Wyatt","doi":"10.1158/1078-0432.ccr-25-4001","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4001","url":null,"abstract":"Background: Clonal hematopoiesis (CH) is a precursor state linked to risk of hematological neoplasms, and may be exacerbated by radiation exposure. We aimed to compare CH prevalence after the new radioligand therapy 177Lu-PSMA-617 versus the alternative standard-of-care cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). Methods: This post hoc correlative analysis used serial blood samples from TheraP (ANZUP 1603), a randomized phase II trial in docetaxel-refractory mCRPC. Cell-free DNA and leukocyte DNA underwent deep error-corrected targeted sequencing. CH mutations were called at variant allele frequency (VAF)≥0.25%. Variants detected at progression but undetected at baseline were defined as treatment-emergent CH. 178 patients had a baseline sample; 107 (60 177Lu-PSMA-617; 47 cabazitaxel) had paired baseline–progression samples (median interval 29 versus 27 weeks). Results: Baseline CH was detected in 77% (138/178) of patients, with similar prevalence and gene distribution between arms. Treatment-emergent CH occurred more often after 177Lu-PSMA-617 than cabazitaxel (62% [37/60] vs 40% [19/47]; P=0.03), and 83% (121/146) of all emergent mutations were detected after 177Lu-PSMA-617. The DNA damage response gene PPM1D accounted for 42% (51/121) of 177Lu-PSMA-617-emergent mutations; with odds ratios of 3.2 for any treatment-emergent CH and 5.4 for PPM1D, relative to cabazitaxel. CH clones expanded more frequently and to a greater magnitude with 177Lu-PSMA-617 (proportion expanding, 70.9% vs 29.5%; P=7.5×10-5), and increases in maximal CH VAF correlated with number of 177Lu-PSMA-617 cycles received (+2.9% per cycle; P=0.002). Conclusion: 177Lu-PSMA-617 strongly promotes CH, supporting integration of longitudinal monitoring for long-term hematologic sequelae as radioligand therapy is implemented earlier in prostate cancer care.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"302 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146129320","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 : 2026-02-06DOI: 10.1158/1078-0432.ccr-25-4080
Jiaying Chen, Nancy Ann Oberheim Bush, Jennifer A. Grabowsky, Cassie Kline, Deanna L. Kroetz, Jennie W. Taylor, Javier Villanueva-Meyer, Annette M. Molinaro, John F. de Groot, Nicholas A. Butowski, Meghan Tedesco, Jane Rabbitt, Joanna J. Phillips, Shawn Hervey-Jumper, Manish K. Aghi, Mitchel S. Berger, Edward F. Chang, Susan M. Chang, David A. Solomon, Jennifer L. Clarke
Purpose: Existing salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median survival of approximately 9 months. Given the complex molecular heterogeneity of GBM, single-target approaches have consistently failed as a treatment strategy. We conducted a phase 1 clinical trial to assess the feasibility, safety, and efficacy of a genomically-tailored multi-agent regimen in 30 adults with surgically-treated rGBM. Patients and Methods: Adults with IDH-wildtype glioblastoma (n=29) or grade 4 IDH-mutant astrocytoma (n=1) were consented and underwent clinically-indicated surgery for recurrent disease. Comprehensive genomic profiling was performed on the recurrent tumors, and results for each patient were discussed at an individualized molecular tumor board to determine a personalized treatment regimen combining up to 4 FDA-approved drugs, including one cytotoxic agent as backbone. Results: A total of 12 drugs were used in 18 combinations – the most common regimen was lomustine, afatinib, and abemaciclib (n=8). The most common toxicities included cytopenias, rash, and gastrointestinal symptoms, requiring frequent dose reductions. Measured from surgery at trial enrollment, progression-free survival at 6 months (PFS-6) was 40%, overall survival at 9 months (OS-9) was 73%, and median OS was 12.7 months. After trial therapy, genomic profiling performed on subsequent recurrent tumor specimens identified genetic evolution corresponding to putative treatment resistance mechanisms. Conclusions: Implementation of individualized treatment regimens in a timely fashion was feasible for patients with surgically resectable rGBM. Overall efficacy was not significantly improved compared to a contemporary patient cohort treated without experimental regimens, with full dosing of most combination therapies limited by toxicities.
{"title":"A genomically-tailored multi-agent precision medicine clinical trial for adults with recurrent glioblastoma","authors":"Jiaying Chen, Nancy Ann Oberheim Bush, Jennifer A. Grabowsky, Cassie Kline, Deanna L. Kroetz, Jennie W. Taylor, Javier Villanueva-Meyer, Annette M. Molinaro, John F. de Groot, Nicholas A. Butowski, Meghan Tedesco, Jane Rabbitt, Joanna J. Phillips, Shawn Hervey-Jumper, Manish K. Aghi, Mitchel S. Berger, Edward F. Chang, Susan M. Chang, David A. Solomon, Jennifer L. Clarke","doi":"10.1158/1078-0432.ccr-25-4080","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4080","url":null,"abstract":"Purpose: Existing salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median survival of approximately 9 months. Given the complex molecular heterogeneity of GBM, single-target approaches have consistently failed as a treatment strategy. We conducted a phase 1 clinical trial to assess the feasibility, safety, and efficacy of a genomically-tailored multi-agent regimen in 30 adults with surgically-treated rGBM. Patients and Methods: Adults with IDH-wildtype glioblastoma (n=29) or grade 4 IDH-mutant astrocytoma (n=1) were consented and underwent clinically-indicated surgery for recurrent disease. Comprehensive genomic profiling was performed on the recurrent tumors, and results for each patient were discussed at an individualized molecular tumor board to determine a personalized treatment regimen combining up to 4 FDA-approved drugs, including one cytotoxic agent as backbone. Results: A total of 12 drugs were used in 18 combinations – the most common regimen was lomustine, afatinib, and abemaciclib (n=8). The most common toxicities included cytopenias, rash, and gastrointestinal symptoms, requiring frequent dose reductions. Measured from surgery at trial enrollment, progression-free survival at 6 months (PFS-6) was 40%, overall survival at 9 months (OS-9) was 73%, and median OS was 12.7 months. After trial therapy, genomic profiling performed on subsequent recurrent tumor specimens identified genetic evolution corresponding to putative treatment resistance mechanisms. Conclusions: Implementation of individualized treatment regimens in a timely fashion was feasible for patients with surgically resectable rGBM. Overall efficacy was not significantly improved compared to a contemporary patient cohort treated without experimental regimens, with full dosing of most combination therapies limited by toxicities.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"302 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146129335","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 : 2026-02-06DOI: 10.1158/1078-0432.ccr-25-2633
Kum-Hee Yun, Nam Suk Sim, Su-Jin Shin, Young Han Lee, Wooyeol Baek, Yoon Dae Han, Ji Woo Park, Sang Kyum Kim, Iksung Cho, Inkyung Jung, Jill P. Mesirov, Sun Young Rha, Seo Hee Choi, Hong In Yoon, Seung Hyun Kim, Hyo Song Kim
Purpose: This open-label, phase IB/II study evaluated the efficacy and safety of standard-of-care doxorubicin combined with durvalumab (a programmed death 1 ligand [PD-L1] immune checkpoint inhibitor) in patients with advanced anthracycline-naïve soft tissue sarcoma (STS) and to identify patients who would most likely benefit from this combination treatment. Methods: This trial (NCT03802071) included patients with metastatic and/or recurrent STS not previously treated with anthracycline or a PD-1/PD-L1 inhibitor. Phase IB assessed the safety and tolerability of doxorubicin (level 1 [75 mg/m2]; level –1 [60 mg/m2]), in combination with durvalumab 1500 mg once every 3 weeks until documented disease progression or unacceptable toxicity. Phase II evaluated treatment efficacy, with the primary endpoint being the objective response rate (ORR). Results: As no dose-limiting toxicities were observed during the phase IB trial (n=3), the recommended phase II dose was 75 mg/m2 of doxorubicin. Of 41 evaluable patients, 1 (2.4%) achieved a complete response and 12 (29.3%) achieved a confirmed partial response, yielding an ORR of 31.7%. Median progression-free survival (PFS) was 7.6 months and median overall survival was 23.8 months. The most common treatment-related grade 3-4 adverse events were neutropenia (n=23, 53.4%), thrombocytopenia (n=6, 13.9%), and anemia (n=5, 11.6%). In prespecified exploratory correlative analyses, absence of RTK-RAS pathway genetic alterations (hazard ratio [HR], 6.446; 95% CI, 1.934-21.486; p=0.002) and high PD-1 expression (HR, 0.214; 95% CI, 0.071-0.649; p=0.006) were identified as independent predictors of longer PFS. Conclusions: Doxorubicin plus durvalumab combination therapy exhibited promising efficacy in advanced STS, with acceptable toxicity profile.
{"title":"Phase IB/II Trial with Correlative Analyses of Doxorubicin plus Durvalumab Combination in Patients with Advanced Soft Tissue Sarcoma","authors":"Kum-Hee Yun, Nam Suk Sim, Su-Jin Shin, Young Han Lee, Wooyeol Baek, Yoon Dae Han, Ji Woo Park, Sang Kyum Kim, Iksung Cho, Inkyung Jung, Jill P. Mesirov, Sun Young Rha, Seo Hee Choi, Hong In Yoon, Seung Hyun Kim, Hyo Song Kim","doi":"10.1158/1078-0432.ccr-25-2633","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2633","url":null,"abstract":"Purpose: This open-label, phase IB/II study evaluated the efficacy and safety of standard-of-care doxorubicin combined with durvalumab (a programmed death 1 ligand [PD-L1] immune checkpoint inhibitor) in patients with advanced anthracycline-naïve soft tissue sarcoma (STS) and to identify patients who would most likely benefit from this combination treatment. Methods: This trial (NCT03802071) included patients with metastatic and/or recurrent STS not previously treated with anthracycline or a PD-1/PD-L1 inhibitor. Phase IB assessed the safety and tolerability of doxorubicin (level 1 [75 mg/m2]; level –1 [60 mg/m2]), in combination with durvalumab 1500 mg once every 3 weeks until documented disease progression or unacceptable toxicity. Phase II evaluated treatment efficacy, with the primary endpoint being the objective response rate (ORR). Results: As no dose-limiting toxicities were observed during the phase IB trial (n=3), the recommended phase II dose was 75 mg/m2 of doxorubicin. Of 41 evaluable patients, 1 (2.4%) achieved a complete response and 12 (29.3%) achieved a confirmed partial response, yielding an ORR of 31.7%. Median progression-free survival (PFS) was 7.6 months and median overall survival was 23.8 months. The most common treatment-related grade 3-4 adverse events were neutropenia (n=23, 53.4%), thrombocytopenia (n=6, 13.9%), and anemia (n=5, 11.6%). In prespecified exploratory correlative analyses, absence of RTK-RAS pathway genetic alterations (hazard ratio [HR], 6.446; 95% CI, 1.934-21.486; p=0.002) and high PD-1 expression (HR, 0.214; 95% CI, 0.071-0.649; p=0.006) were identified as independent predictors of longer PFS. Conclusions: Doxorubicin plus durvalumab combination therapy exhibited promising efficacy in advanced STS, with acceptable toxicity profile.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"84 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146129319","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 : 2026-02-06DOI: 10.1158/1078-0432.ccr-25-3720
Eun Ji Lee, Ji Ae Ko, Min-je Kim, Jae Seok Cho, Ji-Youn Han, Sang We Kim, Ki Hyeong Lee, Byoung Yong Shim, Jong-Mu Sun, Misako Nagasaka, Sewon Park, Seung Yeon Oh, Min Hee Hong, Jii Bum Lee, Anna Jo, Ethan Seah, Byoung Chul Cho, Sun Min Lim
Purpose: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment of non–small cell lung cancer (NSCLC) with activating EGFR mutations. However, acquired resistance—particularly the EGFR_C797S mutation—remains a major clinical challenge. As no approved targeted therapies are available following disease progression on the third-generation EGFR-TKI osimertinib, this study aimed to evaluate JIN-A02, a novel fourth-generation EGFR-TKI, as a therapeutic strategy to overcome C797S-mediated resistance. Methods: JIN-A02, a fourth-generation EGFR-TKI, was evaluated for its antitumor efficacy and blood–brain barrier penetration in in vitro and in vivo models of NSCLC harboring EGFR_C797S and T790M mutations. Results: JIN-A02 demonstrated potent antiproliferative activity in preclinical NSCLC models harboring EGFR_C797S and T790M mutations, with superior inhibition of EGFR signaling compared to osimertinib. In both subcutaneous and orthotopic intracranial xenograft models, JIN-A02 elicited substantial tumor regression, indicating robust in vivo efficacy. The agent was well tolerated throughout the treatment period without notable toxicity. In line with preclinical data, early clinical trial data showed signs of efficacy including 3 patients showing partial response. Conclusion: These findings highlight JIN-A02 as a promising therapeutic strategy to overcome C797S- and T790M-mediated resistance in EGFR-mutant NSCLC, including intracranial disease, and support its further clinical development.
{"title":"JIN-A02, a Mutant-Selective Fourth-Generation EGFR inhibitor, Overcomes C797S-Mediated Resistance and Demonstrates Intracranial Activity in NSCLC","authors":"Eun Ji Lee, Ji Ae Ko, Min-je Kim, Jae Seok Cho, Ji-Youn Han, Sang We Kim, Ki Hyeong Lee, Byoung Yong Shim, Jong-Mu Sun, Misako Nagasaka, Sewon Park, Seung Yeon Oh, Min Hee Hong, Jii Bum Lee, Anna Jo, Ethan Seah, Byoung Chul Cho, Sun Min Lim","doi":"10.1158/1078-0432.ccr-25-3720","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3720","url":null,"abstract":"Purpose: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment of non–small cell lung cancer (NSCLC) with activating EGFR mutations. However, acquired resistance—particularly the EGFR_C797S mutation—remains a major clinical challenge. As no approved targeted therapies are available following disease progression on the third-generation EGFR-TKI osimertinib, this study aimed to evaluate JIN-A02, a novel fourth-generation EGFR-TKI, as a therapeutic strategy to overcome C797S-mediated resistance. Methods: JIN-A02, a fourth-generation EGFR-TKI, was evaluated for its antitumor efficacy and blood–brain barrier penetration in in vitro and in vivo models of NSCLC harboring EGFR_C797S and T790M mutations. Results: JIN-A02 demonstrated potent antiproliferative activity in preclinical NSCLC models harboring EGFR_C797S and T790M mutations, with superior inhibition of EGFR signaling compared to osimertinib. In both subcutaneous and orthotopic intracranial xenograft models, JIN-A02 elicited substantial tumor regression, indicating robust in vivo efficacy. The agent was well tolerated throughout the treatment period without notable toxicity. In line with preclinical data, early clinical trial data showed signs of efficacy including 3 patients showing partial response. Conclusion: These findings highlight JIN-A02 as a promising therapeutic strategy to overcome C797S- and T790M-mediated resistance in EGFR-mutant NSCLC, including intracranial disease, and support its further clinical development.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146129333","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 : 2026-02-05DOI: 10.1158/1078-0432.ccr-25-0821
Ben Z. Stanger, Robert H. Vonderheide
Oncogenic RAS drives an immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). Inhibition of RAS signaling, as is now possible with an ever-increasing pharmaceutical portfolio, not only directly blocks tumors cells but also reverses immunosuppression, enabling infiltration of cytotoxic T cells and major alteration of the tumor microenvironment. In preclinical studies, the full anti-tumor effects of RAS inhibitors depend on T cells such that regressions in mice lacking T cells (or cross-presenting dendritic cells) are less deep and less durable than those in T cell-replete mice. Moreover, RAS inhibitors given with immune checkpoint blockade and immune agonists produce even more potent anti-tumor effects, especially in tumors with some amount of baseline T cell infiltration. These findings set the stage for testing RAS inhibitors and immunotherapy in combination for pancreatic ductal carcinoma (PDAC), which is otherwise refractory to immunotherapy. Other immune partners might include vaccines, bispecific antibodies, and cell therapy. A major clinical opportunity eventually would be combining RAS inhibitors and immunotherapy in the adjuvant, neo-adjuvant, and interception settings, provided this new class of drugs is developed keeping its immune modulatory power in mind.
{"title":"KRAS Inhibitors in Pancreas Cancer: Facts and Hopes about the Immunotherapy We’ve All Been Waiting For","authors":"Ben Z. Stanger, Robert H. Vonderheide","doi":"10.1158/1078-0432.ccr-25-0821","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0821","url":null,"abstract":"Oncogenic RAS drives an immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). Inhibition of RAS signaling, as is now possible with an ever-increasing pharmaceutical portfolio, not only directly blocks tumors cells but also reverses immunosuppression, enabling infiltration of cytotoxic T cells and major alteration of the tumor microenvironment. In preclinical studies, the full anti-tumor effects of RAS inhibitors depend on T cells such that regressions in mice lacking T cells (or cross-presenting dendritic cells) are less deep and less durable than those in T cell-replete mice. Moreover, RAS inhibitors given with immune checkpoint blockade and immune agonists produce even more potent anti-tumor effects, especially in tumors with some amount of baseline T cell infiltration. These findings set the stage for testing RAS inhibitors and immunotherapy in combination for pancreatic ductal carcinoma (PDAC), which is otherwise refractory to immunotherapy. Other immune partners might include vaccines, bispecific antibodies, and cell therapy. A major clinical opportunity eventually would be combining RAS inhibitors and immunotherapy in the adjuvant, neo-adjuvant, and interception settings, provided this new class of drugs is developed keeping its immune modulatory power in mind.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"223 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121850","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}
Background: Tertiary lymphoid structures (TLSs) are associated with improved survival and enhanced response to anti-cancer immunotherapy. This study aimed to develop a computed tomography (CT) imaging-based approach for non-invasive assessment of TLSs and immunotherapy response. Methods: This study involved 3,155 patients with gastric cancer (GC). TLSs were classified into four stages (absence, Agg, FL-I, FL-II) according to their maturation based on immunohistochemistry staining. A CT imaging-based TLSs scoring model (ctTLSs) was developed to assess TLSs status, subsequently classified into four classes (ctTLSs-0/1/2/3). We next evaluated the model's associations with prognosis and immunotherapy response. To enhance the model's interpretability, we analyzed multi-omics data and employed the Shapley value strategy. Results: The ctTLSs model achieved high accuracies in predicting TLSs status in the internal validation (AUC range: 0.727-0.809) and external validation (0.704-0.807) cohorts. In retrospective and prospective validation cohorts, ctTLSs exhibited significant associations with both disease-free and overall survival (HR range: 0.206-0.634, all P<0.01). Shapley value analysis highlighted ctTLSs as the strongest predictor of TLSs status. Upon analyzing multi-omics data, we found that higher ctTLSs levels positively correlated with tumor immune activation and apoptosis signaling, while displaying a negative correlation with tumor proliferation and metabolism signaling. Intriguingly, patients with high ctTLSs (but not low ctTLSs) exhibited substantial benefits from immunotherapy (P<0.0001). The objective response rate of four ctTLSs classes was 16.7% in ctTLSs-0, 35.5% in ctTLSs-1, 45.8% in ctTLSs-2, and 53.8% in ctTLSs-3. Conclusion: The ctTLSs model could noninvasively assess TLSs status, enabling improved prognosis evaluation and informed decisions regarding immunotherapy.
{"title":"Non-invasive Imaging Assessment of Tertiary Lymphoid Structures and Immunotherapy Response in Gastric Cancer: A Multicenter Study","authors":"Zepang Sun, Zhenhui Li, M. Usman Ahmad, Yun Zhu, Zixia Zhou, Kangneng Zhou, Lin Wu, Chuanli Chen, Qingyu Yuan, Taojun Zhang, Yan Chen, Jingjing Xie, Wanying Feng, Yikai Xu, Wenjun Xiong, Wei Wang, Guoxin Li, Yuming Jiang","doi":"10.1158/1078-0432.ccr-25-3669","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3669","url":null,"abstract":"Background: Tertiary lymphoid structures (TLSs) are associated with improved survival and enhanced response to anti-cancer immunotherapy. This study aimed to develop a computed tomography (CT) imaging-based approach for non-invasive assessment of TLSs and immunotherapy response. Methods: This study involved 3,155 patients with gastric cancer (GC). TLSs were classified into four stages (absence, Agg, FL-I, FL-II) according to their maturation based on immunohistochemistry staining. A CT imaging-based TLSs scoring model (ctTLSs) was developed to assess TLSs status, subsequently classified into four classes (ctTLSs-0/1/2/3). We next evaluated the model's associations with prognosis and immunotherapy response. To enhance the model's interpretability, we analyzed multi-omics data and employed the Shapley value strategy. Results: The ctTLSs model achieved high accuracies in predicting TLSs status in the internal validation (AUC range: 0.727-0.809) and external validation (0.704-0.807) cohorts. In retrospective and prospective validation cohorts, ctTLSs exhibited significant associations with both disease-free and overall survival (HR range: 0.206-0.634, all P&lt;0.01). Shapley value analysis highlighted ctTLSs as the strongest predictor of TLSs status. Upon analyzing multi-omics data, we found that higher ctTLSs levels positively correlated with tumor immune activation and apoptosis signaling, while displaying a negative correlation with tumor proliferation and metabolism signaling. Intriguingly, patients with high ctTLSs (but not low ctTLSs) exhibited substantial benefits from immunotherapy (P&lt;0.0001). The objective response rate of four ctTLSs classes was 16.7% in ctTLSs-0, 35.5% in ctTLSs-1, 45.8% in ctTLSs-2, and 53.8% in ctTLSs-3. Conclusion: The ctTLSs model could noninvasively assess TLSs status, enabling improved prognosis evaluation and informed decisions regarding immunotherapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"21 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121855","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 : 2026-02-05DOI: 10.1158/1078-0432.ccr-24-3934
Mariella Spalato Ceruso, Jean-Philippe Guégan, Aurelien Bourdon, Vanessa Chaire, Yanina Valverde Timana, Alban Giese, Christophe Rey, Alban Bessede, Raoul Perret, Lucile Vanhersecke, Valérie Velasco, Pascal Finetti, François Bertucci, Stéphanie Verbeke, Antoine Italiano
Purpose: Undifferentiated pleomorphic sarcoma (UPS) is an aggressive subtype of soft tissue sarcoma with poor outcomes, particularly in metastatic cases. The mechanisms driving metastasis in UPS remain poorly understood, limiting therapeutic advances. Experimental Design: A multi-omics approach was employed to analyze paired primary and metastatic UPS tumor samples. Spatial transcriptomics, bulk RNA sequencing, and deconvolution analyses were performed to identify molecular pathways and immune microenvironment alterations associated with metastasis. Functional assays using CRISPR-Cas9 knockout UPS cell lines, alongside in vivo models, were used for functional validation experiments. Results: Transcriptomic analyses on 13 UPS patients revealed significant upregulation of hypoxia, epithelial-mesenchymal transition (EMT), and immune-suppressive pathways in metastatic UPS. ADORA2B was identified as a key driver of these processes, with elevated expression correlating with poor disease-free survival in UPS patients. Functional studies confirmed that ADORA2B promotes proliferation, migration, invasion, and matrix remodeling via metalloprotease regulation. In vivo, ADORA2B knockout reduced primary tumor growth and metastatic dissemination in UPS models. Conclusions: This study identifies ADORA2B as a critical regulator of metastatic progression in UPS, implicating it as a promising therapeutic target. Ongoing clinical trials targeting adenosine pathways further support the translational potential of ADORA2B inhibition to disrupt metastasis and improve outcomes for UPS patients.
{"title":"Adenosine A2B Receptor Promotes Tumor Progression and Metastases in Undifferentiated Pleomorphic Sarcoma","authors":"Mariella Spalato Ceruso, Jean-Philippe Guégan, Aurelien Bourdon, Vanessa Chaire, Yanina Valverde Timana, Alban Giese, Christophe Rey, Alban Bessede, Raoul Perret, Lucile Vanhersecke, Valérie Velasco, Pascal Finetti, François Bertucci, Stéphanie Verbeke, Antoine Italiano","doi":"10.1158/1078-0432.ccr-24-3934","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3934","url":null,"abstract":"Purpose: Undifferentiated pleomorphic sarcoma (UPS) is an aggressive subtype of soft tissue sarcoma with poor outcomes, particularly in metastatic cases. The mechanisms driving metastasis in UPS remain poorly understood, limiting therapeutic advances. Experimental Design: A multi-omics approach was employed to analyze paired primary and metastatic UPS tumor samples. Spatial transcriptomics, bulk RNA sequencing, and deconvolution analyses were performed to identify molecular pathways and immune microenvironment alterations associated with metastasis. Functional assays using CRISPR-Cas9 knockout UPS cell lines, alongside in vivo models, were used for functional validation experiments. Results: Transcriptomic analyses on 13 UPS patients revealed significant upregulation of hypoxia, epithelial-mesenchymal transition (EMT), and immune-suppressive pathways in metastatic UPS. ADORA2B was identified as a key driver of these processes, with elevated expression correlating with poor disease-free survival in UPS patients. Functional studies confirmed that ADORA2B promotes proliferation, migration, invasion, and matrix remodeling via metalloprotease regulation. In vivo, ADORA2B knockout reduced primary tumor growth and metastatic dissemination in UPS models. Conclusions: This study identifies ADORA2B as a critical regulator of metastatic progression in UPS, implicating it as a promising therapeutic target. Ongoing clinical trials targeting adenosine pathways further support the translational potential of ADORA2B inhibition to disrupt metastasis and improve outcomes for UPS patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"160 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121853","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 : 2026-02-05DOI: 10.1158/1078-0432.ccr-25-3886
Bridget Adcock, Moaath K. Mustafa Ali, Emily C. Zabor, Hadil Zureigat, Heya Batah, Aastha Dhakal, Monica Lee, Preeyal Patel, Meera Patel, Osama Abu-Shawer, Ahmed Hassan, Jacqulyn Tomer, Austin Ingraham, Vladimir Makarov, Ying Ni, Tyler Alban, Scott Robertson, Wen Wee Ma, Alex A. Adjei, Timothy Chan
Background: Immunotherapy (IT) is widely used across multiple cancer types, yet its impact on second primary cancers (SPCs) remains poorly understood. It is unclear whether IT enhances immune surveillance that prevents progression of pre-clinical malignancies into clinically apparent cancers. Methods: We conducted a retrospective cohort study of adult cancer patients treated between 2010 and 2022 across Cleveland Clinic Ohio centers. Patients (≥18 years) with cancers eligible for first-line IT were included. After excluding ineligible patients, 5,576 patients were included. Patients who received IT (with or without additional systemic therapy or radiation) were compared with those who did not. Multivariable Cox models treated IT as a time-dependent covariate and adjusted for confounders. Follow-up continued until death or loss to follow-up. Results: Among 5,576 patients, 1,296 (23%) received first-line and 948 (17%) received subsequent-line IT, predominantly anti-PD-1/PD-L1 and/or anti-CTLA-4 agents (99.9%). Over a median follow-up of 47.5 months (IQR 27.4-75.4), 264 SPCs were diagnosed. Two- and four-year SPC-free probabilities were 97% (95% CI 96-98) and 94% (95% CI 92-97) in the first-line IT group versus 95% (95% CI 94-96) and 92% (95% CI 91-93) in the non-IT group (log-rank P<0.01). In multivariable analysis, IT was associated with a lower hazard of SPC (HR 0.57, 95% CI 0.41-0.79; P<0.001). Conclusions: Treatment of primary cancer with IT was associated with a reduced clinical incidence of SPCs. These findings support further investigation into the potential of IT as a cancer prevention strategy in both cancer survivors and high-risk, cancer-free individuals.
背景：免疫疗法（IT）广泛应用于多种癌症类型，但其对第二原发癌症（SPCs）的影响仍知之甚少。目前尚不清楚It是否能增强免疫监测，防止临床前恶性肿瘤进展为临床明显的癌症。方法：我们对2010年至2022年间在俄亥俄州克利夫兰诊所中心接受治疗的成年癌症患者进行了回顾性队列研究。符合一线IT治疗条件的癌症患者（≥18岁）被纳入。在排除不符合条件的患者后，纳入了5576名患者。接受IT治疗的患者（有或没有接受额外的全身治疗或放疗）与没有接受的患者进行比较。多变量Cox模型将IT视为时间相关协变量，并对混杂因素进行了调整。随访持续至死亡或失去随访。结果：在5576例患者中，1296例（23%）接受了一线治疗，948例（17%）接受了后续的一线IT治疗，主要是抗pd -1/PD-L1和/或抗ctla -4药物（99.9%）。中位随访47.5个月（IQR 27.4-75.4）， 264例SPCs被诊断。一线IT组2年和4年无spc的概率分别为97% （95% CI 96-98）和94% (95% CI 92-97)，非IT组为95% （95% CI 94-96）和92% (95% CI 91-93) （log-rank P<0.01）。在多变量分析中，IT与较低的SPC风险相关（HR 0.57, 95% CI 0.41-0.79; P<0.001）。结论：原发性肿瘤的IT治疗与SPCs的临床发病率降低相关。这些发现支持进一步研究信息技术作为癌症幸存者和高风险、无癌症个体的癌症预防策略的潜力。
{"title":"The Impact of Immunotherapy on Incidence of Second Primary Malignancies: A Surrogate for Anti-Tumor Surveillance Activation","authors":"Bridget Adcock, Moaath K. Mustafa Ali, Emily C. Zabor, Hadil Zureigat, Heya Batah, Aastha Dhakal, Monica Lee, Preeyal Patel, Meera Patel, Osama Abu-Shawer, Ahmed Hassan, Jacqulyn Tomer, Austin Ingraham, Vladimir Makarov, Ying Ni, Tyler Alban, Scott Robertson, Wen Wee Ma, Alex A. Adjei, Timothy Chan","doi":"10.1158/1078-0432.ccr-25-3886","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3886","url":null,"abstract":"Background: Immunotherapy (IT) is widely used across multiple cancer types, yet its impact on second primary cancers (SPCs) remains poorly understood. It is unclear whether IT enhances immune surveillance that prevents progression of pre-clinical malignancies into clinically apparent cancers. Methods: We conducted a retrospective cohort study of adult cancer patients treated between 2010 and 2022 across Cleveland Clinic Ohio centers. Patients (≥18 years) with cancers eligible for first-line IT were included. After excluding ineligible patients, 5,576 patients were included. Patients who received IT (with or without additional systemic therapy or radiation) were compared with those who did not. Multivariable Cox models treated IT as a time-dependent covariate and adjusted for confounders. Follow-up continued until death or loss to follow-up. Results: Among 5,576 patients, 1,296 (23%) received first-line and 948 (17%) received subsequent-line IT, predominantly anti-PD-1/PD-L1 and/or anti-CTLA-4 agents (99.9%). Over a median follow-up of 47.5 months (IQR 27.4-75.4), 264 SPCs were diagnosed. Two- and four-year SPC-free probabilities were 97% (95% CI 96-98) and 94% (95% CI 92-97) in the first-line IT group versus 95% (95% CI 94-96) and 92% (95% CI 91-93) in the non-IT group (log-rank P&lt;0.01). In multivariable analysis, IT was associated with a lower hazard of SPC (HR 0.57, 95% CI 0.41-0.79; P&lt;0.001). Conclusions: Treatment of primary cancer with IT was associated with a reduced clinical incidence of SPCs. These findings support further investigation into the potential of IT as a cancer prevention strategy in both cancer survivors and high-risk, cancer-free individuals.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"69 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121851","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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