Clinical Cancer Research最新文献

{"title":"Long-term effect and safety of mesenchymal stromal cell therapy for radiation-induced hyposalivation in head and neck cancer survivors: A randomised, phase-2, trial.","authors":"Amanda-Louise Fenger Carlander, Kathrine Kronberg Jakobsen, Tobias Todsen, Natasja Paaske, Anne Kathrine Østergaard Madsen, Simone Kloch Bendtsen, Jens Kastrup, Jeppe Friborg, Charlotte Duch Lynggaard, Anne Werner Hauge, Robin Christensen, Christian Grønhøj, Christian von Buchwald","doi":"10.1158/1078-0432.CCR-24-2663","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2663","url":null,"abstract":"<p><strong>Background: </strong>The long-term effect of adipose-derived mesenchymal stromal cells (ASCs) to restore radiation-induced salivary gland hypofunction in previous head and neck cancer patients have not been validated in larger settings.</p><p><strong>Methods: </strong>The study was the 12-months follow-up of a randomised trial, including patients with hyposalivation. Patients were randomised to receive allogeneic ASCs or placebo in the submandibular glands. Primary endpoint was unstimulated whole saliva (UWS) followed by stimulated whole saliva, patient-reported outcomes (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Head and Neck Module and the Xerostomia Questionnaire) and safety.</p><p><strong>Results: </strong>Of the 120 enrolled patients, 117 (97.5%) were assessed at 12 months. Treatment with ASCs did not increase UWS compared to placebo: increase in UWS was 0.02 mL/min (95% CI 0.01 to 0.04) in the ASC group and 0.02 mL/min (95% CI 0 to 0.03) in the placebo group, p=0.56. ASCs reduced the symptom burden for dry mouth with -10.07 units (95% CI -13.39 to -6.75) compared to -4.15 units (95% CI -7.46 to -0.84) in the placebo group, p=0.01. Compared to placebo, ASCs did not improve sticky saliva (-9.27 vs. -4.55 units, p=0.13), swallowing (-4.50 vs. 3.49 units, p=0.5) or xerostomia -3.12 vs. -2.74 units, p=0.82). Treatment was safe and associated with a transient immune response.</p><p><strong>Conclusion: </strong>Intraglandular ACS therapy in the submandibular glands significantly relieved subjective dry mouth symptoms. Both ASCs and placebo increased UWS, but ASCs did not prove superior to placebo in restoring salivary gland function, based on salivary flow rate.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920887","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}

{"title":"A phase I clinical trial adding OX40 agonism to in situ therapeutic cancer vaccination in patients with low-grade B cell lymphoma highlights challenges in translation from mouse to human studies.","authors":"Tanaya Shree, Debra Czerwinski, Sarah Haebe, Anuja Sathe, Sue Grimes, Brock Martin, Michael Ozawa, Richard Hoppe, Hanlee Ji, Ronald Levy","doi":"10.1158/1078-0432.CCR-24-2770","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2770","url":null,"abstract":"<p><strong>Purpose: </strong>Activating T cell costimulatory receptors is a promising approach for cancer immunotherapy. In preclinical work, adding an OX40 agonist to in situ vaccination (ISV) with SD101, a TLR9 agonist, was curative in a mouse model of lymphoma. We sought to test this combination in a Phase I clinical trial for patients with low-grade B cell lymphoma.</p><p><strong>Patients and methods: </strong>We treated 14 patients with low-dose radiation, intratumoral SD101, and intratumoral and intravenous BMS986178, an agonistic anti-OX40 antibody. The primary outcome was safety. Secondary outcomes included overall response rate and progression-free survival.</p><p><strong>Results: </strong>Adverse events were consistent with prior experience with low-dose radiation and SD101. No synergistic or dose-limiting toxicities were observed. One patient had a partial response, and 9 patients had stable disease, a result inferior to our experience with TLR9 agonism and low-dose radiation alone. Flow cytometry and single cell RNA sequencing of serial tumor biopsies revealed that T and NK cells were activated after treatment. However, high baseline OX40 expression on T follicular helper and T regulatory type 1 cells, as well as high post-treatment soluble OX40, shed from these T cells upon activation, associated with progression-free survival of less than 6 months.</p><p><strong>Conclusions: </strong>Clinical results of T cell costimulatory receptor agonism have now repeatedly been inferior to the motivating preclinical results. Our study highlights potential barriers to clinical translation, particularly differences in preclinical and clinical reagents and the complex biology of these coreceptors in heterogenous T cell subpopulations, some of which may antagonize immunotherapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913791","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}

{"title":"TOP1 Mutations and Cross-Resistance to Antibody-Drug Conjugates in Patients with Metastatic Breast Cancer.","authors":"Rachel O Abelman, Bogang Wu, Haley Barnes, Arielle Medford, Bryanna Norden, Annika Putur, Elena Bitman, Win Thant, Ting Liu, Caroline Weipert, Geoffrey Fell, Laura M Spring, Seth Wander, Beverly Moy, Neelima Vidula, Steven J Isakoff, Andreas Varkaris, Dejan Juric, Ryan Corcoran, Leif W Ellisen, Aditya Bardia","doi":"10.1158/1078-0432.CCR-24-2771","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2771","url":null,"abstract":"<p><strong>Purpose: </strong>Antibody-drug conjugates (ADCs) harboring topoisomerase I (TOP1) inhibitor payloads have improved survival for patients with metastatic breast cancer (MBC). However, knowledge of ADC resistance mechanisms and potential impact on sequential use of ADCs is limited. Here, we report the incidence and characterization of TOP1 mutations arising in the setting of ADC resistance in MBC.</p><p><strong>Methods: </strong>Patients with MBC treated with ADCs with available post-treatment plasma-based genotyping were included. TOP1 mutation incidence, mutant allele frequency (MAF) and functional characterization were assessed, and incidence was compared to that in MBC patients not receiving ADC treatment and in The Cancer Genome Atlas (TCGA).</p><p><strong>Results: </strong>Plasma-based genotyping identified distinct TOP1 mutations (S57C, R364H, W401C, G359E) in 12.9% of patients (4/31) at time of disease progression on ADC, compared to 0.7% (3/420) in non-ADC treated MBC patients and 0.5% reported in TCGA. Appearance of mutations was associated with clinical cross-resistance, as median duration on first ADC was 455 days versus 52 days for second ADC. Functional characterization of three novel TOP1 mutant proteins demonstrated that all exhibited reduced enzymatic activity, attenuated covalent DNA binding, and resistance to TOP1 inhibitor ADC payloads SN38 and Deruxtecan.</p><p><strong>Conclusions: </strong>We describe the recurrent emergence of functionally altered, resistance-associated TOP1 mutations in vivo under selective pressure from ADCs, and the potential impact on mediating cross-resistance to sequential ADCs. TOP1 mutation may represent a biomarker of resistance in this setting, and additional work is needed to optimize biomarkers and ADC payload design to improve outcomes for sequential use of ADCs.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913864","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}

{"title":"Facts and hopes in neoadjuvant immunotherapy combinations in resectable non-small-cell lung cancer.","authors":"Martin Schuler","doi":"10.1158/1078-0432.CCR-24-1441","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1441","url":null,"abstract":"<p><p>Antibodies targeting immune checkpoints, such as PD-1, PD-L1, or CTLA-4, have transformed the treatment of patients with lung cancers. Unprecedented rates of durable responses are achieved in an imperfectly characterized population of patients with metastatic disease. More recently, immune checkpoint inhibitors have been explored in patients with resectable non-small-cell lung cancers. Following a traditional paradigm, antibody therapies were first studied in the adjuvant setting, after surgery and chemotherapy. Pivotal trials supported global approvals of the PD-L1/-1 antibodies atezolizumab and pembrolizumab in this setting. Exciting observations were made when checkpoint inhibitors were moved to the preoperative window: Several signal-finding studies explored a limited number of cycles prior to surgery, and reproducibly reported complete or major histopathological responses. So far, six published phase III trials have demonstrated the superiority of combining the PD-1/-L1 antibodies nivolumab, pembrolizumab, durvalumab, tislelizumab or toripalimab with 3 to 4 courses of preoperative platinum-based chemotherapy over preoperative chemotherapy alone in terms of response rates and survival endpoints. Those patients achieving complete or major histopathological responses experienced particularly favorable long-term outcomes. It is yet unclear, whether there is true synergism between immunotherapy and chemotherapy, and whether outcomes are further improved by adding postoperative checkpoint inhibition. While these pivotal trials qualify neoadjuvant chemo-immunotherapy as another option in curative lung cancer treatment, there is hope that the chemotherapy backbone will be ultimately replaced by rationally selected and targeted combination partners. Here, the current status and future avenues of neoadjuvant combination immunotherapies in patients with non-small-cell lung cancer are reviewed.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913862","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}

{"title":"Structurally-oriented classification of FOXA1 alterations identifies prostate cancers with opposing clinical outcomes and distinct molecular and immunologic subtypes.","authors":"Justin Hwang, Pornlada Likasitwatanakul, Sachin Kumar Deshmukh, Sharon Wu, Jason J Kwon, Eamon Toye, David Moline, Mark G Evans, Andrew Elliott, Rachel Passow, Christine Luo, Emily John, Nishant Gandhi, Rana R McKay, Elisabeth I Heath, Chadi Nabhan, Natalie Reizine, Jacob J Orme, Josep M Domingo Domenech, Oliver Sartor, Sylvan C Baca, Scott M Dehm, Emmanuel S Antonarakis","doi":"10.1158/1078-0432.CCR-24-3471","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3471","url":null,"abstract":"<p><strong>Purpose: </strong>10-15% of prostate cancers (PCa) harbor recurrent FOXA1 aberrations whereby the alteration type and the effect on the forkhead( FKH) domain impacts protein-function. We developed a FOXA1 classification system to inform clinical management.</p><p><strong>Experimental design: </strong>5,014 PCa were examined using whole exome and transcriptome sequencing from the Caris database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain: these were in the first part of the FKH domain (class 1A: amino acids [AA] 168-246), within the Wing2 region of FKH (class 1B: AA 247-269), or outside FKH (class 1C: AA 1-167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted-truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1-269, class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims.</p><p><strong>Results: </strong>FOXA1 alterations did not influence survival when considered in aggregate, but had distinct prognostic effects when stratified by class. Class 1A alterations were associated with overall improved survival (HR=0.57, p=0.03); a similar trend was seen with Class 1B (HR=0.88, p=0.07). Conversely, class 1C exhibited worse survival upon 2nd-generation androgen receptor signaling inhibitor (ARSI) treatment (HR=1.93, p<0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR=2.05, p<0.001) and worse outcomes to first-line androgen-deprivation therapies (HR=2.5, p<0.001). Class 3A alterations indicated improved survival (HR=0.70; p=0.01) whereas class 3B alterations portended poor outcomes (HR=1.50; p<0.001). Amplifications (class 4) indicated poor outcomes (HR=1.48; p=0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European-Americans, African-Americans had increased class 1C alterations whereas Asian-Pacific patients had increased class 1B alterations.</p><p><strong>Conclusions: </strong>FOXA1alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision making for PCa patients and uncovers important racial differences.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913863","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}

{"title":"Activity and safety of avelumab in high-grade neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas progressive after chemotherapy (AveNEC trial)","authors":"Christian Fottner, Leonidas Apostolidis, Sebastian Krug, Anja Rinke, Barbara Grün, Patrick Michl, Thomas M. Gress, Daniel-Christoph Wagner, Wilfried Roth, Esther Mettler, Jana Topsch, Christian Ruckes, Peter R. Galle, Mathias M. Weber","doi":"10.1158/1078-0432.ccr-24-2461","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2461","url":null,"abstract":"Background: Neuroendocrine neoplasias grade 3 (NEN G3) are rare tumors with poor prognosis and no established second-line therapy. The role of immune checkpoint blockade in these aggressive tumors remains unclear. Methods: The phase II AVENEC study evaluated the effect of avelumab (AVE, 10 mg/kg IV Q2W) in 60 patients with well-differentiated high-grade neuroendocrine tumors (NET G3, N=22) or poorly differentiated neuroendocrine carcinomas (NEC, N=38) progressing after ≥ one prior chemotherapy (excluding Merkel cell and small-cell lung cancer). Results: The best overall response according to iRECIST was partial response (PR) in 3 (5%) and stable disease (SD) in 9 (15%) patients, with a disease control rate at 16 weeks of 15% (3 PR, 6 SD), and a median duration of response of 4.3 months. Six patients (10%) achieved SD or PR for &amp;gt; 6 months and two for &amp;gt; one year. Response rates were similar regardless of differentiation, Ki67 expression, or primary localization. The median progression-free survival (PFS) was 1.9 months and overall survival (OS) was 6.6 months. After a median follow-up of 3.6 years, only four (7%) patients were still alive. One- and two-year survival rates were 33% and 17%, respectively. Responders had significantly longer OS of 30.2 months compared to 4.8 months in non-responders. AVE was well tolerated, with few treatment-related grade 3/4 adverse events, and quality of life remained stable during treatment. Conclusions: In patients with progressive high-grade NEN G3, avelumab was well tolerated and provided disease control with significant clinical benefit in 15% of heavily pretreated patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"13 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904835","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}

{"title":"Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models","authors":"Sara Ortega-Bertran, Juana Fernández-Rodríguez, Miriam Magallón-Lorenz, Xiaohu Zhang, Edgar Creus-Bachiller, Adriana Paola Diazgranados, Itziar Uriarte-Arrazola, Helena Mazuelas, Ignacio Blanco, Claudia Valverde, Meritxell Carrió, Alberto Villanueva, Thomas De Raedt, Cleofé Romagosa, Bernat Gel, Héctor Salvador, Marc Ferrer, Conxi Lázaro, Eduard Serra","doi":"10.1158/1078-0432.ccr-24-2807","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2807","url":null,"abstract":"Purpose: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma that develops sporadically or in Neurofibromatosis type 1 patients. Its development is marked by the inactivation of specific tumor suppressor genes (TSGs): NF1, CDKN2A and SUZ12EED (Polycomb Repressor Complex 2). Each TSG loss can be targeted by particular drug inhibitors and we aimed to systematically combine these inhibitors, guided by TSG inactivation status, to test their precision medicine potential for MPNSTs. Experimental Design: We performed a high-throughput screening in three MPNST cell lines testing 14 MEK (MEKi), 11 CDK4/6 (CDKi) and 3 bromodomain (BETi) inhibitors as single agents and 147 pair-wise co-treatments. Best combinations were validated in 9 MPNST cell lines and three were tested in one sporadic and one NF1-associated patient-derived orthotopic xenograft (PDOX) MPNST mouse models. A final combination of the three inhibitor classes was tested in the same PDOX models. Results: A high degree of redundancy was observed in the effect of compounds of the same inhibitory class, individually or in combination, and responses matched with TSG inactivation status. The MEKi-BETi (Arry-162+I-BET151) co-treatment triggered reduction of half of the NF1-related MPNST-PDOXs, and all the sporadic tumors, reaching 65% reduction in tumor volume in the latter. Remarkably, this reduction was further increased in both models combining the three inhibitor classes, reaching 85% shrinkage on average in the sporadic MPNST. Conclusions: Our results strongly support precision therapies for MPNSTs guided by TSG inactivation status. MEKi-BETi-CDKi triple treatment elicits a significant reduction of human MPNST PDOX.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"3 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904833","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}

{"title":"Genomic profiling reveals SMARCA4 mutations are associated with shorter overall and intracranial progression free survival in melanoma brain metastasis patients","authors":"Grant M. Fischer, Nayan Lamba, Jayne Vogelzang, Ayal Aizer, Keith L. Ligon","doi":"10.1158/1078-0432.ccr-24-0301","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0301","url":null,"abstract":"Purpose: Melanoma brain metastases (MBMs) are a common, lethal complication of metastatic melanoma. Despite improvements in treatments, subsets of MBM patients experience rapid decline, and few prognostic biomarkers have been identified. An improved understanding of the molecular features specifically associated with MBM overall survival (OS) and intracranial progression free survival (PFS) could facilitate the development of more effective clinical management strategies. Experimental Design: We established an initial cohort of 102 MBMs, 970 unmatched melanoma extracranial metastases (ECMs), and 569 unmatched melanoma primaries with available targeted exome sequencing data covering 182 genes and a validation cohort of 50 MBMs with SMARCA4 genomically profiled. Kaplan-Meier analysis, log-rank test, and Cox proportional hazards model were used to evaluate associations between pathogenic genomic alterations and OS and intracranial PFS. We evaluated 14 MBMs and 19 ECMs with paired RNA sequencing and whole exome sequencing data to identify genotype-transcriptome correlations. Results: Of 43 genes significantly mutated amongst MBMs, only pathogenic mutations in SMARCA4 significantly associated with shorter OS and intracranial PFS on univariable and multivariable analyses in MBM patients but not from first ECM or primary tumor diagnosis. SMARCA4 mutations significantly associated with enrichment of oxidative phosphorylation (OXPHOS) and depletion of immune signaling gene sets. Conclusions: Pathogenic SMARCA4 mutations independently predict an association with shorter OS and intracranial PFS in MBM patients and associate with expression of pathways known to mediate melanoma virulence. These findings add to our understanding of MBM pathogenesis and suggest their potential use as prognostic biomarkers and possible therapeutic opportunities.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904869","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}

{"title":"RAD51 testing in patients with early HER2-negative breast cancer and homologous recombination deficiency: post-hoc analysis of the GeparOla trial","authors":"Guillermo Villacampa, Alba Llop-Guevara, Natalie Filmann, Andrea Herencia, Peter A. Fasching, Thomas Karn, Frederik Marmé, Peter Klare, Volkmar Müller, Andrea Stefek, Christian Schem, Christoph Uleer, Tanja Fehm, Gabriele Doering, Elmar Stickeler, Marion van Mackelenbergh, Bärbel Felder, Valentina Nekljudova, Judith Balmaña, Carsten Denkert, Sibylle Loibl, Violeta Serra","doi":"10.1158/1078-0432.ccr-24-3148","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3148","url":null,"abstract":"Purpose: The randomized GeparOla trial reported comparable pathological complete response (pCR) rates with neoadjuvant containing olaparib vs. carboplatin treatment. Here, we evaluate the association between functional homologous repair deficiency (HRD) by RAD51 foci and pCR, and the potential of improving patient selection by combining RAD51 and stromal tumor infiltrating lymphocytes (sTILs). Patients and methods: This is a post-hoc blinded, biomarker analysis from the randomized GeparOla trial. Patients with early-stage HER2-negative breast cancer and HRD assessed by Myriad myChoice or BRCA1/BRCA2 mutation were randomized 1:1 to receive i) paclitaxel plus olaparib or ii) paclitaxel plus carboplatin, both followed by epirubicin/cyclophosphamide. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). Results: Overall, 90/97 (92.8%) samples were evaluable for RAD51 testing and 72/90 (80.0%) were RAD51-low. The pCR rate in patients with RAD51-low tumors was 66.7% (48/72), while it decreased to 22.2% (4/18) in those with RAD51-high. In the multivariable model including clinicopathological factors and treatment, the RAD51 score remained significantly associated with pCR (OR=12.03, 95%CI 2.60–55.73, p=0.002). Patients with RAD51-low and high sTILs in their tumors achieved a pCR rate of 75.0% (27/36). Similar results were observed for olaparib or carboplatin. In the exploratory DFS analysis, no differences were observed between RAD51 groups (high vs. low: HR=0.85, 95% CI 0.25–2.97). Conclusions: In a pre-selected population with HRD according to a genetic test, RAD51 testing identifies patients with different pCR rates under PARPi or platinum-based therapies. Future biomarker-driven studies should consider this information to refine stratification factors and to improve patient selection.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"33 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904868","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}

{"title":"Phase 2 Open-Label Trial of Brentuximab Vedotin with Pembrolizumab in PD-1 Pretreated Metastatic Non-Small Cell Lung Cancer and Metastatic Cutaneous Melanoma","authors":"Sylvia Lee, Omid Hamid, Robert Jotte, Yousef Zakharia, Theresa Medina, Amanda Gillespie-Twardy, Inderjit Mehmi, Sunandana Chandra, Graham Watson, Patrick Ward, Marya Chaney, Hailing Lu, Jason Berndt, Brian P. O'Connor, Kapil Rathi, Eeman Shaikh, C. Lance. Cowey","doi":"10.1158/1078-0432.ccr-24-1478","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1478","url":null,"abstract":"Purpose: Brentuximab vedotin (BV) is hypothesized to selectively deplete T regulatory cells (Tregs) that express CD30 and re-sensitize tumors to anti-(PD-1) therapy. This study evaluated responses to BV+pembrolizumab post PD-1 and explored corresponding biomarkers. Methods: 55 patients with metastatic non-small cell lung cancer (NSCLC) and 58 with metastatic cutaneous melanoma received ≥1 dose of BV+pembrolizumab. Patients had received a median of 2.0 prior lines of systemic therapies (range, 1-7). The primary endpoint was confirmed objective response rate (ORR). Exploratory endpoints included overall survival (OS) and biomarker analysis in blood and tumor. Results: For the secondary refractory metastatic NSCLC cohort (RECIST v1.1), ORR was 14%, median progression-free survival (PFS) was 5.85 months, and median OS was 14.4 months. For the secondary refractory metastatic cutaneous melanoma cohort (iRECIST), ORR was 24%, median iPFS was 4.44 months, and median OS was 21.9 months. Overall, median duration of OS follow-up was 17.2 months (95% CI 14.62, 22.87). No new safety signals were identified. No treatment-related grade 5 toxicity was seen. Longitudinal immune phenotyping in peripheral blood demonstrated a transient decrease in Tregs. Paired tumor biopsies from baseline and Cycle 3 Day 1 showed a trend of increased CD8 T cell infiltration, especially in responding patients. Conclusions: BV+pembrolizumab in solid tumor malignancies resulted in clinically meaningful, durable responses with encouraging OS and PFS rates supportive of the immunomodulatory activity of this combination. Stronger antitumor activity was observed in secondary refractory cohorts. The safety profile of this combination was consistent with the individual drug risk profiles.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"65 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904834","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}