Literatura científica selecionada sobre o tema "American Medical Association. Meeting 1876 : Philadelphia, Pa.)"

Abstract Background: Programmed cell death protein 1 (PD-1) inhibitors are approved as second-line (2L) therapy for patients (pts) with ESCC. TMB is a predictive biomarker of response to immune checkpoint blockade in multiple cancers, but its role in ESCC is unclear. Here, we retrospectively investigated the association between TMB and clinical outcomes in the phase 3 RATIONALE-302 study of anti-PD-1 antibody tislelizumab (TIS) vs investigator-chosen chemotherapy (ICC) as 2L treatment for advanced unresectable/metastatic ESCC (NCT03430843). Methods: Genomic profiling was assessed on tumor tissues collected at baseline using BurningRock OncoScreen Plus 520 NGS panel to determine TMB status. Median progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Objective response rate (ORR) was calculated using the binomial exact method. Cox model was applied to assess the effect of TMB on survival outcomes. Hazard ratio (HR) and 95% confidence interval (CI) for OS and PFS in TMB subgroups were estimated. Results: Of 512 pts enrolled, 209 had evaluable tumor samples (TIS, n=105; ICC, n=104). Using the widely used cutoff of 10 mutations per megabase (mut/Mb), numerically higher ORR and survival benefit with TIS over ICC were observed in the high TMB (TMB-H) vs the low TMB (TMB-L) subgroup (Table). The predictive effect of TMB on survival outcomes was not significant (interaction p-value = 0.0537 for PFS, 0.5374 for OS); however, the effect became significant using the increased cutoff of 12 mut/Mb (TMB-H prevalence = 16.7%; interaction p-value = 0.0267 for PFS, 0.0175 for OS). Conclusions: TMB status may play a role in predicting clinical outcomes in pts with advanced ESCC treated with TIS versus ICC, especially when a higher TMB cutoff is chosen. These findings need further prospective validation. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Sophie Cook, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Table. Clinical outcomes by TMB status (cutoff 10 mut/Mb) TMB status TMB-H TMB-L Treatment TIS ICC TIS ICC n (% in TMB BEP, N=209) 27 (12.9) 31 (14.8) 78 (37.3) 73 (34.9) ORR, % (95% CI) 33.3 (16.5, 54.0) 6.5 (0.8, 21.4) 16.7 (9.2, 26.8) 17.8 (9.8, 28.5) Median PFS, months (95% CI) 2.4 (1.4, 5.5) 2.3 (1.3, 2.9) 1.4 (1.3, 2.7) 2.7 (1.5, 3.3) PFS HR (95% CI) 0.52 (0.28, 0.97) 1.06 (0.73, 1.53) Interaction p-value 0.0537 Median OS, months (95% CI) 6.1 (4.2, 18.6) 4.7 (3.4, 7.0) 8.6 (4.6, 11.8) 7.0 (4.6, 8.6) OS HR (95% CI) 0.58 (0.32, 1.04) 0.72 (0.50, 1.03) Interaction p-value 0.5374 TMB-adjusted OS HR (95% CI) 0.68 (0.5, 0.92) BEP, biomarker evaluable population; CI, confidence interval; HR, hazard ratio; ICC, investigator chosen chemotherapy; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; TIS, tislelizumab; TMB-H, high tumor mutational burden; TMB-L, low tumor mutational burden; TMB-adjusted OS HR, overall HR adjusted for the impact of TMB on OS Citation Format: Lin Shen, Yongqian Shu, Kuaile Zhao, Taroh Satoh, Zhendong Chen, Eric Van Cutsem, Guohua Yu, Jun Wu, Chih-Hung Hsu, Sung Bae Kim, Wenting Du, Yang Shi, Ruiqi Huang, Qiao Li, Jingwen Shi, Yun Zhang, Kato Ken. Association of tumor mutational burden (TMB) and clinical outcomes with tislelizumab versus chemotherapy in esophageal cell carcinoma (ESCC) from RATIONALE-302 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT077.

Abstract Background: MTAP-loss is an emerging biomarker guiding druggable targets in cholangiocarcinoma and almost exclusively occurs in the setting of 9p21 loss, which has itself been associated with reduced IO responsiveness and poorer survival outcomes on a pan-cancer analysis. We sought to understand the clinical impact of MTAP status on treatment and survival outcomes, in a clinical cohort of molecularly characterized advanced cholangiocarcinoma patients. Methods: We analyzed advanced cholangiocarcinoma patients treated and evaluated at MD Anderson Cancer Center, tested for MTAP. Clinical information including genomic co-alterations, demographic information, treatment history and response to treatment were retrieved from retrospective medical record review. Comprehensive genomic profiling was performed with FDA-approved assays. Statistical analysis was performed with SPSS24 using Fisher's exact test, multivariate Cox regression and Kaplan-Meyer method for survival analysis. Results: 71 patients were identified (MTAP loss 31% (22/71); MTAP intact 69% (49/71)); 54,9% (39/71) were females. No significant difference in gender, age or ethnicity was seen between MTAP cohorts. We found that altered CDKN2A (p<0.01), CDKN2B (p<0.01), and IDH1 (p=0.048) were highly correlated with MTAP loss, while STK11 (p=0.095), a prognostic indicator of IO resistance, also showed a tendency to be a surrogate marker of MTAP loss status. Tumor mutational burden (TMB) was lower in MTAP loss group (2.18 vs. 4.88, p <0.01), but no difference was found in microsatellite instability (MSI) or PD-L1 status between groups. On multivariate analysis, patients harboring CDKN2A loss were noted to have worse OS compared to those without CDKN2A intact (18.6 vs 29.9 months, 95% CI, p=0.035). No statistically significant difference in OS was observed by MTAP status (25.9 vs. 29.2 months, 95% CI, p=0.168). Other genomic alterations with significant impact on OS were CCNE1 (p<0.01), FGF19 (p=0.04), and MYC (p=0.043). Treatment with chemotherapy regimens containing Gemcitabine in the first line setting of metastatic disease showed higher disease control rate in the MTAP intact cohort (91.4%) vs. MTAP loss cohort (38.5%) (p<0.01), but no statistically significant difference in response (PR/CR) (p=0.421). Few patients (14/71) received IO in this cohort; no significant difference in IO response was observed by MTAP status (p=0.152). Conclusions: MTAP loss cholangiocarcinoma has a distinct molecular profile compared with MTAP intact including key differences in co-altered tumor suppressor genes and TMB. To our knowledge, this is the first real-world data describing the clinical and genomic differences in advanced cholangiocarcinoma by MTAP status. Further prospective data are required to validate these findings. Citation Format: Cátia F. Gaspar, Natalie Y. Ngoi, Tin Tang, Jeffrey Ross, Dean Pavlick, Gregory Buchold, Shubham Pant, Milind Javle, Jordi Ahnert. Clinical impact of MTAP status in advanced cholangiocarcinoma: Genomic profile and response to treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 963.

Abstract Subsets of tumor-produced proteins, referred to as Humoral Immuno-Oncology (HIO) factors, can bind to IgG1 antibodies and suppress their immune-effector activities. Antibody-drug conjugates (ADCs) targeting tumor cell surface antigens can internalize and kill target cells upon liberation of their cytotoxic payload. Binding of the antibody component of an ADC by a HIO factor may potentially hamper the efficacy of a bound ADC. To assess any suppression of ADC’s activity by HIO factors, we evaluated the efficacy of a HIO-refractory ADC, NAV-001, and a HIO-bound ADC, SS1, both targeting mesothelin. The HIO factor MUC16/CA125 protein, which binds to SS1 ADC, was shown to have a negative effect on its internalization and tumor cell killing. The MUC16/CA125 refractory NAV-001 ADC was shown to have robust killing of tumor cells regardless of MUC16/CA125 expression in vitro (EC50 ~20 pM) as well as in vivo at single, sub-mg/kg dosing. Moreover, NAV-001-PNU, which contains the PNU-159682 topoisomerase II inhibitor as a payload, demonstrated good stability in vitro and in vivo as well as robust bystander activity against tumor and stromal cells not expressing the target antigen mesothelin, while maintaining a tolerable safety profile in vivo. Single-dose NAV-001-PNU demonstrated robust tumor regression of a number of patient-derived xenograft models from different tumor types regardless of MUC16/CA125 expression. These findings suggest that identification of HIO-refractory antibodies to be used in ADC format may improve therapeutic efficacy as observed for NAV-001 and warrants NAV-001-PNU’s advancement to human clinical trials as a monotherapy to treat mesothelin-positive cancers. Citation Format: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides. NAV-001, a high-efficacy antibody-drug conjugate targeting mesothelin with improved delivery of potent payload by counteracting MUC16/CA125 effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1876.

Abstract Background: Upregulated glucose metabolism is one of the strategies cancer cells use to fuel their abnormal cell growth and division. Targeting the cancer-specific glucose transporter GLUT-1 is a promising approach to restrict glucose uptake and challenge the metabolic needs of tumor cells. Antibodies, as opposed to small molecule inhibitors, are an attractive modality to therapeutically target complex muti-pass membrane transporters. Here we report the development of antibodies that very specifically block the function of only GLUT-1. Methods: Monoclonal antibodies against GLUT-1 were generated using virus-like particles. For immunization, chickens were used as they are evolutionarily distant from mammals and can produce antibodies with prolonged CDR3-s in VH, which could facilitate their binding to the limited extracellular region of GLUT-1. Antibody discovery was performed with HybriFree B cell cloning technology followed by functional screens with 2-deoxyglucose uptake interference or cell proliferation measurements. Results: The discovered antibodies specifically bind to GLUT-1 with low nanomolar EC50 values and do not target other glucose transporters. The lead candidate, ICO-33, inhibits glucose uptake and rewires the metabolism of GLUT-1-dependent cancer cells to rely on oxidative phosphorylation. This results in a significantly synergistic cancer proliferation inhibition with ICO-33 and OXPHOS inhibitor combinations in doses that do not inhibit proliferation as single agents. ICO-33 and OXPHOS inhibitor treatment is well-tolerated and demonstrates a drastic tumor growth inhibition in in vivo colorectal and pancreatic cancer models. Conclusions: We describe the discovery of highly specific monoclonal antibodies targeting GLUT-1. We further demonstrate that the restriction of the much-needed glucose uptake by ICO-33 makes cancer cells highly susceptible to OXPHOS inhibitor co-therapy both in vitro and in vivo, validating the antibody as a promising candidate for clinical development. Citation Format: Siret Tahk, Kai Virumae, Korneelia Anton, Paule Hermet, Robin Pau, Mario Plaas, Maiken Abel, Denis Belitškin, Luciano Galdieri, Steven Garner, Jillian Krings, Kaleb Collver, Emily Schultz, Kaitlyne Powers, Alastair King, Francisca Neethling, Anu Planken, Mart Ustav, Joan Terya, Andres Mannik, Mart Ustav. Development of therapeutic antibodies targeting the GLUT-1 transporter to restrict cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1876.