Background Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. Methods This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n=8; cohort 1), asymptomatic untreated BMs (n=4; cohort 2), or progressing BMs after local therapy (n=9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial overall response rate (ORR-IC) for cohorts 2 and 3. Results As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3–99.7; P<.001). ORR-IC was 50.0% (95%CI, 6.7–93.2) in cohort 2 and 44.4% (95%CI, 13.7–78.8; P<.001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2–74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0–86.7), 80.0% (95%CI, 28.4–99.5) in cohort 1, 50.0% (95%CI, 6.7–93.2) in cohort 2, and 66.7% (95%CI, 29.9–92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade≥3), nausea (42.9%; 0% grade≥3), neutropenia (28.6%; 19% grade≥3), and constipation (28.6%; 0% grade≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. Conclusions T-DXd showed intracranial activity with manageable toxicity and maintained quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.
Several fibrinolytic variables, including plasminogen activator inhibitor activity, were studied before and after exercise in 67 normolipidaemic patients with coronary artery disease and in 25 hyperlipidaemic patients with coronary artery disease. Before exercise plasminogen activator inhibitor activity was higher in the patient groups than in a group of 10 healthy volunteers. For those who were normolipidaemic plasminogen activator inhibitor activity was greater in patients with angina pectoris who had had a myocardial infarction. The concentration of antigenic tissue-type plasminogen activator was similar in all the patients with coronary artery disease and higher than in the control group. After the exercise test fibrinolytic capacity was lower in the patients with angina pectoris and a previous history of myocardial infarction. After exercise both the released immunological tissue-type plasminogen activator and fibrinolytic capacity were lower in the hyperlipidaemic patients than in the normolipidaemic patients. The concentration of plasminogen activator inhibitor was also higher in the hyperlipidaemic patients. Patients with hyperlipidaemia IV had the highest plasminogen activator inhibitor activity. The increase in plasminogen activator inhibitor activity found in the patients was partially inhibited by antiserum against plasminogen activator inhibitor-1 in vitro. The formation of a complex of about 115,000 daltons between plasminogen activator inhibitor and purified tissue-type plasminogen activator was detected by a zymographic fibrin technique. These findings show that in patients with coronary artery disease fibrinolytic activity is impaired by an increase in plasminogen activator inhibitor. Impaired fibrinolysis may be related to the clinical evolution of coronary artery disease in these patients.
Background The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed. Methods Postmenopausal women with untreated stage I–III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures. Results Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1–2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (− 73.2%) was superior to both monotherapy arms combined (− 49.9%; p = 0.001) and mVNB (− 19.1%; p < 0.001). The anti-proliferative effect of LTZ+mVNB (− 73.2%) was numerically higher compared to LTZ (− 65.7%) but did not reach statistical significance (p = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p = 0.049) and LTZ+mVNB (p = 0.012). Grade 3 adverse events occurred in 3.4% of the cases. Conclusions Short-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted. Trial registration NCT02802748, registered 16 June 2016.
Background: Approximately 30% to 40% of patients (pts) with HER2[+] advanced breast cancer (ABC) will develop brain metastases (BM) during the course of their disease. Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate containing an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In the phase 2 DESTINY-Breast01 trial, T-DXd showed efficacy in the subgroup of HER2[+] ABC pts with stable BM at baseline. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2[+] and HER2-low-expressing ABC pts with a history of BM and/or leptomeningeal carcinomatosis (LMC). Here, we report primary results from cohorts A and C. Methods: This is an ongoing, multicenter, open-label, 5-cohort, non-comparative, phase 2 study across 18 hospitals in 2 countries. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low-expressing ABC with stable, progressing, or untreated BM and/or LMC are being enrolled in 5 cohorts: (A) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (B) HER2[+] or HER2-low-expressing ABC with asymptomatic untreated BM; (C) HER2[+] ABC with progressing BM after local treatment; (D) HER2-low-expressing ABC with progressing BM after local treatment; (E) HER2[+] or HER2-low-expressing ABC with LMC. In cohorts A and C, pts must have received prior taxane and ≥1 HER2-targeted therapy for ABC. Pts received 5.4 mg/kg T-DXd intravenously on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint for cohort A is 16-week progression-free survival (PFS) per local assessment using RANO-BM for central nervous system (CNS) lesions and RECIST v.1.1 for extracranial lesions (H0: 5%); for cohort C, CNS overall response rate (ORR; H0: 10%). A single-arm binomial design is used for cohorts A and C. A futility interim analysis has been planned in cohort A after accrual of 4 pts. Sample size was planned to attain an 80% power at nominal level of one-sided α of 0.05 in each cohort. Results: Between Jun 29, 2020, and Feb 18, 2021, 26 pts were allocated in the study. Enrollment is complete in cohorts A (n=8 pts) and C (n=9 pts), and ongoing in the remaining cohorts. At data cutoff (May 21, 2021), median follow-up for the cohort A was 5.5 months (IQR 4.4-6.9) and 6.2 months (IQR 5.1-6.4) for the cohort C. In the cohort A, 6 (75.0%) of 8 pts were alive without disease progression at 16 weeks, reaching the primary endpoint (p<0.01). In the cohort C, the CNS ORR was 55.6% (5 pts with partial response), also meeting the primary endpoint (p<0.01). At the time of this analysis, 75.0% of pts of the cohort A and 55.6% of the cohort C remained on therapy. The most frequent adverse events of any grade in 26 pts who received at least 1 dose of T-DXd were fatigue (11 [42.3%]; 3.8% of grade 3), nausea (10 [38.5%]), a decreased neutrophil count (9 [34.6%]; 11.5% of grade 3), and anemia (6 [23.1%]). Treatment-related serious adverse events occurred in 1 (3.8%) of 26 pts due to grade 1 pneumonitis. No treatment-related deaths were reported. Conclusions: T-DXd demonstrated preliminary efficacy with manageable toxicity in pretreated pts with HER2[+] ABC with stable and progressing BM after local treatment. Further investigation is required in larger cohorts to validate these findings. The assessment of the T-DXd antitumor activity in cohorts B, D, and E is currently ongoing. Citation Format: Marta Vaz Batista, Patricia Cortez, Manuel Ruiz, Juan Miguel Cejalvo, Juan de la Haba, Laia Garrigós, Fabricio Racca, Sonia Servitja, Salvador Blanch, Iris Teruel, José Manuel Pérez-García, María Gion, Monica Nave, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Sofia Braga. Trastuzumab deruxtecan in patients with HER2[+] or HER2-low-expressing advanced breast cancer and central nervous system involvement: Preliminary results from the DEBBRAH phase 2 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-06.
Background This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2 - ) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methods Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR + /HER2 - mBC who had progressed on ≥4 treatments for advanced disease were eligible. Results A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7–7.0) and the median overall survival was 19.0 months (95% CI 16.4–21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37–2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. Conclusions Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.
Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela), an intravenously delivered immuno-oncolytic reovirus, given in combination with paclitaxel (PTX) versus PTX alone [1]. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive T cell response triggered by pela. To examine if pela can mediate the priming of an anti-tumor immune response, and the impact of checkpoint blockade therapy on this response, we and SOLTI research group are conducting the AWARE-1 study (NCT04102618) in patients with early breast cancer. The initial translational research results from this study are presented here. Methods: AWARE-1 is a window-of-opportunity study to evaluate the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, and atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five patient cohorts are being examined: Cohort 1: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole (without atezolizumab); Cohort 2: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole + atezolizumab; Cohort 3: TNBC (6 patients) receiving pelareorep + atezolizumab; Cohort 4: HR+/HER2+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab; Cohort 5: HR-neg/HER+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab. The primary endpoint is CelTIL score [2], a metric for quantifying changes in tumor cellularity and the number of tumor infiltrating lymphocytes (TILs), where an increase in CelTIL score has been associated with a favorable response to treatment. Tumor tissue is being examined for pela replication, changes to the TME by immunohistochemistry (IHC), PD-L1 expression by the Ventana SP142 assay used as the atezolizumab companion diagnostic, and T cell clonality by T cell receptor sequencing (TCR-seq). Peripheral blood is also being examined by TCR-seq. Results: Changes in the TME by IHC demonstrate that treatment with pela in the presence of atezolizumab increases the CD8/Treg ratio, a predictor of greater therapeutic efficacy, similar to preclinical breast cancer mouse models [3, 4]. Detailed TCR-seq, Ventana PD-L1 assay results, and IHC analysis will be presented, focusing on differences between patients receiving pela in the absence or presence of atezolizumab (Cohorts 1 and 2, respectively), and between CelTIL scores of responders and non-responders. Overall, these data demonstrate that pela can promote an inflamed tumor phenotype that allows for synergy with checkpoint blockade therapy in breast cancer. References: [1] Bernstein, V., et al. Breast Cancer Res Treat, 2018. 167(2): p. 485-493. [2] Nuciforo, P., et al. Ann Oncol, 2018. 29(1): p. 170-177. [3] Mostafa, A.A., et al. Cancers (Basel), 2018. 10(6). [4] Lee, J., et al. Cancer Research, 2020. 80(16 Supplement): p. 2206-2206. Citation Format: Luis Manso, Fernando Salvador, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan M. Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose L. Alonso, Alejandro Martínez, Rafael Villanueva, Juan A. Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca Gonzalez-Farre, Grey A. Wilkinson, Thomas C. Heineman, Gerard Nuovo, Houra Loghmani, Matt Coffey, Azucena Gonzalez, Débora Martínez, Laia Paré, Tomás Pascual, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (AWARE-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT191.
Background: A previous phase 2 study in metastatic breast cancer compared treatment with intravenously delivered oncolytic reovirus, pelareorep (pela), in combination with paclitaxel (PTX) versus PTX alone. This study demonstrated a statistically significant improvement in overall survival (OS), without differences in objective response or progression-free survival. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive immune response triggered by pela. To test this hypothesis, and examine if pela can mediate the priming of an anti-tumor immune response, we designed a study called AWARE-1 (A window-of-opportunity study of pela in Early Breast Cancer), which is currently enrolling and for which initial translational research results are presented. Methods: AWARE-1 is evaluating the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, while atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five cohorts will be examined: Cohort 1: Hormone Receptor-positive/HER2-negative (HR+/HER2-neg) (10 patients), pelareorep + letrozole. Cohort 2: HR+/HER2-neg (10 patients), pelareorep + letrozole + atezolizumab. Cohort 3: Triple Negative Breast Cancer (TNBC) (6 patients), pelareorep + atezolizumab. Cohort 4: Hormone Receptor-positive/HER2-positive (HR+/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. Cohort 5: Hormone Receptor-negative/HER2-positive (HR-/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. The primary endpoint of the study is CelTIL score, a metric for quantifying the changes in tumor cellularity and infiltration of TILs, where an increase in CelTIL is associated with a favorable response to treatment. Tumor tissue was examined for pela replication, and changes to the TME were assessed by imaging mass cytometry (IMC), immunohistochemistry, and T cell receptor sequencing (TCR-seq). Peripheral blood was also examined by TCR-seq. Results: Detailed translational research results will be presented from patients in cohort 1, who received just pelareorep and letrozole. CelTIL score increased in 5/10 patients at day 3 biopsies and 6/10 patients at day 21 biopsies. Preliminary results show high levels of viral replication (>50% of tumor cells) while immunohistochemistry and IMC analysis revealed changes to the TME, with increases in CD8+ T cells and upregulation of PD-L1 at both day 3 and day 21 biopsies. Overall, preliminary data from cohort 1 of AWARE-1 demonstrate pela-mediated priming of an adaptive immune response. (NCT04102618) Citation Format: Luis Manso, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan Miguel Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose Luis Alonso, Alejandro Martínez, Rafael Villanueva, Juan Antonio Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca González, Rita Laeufle, Gerard Nuovo, Grey Wilkinson, Matt Coffey, Azucena González, Débora Martínez, Laia Paré, Fernando Salvador, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (REO-027, AWARE-1) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-08.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.