Asunto(s)
Camptotecina , Neoplasias Colorrectales , Inmunoconjugados , Metástasis de la Neoplasia , Receptor ErbB-2 , Trastuzumab , Humanos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Inmunoconjugados/administración & dosificación , Inmunoconjugados/uso terapéutico , Receptor ErbB-2/metabolismo , Trastuzumab/administración & dosificación , Trastuzumab/uso terapéuticoRESUMEN
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new therapeutic approach for patients with peritoneal cancer. So far, most published studies investigated the administration of established cytostatic agents through PIPAC. This study aimed to evaluate the effect of PIPAC on two breakthrough anti-cancer agents, specifically anti-PD1 pembrolizumab, and anti-HER2 antibody-drug conjugate (ADC) - trastuzumab-deruxtecan. We conducted systematic analyses on samples of pembrolizumab and trastuzumab-deruxtecan at clinically relevant concentrations before and after PIPAC administration using an experimental setup of a hermetic container system, mimicking the abdominal cavity and using identical features as in clinical use. We utilized a range of chromatographic and spectroscopic techniques to explore potential alterations in the primary, secondary, and tertiary structures of the drugs, focusing on post-translational modifications resulting from the aerosolization. Our findings indicate that PIPAC did not compromise the integrity of tested biopharmaceuticals. The size variants of both drugs, assessed by size exclusion chromatography (SEC), remained unchanged. Reversed-phase liquid chromatography (RPLC) and hydrophobic interaction chromatography (HIC) revealed no significant differences in hydrophobicity variants, the average drug-to-antibody ratio (DAR), or DAR distribution before and after PIPAC treatment. Circular dichroism (CD) spectroscopy confirmed that the secondary and tertiary structures were preserved. While pembrolizumab showed no change in charge variants post-PIPAC, trastuzumab-deruxtecan exhibited a non-negligible change in the quantity of charge variants on the monoclonal antibody itself, while the payload remained unchanged. This shift could possibly be related to the metallic composition of the CapnoPen® device (made of nickel and chromium) used in PIPAC and for these experiments. Together, our results suggest that PIPAC does not alter the structure of pembrolizumab and trastuzumab-deruxtecan, paving the way for future clinical trials.
Asunto(s)
Aerosoles , Anticuerpos Monoclonales Humanizados , Estabilidad de Medicamentos , Inmunoconjugados , Trastuzumab , Aerosoles/química , Trastuzumab/química , Inmunoconjugados/química , Inmunoconjugados/análisis , Inmunoconjugados/administración & dosificación , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/análisis , Anticuerpos Monoclonales Humanizados/administración & dosificación , Humanos , Neoplasias Peritoneales/tratamiento farmacológico , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/administración & dosificación , Receptor ErbB-2/antagonistas & inhibidores , PresiónRESUMEN
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma subtype with a significant relapse rate and poor prognosis in relapsed/refractory (R/R) patients. Polatuzumab vedotin in combination with bendamustine and rituximab (Pola-BR) has demonstrated promising efficacy and safety as salvage therapy for R/R DLBCL. This systematic review protocol aims to comprehensively evaluate the efficacy of Pola-BR for the treatment of R/R DLBCL by synthesizing data from relevant randomized controlled trials. METHODS: This protocol details the eligibility criteria, search strategy, study selection, data extraction, and analysis methods for the systematic review. Randomized controlled trials comparing Pola-BR with other interventions for R/R DLBCL will be included. The primary endpoint is overall survival, with secondary endpoints being progression-free survival and incidence of adverse events. A comprehensive search will be conducted across databases such as Medline/PubMed, Cochrane Library, Web of Science, Scopus, EMBASE, ProQuest, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov from the January 2000 to April 2024. To assess the potential risk of bias, the Cochrane Risk of Bias 1 tool will be used. Data synthesis will utilize fixed-effect or random-effects models, and subgroup and meta-regression analyses will examine heterogeneity. Additionally, publication bias and sensitivity analyses will be performed, and the GRADE approach will be applied to assess the certainty of the evidence. CONCLUSION: This systematic review and meta-analysis protocol provides a rigorous framework for evaluating the efficacy of Pola-BR in the treatment of R/R DLBCL. The results will inform clinical decision-making and guideline development, addressing the unmet need for effective and tolerable treatments for this challenging patient population. Potential limitations and biases will be acknowledged, and future research directions will be discussed.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Clorhidrato de Bendamustina , Linfoma de Células B Grandes Difuso , Rituximab , Revisiones Sistemáticas como Asunto , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Anticuerpos MonoclonalesAsunto(s)
Enfermedad de Hodgkin , Tomografía de Emisión de Positrones , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/diagnóstico por imagen , Brentuximab Vedotina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estadificación de Neoplasias , Inmunoconjugados/uso terapéutico , Inmunoconjugados/administración & dosificaciónRESUMEN
INTRODUCTION: Antibody-drug conjugates (ADCs) represent a revolutionary approach in the systemic treatment for both solid and hematologic tumors. Constituted by an antibody, a cytotoxic payload, and a linker, ADCs aim to selectively deliver cytotoxic agents to tumors while sparing normal tissues. Various ADCs have been tested and approved for multiple solid tumors so far, but if there is one that had a major impact on clinical practice, this is Trastuzumab-deruxtecan (T-DXd). Notably, T-DXd was approved for HER2-positive and HER2-low metastatic breast cancer (MBC), HER2-positive gastric cancer (GC), HER2-mutant non-small cell lung cancer (NSCLC) and HER2 3+ solid tumors. Moreover, it received Breakthrough Therapy Designation for HER2-positive colorectal cancer (CRC). AREAS COVERED: We review preclinical and clinical data of T-DXd, focusing on early-phase ongoing trials exploring combination therapies to enhance the activity of T-DXd in HER2-expressing solid tumors. EXPERT OPINION: The clinical use of T-DXd still raises questions about selection of patients, treatment duration, prioritization over other approved ADCs, and management of resistance. Concerns regarding the toxicity of T-DXd remain, particularly with combinations involving potentially toxic drugs. Advancements in biomarker identification and combination therapies offer promising avenues to enhance efficacy and overcome resistance to T-DXd, ultimately improving outcomes for patients with cancer.
Asunto(s)
Camptotecina , Desarrollo de Medicamentos , Inmunoconjugados , Receptor ErbB-2 , Trastuzumab , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Receptor ErbB-2/metabolismo , Trastuzumab/farmacología , Trastuzumab/administración & dosificación , Animales , Camptotecina/farmacología , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversosAsunto(s)
Receptor 1 de Folato , Inmunoconjugados , Neoplasias Ováricas , Medicina de Precisión , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Medicina de Precisión/métodos , Inmunoconjugados/uso terapéutico , Inmunoconjugados/administración & dosificación , Receptor 1 de Folato/antagonistas & inhibidores , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/patologíaRESUMEN
Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs.
Asunto(s)
Inmunidad Innata , Inmunoconjugados , Interferones , Proteínas de la Membrana , Animales , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/inmunología , Inmunidad Innata/efectos de los fármacos , Femenino , Humanos , Ratones , Línea Celular Tumoral , Inmunoconjugados/farmacología , Inmunoconjugados/administración & dosificación , Interferones/metabolismo , Interferón lambda , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Interferón Tipo I/inmunología , Citocinas/metabolismo , Células Mieloides/inmunología , Células Mieloides/efectos de los fármacos , Inmunoterapia/métodos , Ratones Endogámicos C57BL , Receptores de IgG/agonistas , Receptores de IgG/metabolismo , Receptores de IgG/inmunologíaRESUMEN
Objective: To evaluate the efficacy and safety of CD30 antibody-drug conjugates (ADC) brentuximab vedotin (BV) combined with chemotherapy in children with refractory or relapsed classic Hodgkin's lymphoma (R/R cHL). Methods: Clinical data (including age, gender, B symptoms, clinical stage, previous treatment, etc.) of the 10 R/R cHL children diagnosed and treated at Beijing Children's Hospital Affiliated to Capital Medical University from October 2021 to August 2023 were analyzed retrospectively. According to the different intensity of chemotherapy drugs, the dose of BV applied in the same course of treatment was 1.8 mg/kg for BV applied once every 3 weeks, and 1.2 mg/kg for BV applied once every 2 weeks. All 10 patients received at least 2 cycles of BV combined with chemotherapy and were evaluated every 2 cycles. The patients were followed up until May 31, 2024. The infusion reactions and adverse reactions after treatment were recorded. Results: In all 10 patients, there were 7 males and 3 females, the age ranged from 5.3-16.9 years, and there were 6 cases of refractory and 4 cases of relapsed. There were 6 cases of nodular sclerosis type, 2 cases of mixed cell type, 1 case of lymphocyte-rich type, and 1 case of lymphodepletion type. There were 5 cases of stage â £ and 5 cases of stage â ¢. Previous treatment was mainly chemotherapy, 4 cases received radiotherapy and 1 case received programmed cell death protein 1 (PD-1) antibody therapy. The follow-up time ranged from 9 to 27 months. A total of 43 courses with 49 doses of BV alone or combined with chemotherapy were recorded, and the number of courses was 2 to 10 times. All 10 children responded to the treatment, and 9 achieved complete remission. BV infusion was successfully completed in all cases. A total of 28 cases of grade 3 or above adverse events were recorded, mainly myelosuppression, all of which were related to chemotherapy and did not affect sequential treatment. Conclusion: Brentuximab vedotin has demonstrated efficacy and a tolerable safety profile in the treatment of refractory and relapsed CD30-positive Hodgkin's lymphoma in children.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotina , Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Femenino , Masculino , Niño , Adolescente , Estudios Retrospectivos , Preescolar , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resultado del Tratamiento , Inmunoconjugados/administración & dosificaciónRESUMEN
AIMS: We studied the pharmacokinetics and exposure-response relationships of the brentuximab vedotin (BV) antibody-drug conjugate (ADC) and unconjugated monomethyl auristatin E in haematologic malignancies. METHODS: This population pharmacokinetic analysis included data from five adult and three paediatric studies. Exposures in virtual adult and paediatric populations following BV 1.8 mg/kg (maximum 180 mg) intravenously every 3 weeks were simulated. Clinical endpoints included overall response rate, grade ≥2 peripheral neuropathy (PN) and grade ≥3 neutropenia. RESULTS: BV ADC exhibited linear pharmacokinetics, well-described by a three-compartment model, with body weight being the only significant covariate for exposure. Monomethyl auristatin E exhibited time-varying formation rate. Simulated steady-state BV ADC exposures in patients aged 12 to <18 years were similar to those of adult patients, but 23%-38% lower in patients aged 2 to <12 years. Despite lower exposure, clinical activity was observed with BV 1.8 mg/kg every 3 weeks in those aged 2 to <12 years (overall response rate: 2 to <12 years, 60%; 12 to <18 years, 43%). In adult, but not paediatric patients, increased BV ADC exposures were associated with grade ≥2 PN and grade ≥3 neutropenia occurrence. CONCLUSIONS: BV pharmacokinetics in adult and paediatric patients were consistent. BV ADC exposures were lower in patients aged 2 to <12 years vs. ≥12 years, but no apparent clinically relevant differences in efficacy, grade ≥2 PN or grade ≥3 neutropenia were observed. These data support body weight-based dosing of BV in patients irrespective of age; thus, dose adjustment in those 2 to <12 years does not appear warranted.
Asunto(s)
Peso Corporal , Brentuximab Vedotina , Inmunoconjugados , Humanos , Niño , Brentuximab Vedotina/administración & dosificación , Brentuximab Vedotina/farmacocinética , Brentuximab Vedotina/efectos adversos , Adolescente , Preescolar , Inmunoconjugados/farmacocinética , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Masculino , Femenino , Adulto , Modelos Biológicos , Neoplasias Hematológicas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Adulto Joven , Factores de Edad , Neutropenia/inducido químicamente , Oligopéptidos/farmacocinética , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , Persona de Mediana Edad , Anciano , Simulación por ComputadorRESUMEN
BACKGROUND: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown. METHODS: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC. RESULTS: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2. CONCLUSIONS: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama , Camptotecina , Inmunoconjugados , Receptor ErbB-2 , Trastuzumab , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Trastuzumab/uso terapéutico , Trastuzumab/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Persona de Mediana Edad , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/administración & dosificación , Anciano , Receptor ErbB-2/metabolismo , Inmunoconjugados/uso terapéutico , Inmunoconjugados/administración & dosificación , Estudios Retrospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Metástasis de la Neoplasia , Supervivencia sin Progresión , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Asunto(s)
Anticuerpos Biespecíficos , Receptores ErbB , Inmunoconjugados , Neoplasias , Receptor ErbB-3 , Humanos , Persona de Mediana Edad , Masculino , Femenino , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/uso terapéutico , Anciano , Adulto , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/inmunología , Receptor ErbB-3/antagonistas & inhibidores , Receptor ErbB-3/inmunología , Adulto Joven , Dosis Máxima Tolerada , Adolescente , Metástasis de la Neoplasia , China , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
OBJECTIVE: The single-arm, phase II SORAYA trial (NCT04296890) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)-high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. METHODS: Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. RESULTS: At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. CONCLUSION: These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Resistencia a Antineoplásicos , Receptor 1 de Folato , Inmunoconjugados , Maitansina , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Receptor 1 de Folato/metabolismo , Persona de Mediana Edad , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Maitansina/administración & dosificación , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Adulto , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Anciano de 80 o más AñosRESUMEN
The higher frequency of metastasization and poor prognosis of triple-negative breast cancer require suitable expertise in order to set up an appropriate and effective treatment plan for these patients. Our case describes the clinical history of a 63-year-old BRCA1/2 wild-type woman with excellent ECOG performance status and advanced PD-L1 negative breast cancer with brain, nodal and hepatic metastases. When occurred the brain progression within one year from neoadjuvant chemotherapy for a locally advanced tumor, the patient was treated with brain stereotaxis and a systemic platinum-based therapy that was not completed due to poor tolerance. Later instrumental examinations confirmed a new systemic and visceral progression, for which the patient underwent new therapy with sacituzumab govitecan (SG). During this treatment, we observed a reduction of the target liver and nodal lesions. The onset after several months of two very small cortico-subcortical metastases, on which stereotactic radiotherapy was performed, did not lead us to discontinuate the treatment, that was ongoing for another six months, with an excellent control both of brain and systemic disease without any symptoms, until a new disease progression at other sites requiring a therapeutic change. The use of antibody-drug conjugates allowed a significant prolongation of time to progression and overall survival in our clinical scenario characterized by poor prognosis due to early recurrence and brain involvement.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias Encefálicas , Camptotecina , Neoplasias de la Mama Triple Negativas , Humanos , Persona de Mediana Edad , Femenino , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Inmunoconjugados/administración & dosificación , Inmunoconjugados/farmacología , Factores de Tiempo , Progresión de la Enfermedad , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients.
Asunto(s)
Neoplasias de la Mama , Inmunoconjugados , Dosis Máxima Tolerada , Receptor ErbB-2 , Humanos , Femenino , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Inmunoconjugados/uso terapéutico , Inmunoconjugados/administración & dosificación , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Metástasis de la NeoplasiaRESUMEN
Antibody-drug conjugates (ADCs), from prototypes in the 1980s to first- and second-generation products in the 2000s, and now in their multiformats, have progressed tremendously to meet oncological challenges. Currently, 13 ADCs have been approved for medical practice, with over 200 candidates in clinical trials. Moreover, ADCs have evolved into different formats, including bispecific ADCs, probody-drug conjugates, pH-responsive ADCs, target-degrading ADCs, and immunostimulating ADCs. Technologies from biopharmaceutical industries have a crucial role in the clinical transition of these novel biotherapeutics. In this review, we highlight several features contributing to the prosperity of bioindustrial ADC development. Various proprietary technologies from biopharmaceutical companies are discussed. Such advances in biopharmaceutical industries are the backbone for the success of ADCs in development and clinical application.
Asunto(s)
Biotecnología , Desarrollo de Medicamentos , Industria Farmacéutica , Inmunoconjugados , Inmunoconjugados/uso terapéutico , Inmunoconjugados/administración & dosificación , Humanos , Biotecnología/métodos , Industria Farmacéutica/métodos , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/tendencias , AnimalesRESUMEN
Brentuximab vedotin (BV), a conjugate of anti-CD30 antibody and monomethyl auristatin E, has emerged as a promising treatment option for refractory CD30+ mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). BV has been shown to be safe and effective in treating Hodgkin's lymphoma and peripheral T-cell lymphoma. This multicenter, prospective, single-arm phase I/II study evaluated the efficacy of BV in Japanese patients with CD30+ cutaneous lymphomas, namely CD30+ cutaneous T-cell lymphoma. Participants were divided into two groups: those with CD30+ MF or pcALCL (cohort 1, n = 13) and those with CD30+ lymphoproliferative disorders other than those in cohort 1 (cohort 2, n = 3). The studied population included the full analysis set (FAS), modified FAS (mFAS), and safety analysis set (SAF). These sets were identified in cohorts 1 and 1 + 2 and labeled FAS1 and FAS2, mFAS1 and mFAS2, and SAF1 and SAF2, respectively. Each treatment cycle lasted 3 weeks, and BV was continued for up to 16 cycles after the third cycle based on treatment response. The primary endpoint was the 4-month objective response rate (ORR4) determined by the Independent Review Forum (IRF). ORR4 was 69.2% for FAS1 and 62.5% for FAS2 (P < 0.0001). Secondary endpoints of ORR, assessed using the global response score (53.8% in FAS1) and modified severity-weighted assessment tool (62.5% in FAS1), using the IRF, provided results comparable to the primary findings. The incidence of ≥grade 3 adverse events (≥15%) in SAF1 was peripheral neuropathy in three patients (23%) and fever and eosinophilia in two patients (15%). In conclusion, BV showed favorable efficacy, tolerability, and safety profile in Japanese patients with relapsed or refractory CD30+ primary cutaneous T-cell lymphoma. The trial was registered with University Hospital Medical Information Network Clinical Trials Registry, Japan (protocol ID: UMIN000034205).
Asunto(s)
Brentuximab Vedotina , Antígeno Ki-1 , Neoplasias Cutáneas , Humanos , Brentuximab Vedotina/administración & dosificación , Brentuximab Vedotina/uso terapéutico , Masculino , Persona de Mediana Edad , Antígeno Ki-1/inmunología , Antígeno Ki-1/análisis , Femenino , Anciano , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Estudios Prospectivos , Japón , Adulto , Anciano de 80 o más Años , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/patología , Micosis Fungoide/inmunología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Resultado del Tratamiento , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Disitamab vedotin (DV; RC48-ADC) is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)-directed antibody, linker and monomethyl auristatin E. Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast, gastric, and ovarian cancers with different levels of HER2 expression. In this pooled analysis, we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer (ABC). METHODS: In the phase I dose-escalation study (C001 CANCER), HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The dose range, safety, and pharmacokinetics (PK) were determined. The phase Ib dose-range and expansion study (C003 CANCER) enrolled two cohorts: HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W, with the recommended phase 2 dose (RP2D) determined, and HER2-low ABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC. RESULTS: Twenty-four patients with HER2-overexpression ABC in C001 CANCER, 46 patients with HER2-overexpression ABC and 66 patients with HER2-low ABC in C003 CANCER were enrolled. At 2.0 mg/kg RP2D Q2W, the confirmed objective response rates were 42.9% (9/21; 95% confidence interval [CI]: 21.8%-66.0%) and 33.3% (22/66; 95% CI: 22.2%-46.0%), with median progression-free survival (PFS) of 5.7 months (95% CI: 5.3-8.4 months) and 5.1 months (95% CI: 4.1-6.6 months) for HER2-overexpression and HER2-low ABC, respectively. Common (≥5%) grade 3 or higher treatment-emergent adverse events included neutrophil count decreased (17.6%), gamma-glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy such as hypoesthesia (5.9%) and neurotoxicity (0.7%), and pain (5.9%). CONCLUSION: DV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC, with a favorable safety profile at 2.0 mg/kg Q2W.
Asunto(s)
Neoplasias de la Mama , Inmunoconjugados , Receptor ErbB-2 , Humanos , Femenino , Receptor ErbB-2/metabolismo , Persona de Mediana Edad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Inmunoconjugados/administración & dosificación , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacocinética , Inmunoconjugados/efectos adversos , Anciano , Adulto , Anciano de 80 o más AñosRESUMEN
INTRODUCTION: Modern immunotherapy approaches are revolutionizing the treatment scenario of relapsed/refractory (RR) multiple myeloma (MM) patients, providing an opportunity to reach deep level of responses and extend survival outcomes. AREAS COVERED: Antibody-drug conjugates (ADCs) and T-cell redirecting treatments, including bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T cells therapy, have been recently introduced in the treatment of RRMM. Some agents have already received regulatory approval, while newer constructs, novel combinations, and applications in earlier lines of therapy are currently being explored. This review discusses the current landscape and possible development of ADCs, BsAbs and CAR-T cells immunotherapies. EXPERT OPINION: ADCs, BsAbs, and CAR-T therapy have demonstrated substantial activity in heavily pretreated, triple-class exposed (TCE) MM patients, and T-cell redirecting treatments represent new standards of care after third (European Medicines Agency, EMA), or fourth (Food and Drug Administration, FDA), line of therapy. All these three immunotherapies carry advantages and disadvantages, with different accessibility and new toxicities that require appropriate management and guidelines. Multiple on-going programs include combinations therapies and applications in earlier lines of treatment, as well as the development of novel agents or construct to enhance potency, reduce toxicity and facilitate administration. Sequencing is a challenge, with few data available and mechanisms of resistance still to be unraveled.
Asunto(s)
Anticuerpos Biespecíficos , Inmunoconjugados , Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/farmacología , Mieloma Múltiple/terapia , Mieloma Múltiple/inmunología , Mieloma Múltiple/tratamiento farmacológico , Inmunoconjugados/farmacología , Inmunoconjugados/administración & dosificación , Inmunoterapia Adoptiva/métodos , Animales , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Tasa de Supervivencia , Inmunoterapia/métodos , Desarrollo de MedicamentosRESUMEN
INTRODUCTION: Antibody-drug conjugates (ADCs) show significant clinical efficacy in the treatment of solid tumors, but a major limitation to their success is poor intratumoral distribution. Adding a carrier dose improves both distribution and overall drug efficacy of ADCs, but the optimal carrier dose has not been outlined for different payload classes. OBJECTIVE: In this work, we study two carrier dose regimens: 1) matching payload potency to cellular delivery but potentially not reaching cells farther away from blood vessels, or 2) dosing to tumor saturation but risking a reduction in cell killing from a lower amount of payload delivered per cell. METHODS: We use a validated computational model to test four different payloads conjugated to trastuzumab to determine the optimal carrier dose as a function of target expression, ADC dose, and payload potency. RESULTS: We find that dosing to tumor saturation is more efficacious than matching payload potency to cellular delivery for all payloads because the increase in the number of cells targeted by the ADC outweighs the loss in cell killing on targeted cells. An important exception exists if the carrier dose reduces the payload uptake per cell to the point where all cell killing is lost. Likewise, receptor downregulation can mitigate the benefits of a carrier dose. CONCLUSIONS: Because tumor saturation and in vitro potency can be measured early in ADC design, these results provide insight into maximizing ADC efficacy and demonstrate the benefits of using simulation to guide ADC design.