RESUMO
Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8+ T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I trial on the combination of eliglustat and an anti-PD-1 antibody for the treatment of advanced cancers (NCT04944888). The primary endpoints were safety and feasibility, and the secondary endpoint was antitumor activity. All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed. The objective response rate was 22.6% and the disease control rate reached 71%. Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach.
Assuntos
Glicoesfingolipídeos , Inibidores de Checkpoint Imunológico , Pirrolidinas , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , Glicoesfingolipídeos/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Pirrolidinas/uso terapêutico , Pirrolidinas/farmacologia , Animais , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Camundongos , Glucosiltransferases/antagonistas & inibidores , Adulto , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
PURPOSE: Real-world data (RWD) holds promise for ascribing a real-world (rw) outcome to a drug intervention; however, ascertaining rw-response to treatment from RWD can be challenging. Friends of Cancer Research formed a collaboration to assess available data attributes related to rw-response across RWD sources to inform methods for capturing, defining, and evaluating rw-response. MATERIALS AND METHODS: This retrospective noninterventional (observational) study included seven electronic health record data companies (data providers) providing summary-level deidentified data from 200 patients diagnosed with metastatic non-small cell lung cancer (mNSCLC) and treated with first-line platinum doublet chemotherapy following a common protocol. Data providers reviewed the availability and frequency of data components to assess rw-response (ie, images, radiology imaging reports, and clinician response assessments). A common protocol was used to assess and report rw-response end points, including rw-response rate (rwRR), rw-duration of response (rwDOR), and the association of rw-response with rw-overall survival (rwOS), rw-time to treatment discontinuation (rwTTD), and rw-time to next treatment (rwTTNT). RESULTS: The availability and timing of clinician assessments was relatively consistent across data sets in contrast to images and image reports. Real-world response was analyzed using clinician response assessments (median proportion of patients evaluable, 77.5%), which had the highest consistency in the timing of assessments. Relative consistency was observed across data sets for rwRR (median 46.5%), as well as the median and directionality of rwOS, rwTTD, and rwTTNT. There was variability in rwDOR across data sets. CONCLUSION: This collaborative effort demonstrated the feasibility of aligning disparate data sources to evaluate rw-response end points using clinician-documented responses in patients with mNSCLC. Heterogeneity exists in the availability of data components to assess response and related rw-end points, and further work is needed to inform drug effectiveness evaluation within RWD sources.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Registros Eletrônicos de Saúde , Estudos de Viabilidade , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Metástase Neoplásica , Idoso de 80 Anos ou maisRESUMO
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death all over the world, and brings a heavy social economic burden especially in China. Several immuno-combination therapies have shown promising efficacy in the first-line treatment of unresectable HCC and are widely used in clinical practice. Nevertheless, which combination is the most affordable one is unknown. Our study assessed the cost-effectiveness of the immuno-combinations as first-line treatment for patients with unresectable HCC from the perspective of Chinese payers. METHODS: A Markov model was built according to five multicenter, phase III, open-label, randomized trials (Himalaya, IMbrave150, ORIENT-32, CARES-310, LEAP-002) to investigate the cost-effectiveness of tremelimumab plus durvalumab (STRIDE), atezolizumab plus bevacizumab (A + B), sintilimab plus bevacizumab biosimilar (IBI305) (S + B), camrelizumab plus rivoceranib (C + R), and pembrolizumab plus lenvatinib (P + L). Three disease states were included: progression free survival (PFS), progressive disease (PD) as well as death. Medical costs were searched from West China Hospital, published literatures or the Red Book. Cost-effectiveness ratios (CERs) and incremental cost-effectiveness ratios (ICERs) were evaluated to compare costs among different combinations. Sensitivity analyses were performed to assess the robust of the model. RESULTS: The total cost and quality-adjusted life years (QALYs) of C + R, S + B, P + L, A + B and STRIDE were $12,109.27 and 0.91, $26,961.60 and 1.12, $55,382.53 and 0.83, $70,985.06 and 0.90, $84,589.01 and 0.73, respectively, resulting in the most cost-effective strategy of C + R with CER of $13,306.89 per QALY followed by S + B with CER of $24,072.86 per QALY. Compared with C + R, the ICER of S + B strategy was $70,725.38 per QALY, which would become the most cost-effective when the willing-to-pay threshold exceeded $73,500/QALY. In the subgroup analysis, with the application of Asia results in Leap-002 trial, the model results were the same as global data. In the sensitivity analysis, with the variation of parameters, the results were robust. CONCLUSION: As one of the promising immuno-combination therapies in the first-line systemic treatment of HCC, camrelizumab plus rivoceranib demonstrated the potential to be the most cost-effective strategy, which warranted further studies to best inform the real-world clinical practices.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Análise de Custo-Efetividade , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Humanos , Anticorpos Monoclonais Humanizados/economia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Bevacizumab/economia , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/economia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , China/epidemiologia , Ensaios Clínicos Fase III como Assunto , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/economia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/economia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Cadeias de Markov , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/economia , Intervalo Livre de Progressão , Anos de Vida Ajustados por Qualidade de Vida , Quinolinas/uso terapêutico , Quinolinas/economia , Quinolinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Many therapies are available for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥ 2 lines of therapy, albeit with scant evidence on the comparative effectiveness of these therapies. This study used inverse probability of treatment weighting to indirectly compare treatment outcomes of epcoritamab from the EPCORE NHL-1 trial with individual patient data from clinical practice cohorts treated with chemoimmunotherapy (CIT) and novel therapies (polatuzumab-based regimens, tafasitamab-based regimens, and chimeric antigen receptor T-cell [CAR T] therapies) for third-line or later R/R large B-cell lymphoma (LBCL) and DLBCL. In this analysis, epcoritamab demonstrated significantly better response rates and overall survival rates than CIT, polatuzumab-based regimens, and tafasitamab-based regimens. No statistically significant differences in response rates or survival were found for epcoritamab compared with CAR T in R/R LBCL.
Assuntos
Anticorpos Monoclonais Humanizados , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/terapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Resultado do Tratamento , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Adulto , Recidiva Local de Neoplasia/tratamento farmacológicoAssuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Quimioterapia Adjuvante , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Ensaios Clínicos Controlados Aleatórios como AssuntoAssuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Bevacizumab/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêuticoAssuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Bevacizumab , Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêuticoAssuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Bevacizumab/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
The effect of chemotherapy for anti-glioblastoma is limited due to insufficient drug delivery across the blood-brain-barrier. Poloxamer 188-coated nanoparticles can enhance the delivery of nanoparticles across the blood-brain-barrier. This study presents the design, preparation, and evaluation of a combination of PLGA nanoparticles (PLGA NPs) loaded with methotrexate (P-MTX NPs) and PLGA nanoparticles loaded with paclitaxel (P-PTX NPs), both of which were surface-modified with poloxamer188. Cranial tumors were induced by implanting C6 cells in a rat model and MRI demonstrated that the tumors were indistinguishable in the two rats with P-MTX NPs + P-PTX NPs treated groups. Brain PET scans exhibited a decreased brain-to-background ratio which could be attributed to the diminished metabolic tumor volume. The expression of Ki-67 as a poor prognosis factor, was significantly lower in P-MTX NPs + P-PTX NPs compared to the control. Furthermore, the biodistribution of PLGA NPs was determined by carbon quantum dots loaded into PLGA NPs (P-CQD NPs), and quantitative analysis of ex-vivo imaging of the dissected organs demonstrated that 17.2 ± 0.6% of the NPs were concentrated in the brain after 48 h. The findings highlight the efficacy of combination nanochemotherapy in glioblastoma treatment, indicating the need for further preclinical studies.
Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas , Glioblastoma , Metotrexato , Nanopartículas , Poloxâmero , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/diagnóstico por imagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Nanopartículas/química , Ratos , Poloxâmero/química , Metotrexato/química , Metotrexato/administração & dosagem , Metotrexato/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Distribuição Tecidual , Portadores de Fármacos/química , Masculino , Sistemas de Liberação de Medicamentos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , HumanosRESUMO
BACKGROUND: The combination of targeted therapy and immunotherapy has improved the clinical outcomes of unresectable hepatocellular Carcinoma (HCC). However, the overall prognosis remains suboptimal. This study aims to evaluate the efficacy and safety of a novel combination of radiofrequency ablation (RFA) with lenvatinib plus sintilimab in unresectable HCC. METHODS: In this retrospective study, patients diagnosed with unresectable HCC were included and divided into two cohorts: RFA combined with lenvatinib plus sintilimab (R-L-S group) and lenvatinib plus sintilimab (L-S group). The primary efficacy endpoints were objective response rate (ORR) and progression free survival (PFS). Adverse events were analyzed to assess the safety profiles. RESULTS: The median follow-up periods for the entire cohort were 14.0 months. The R-L-S group (n = 60) had a significantly higher ORR than those with L-S alone (n = 62) (40.0% vs. 20.9%; p = 0.022). Moreover, patients in the R-L-S group had improved median PFS (12 vs. 8 months; p = 0.013) and median overall survival (24 vs. 18 months; p = 0.037), as compared with lenvatinib and sintilimab alone. No significant difference in treatment related adverse event (TRAE) of any grade between the two groups. The most common TRAEs of grade ≥ 3 were fatigue 10.0% (6/60) and hand-foot skin reaction 10.0% (6/60) in the R-L-S group and hand-foot skin reaction 11.3% (7/62) in the L-S group. CONCLUSION: In unresectable HCC patients, the incorporation of RFA to lenvatinib plus sintilimab demonstrated improved efficacy without compromising safety compared with lenvatinib plus sintilimab alone.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Ablação por Radiofrequência , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Quinolinas/uso terapêutico , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Masculino , Feminino , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Ablação por Radiofrequência/métodos , Ablação por Radiofrequência/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Resultado do Tratamento , Idoso de 80 Anos ou maisRESUMO
There are no standard third-line or beyond treatments for patients with driver mutation-positive advanced lung adenocarcinoma (LUAD). Anlotinib was approved as a third-line multitarget drug in China in 2018. Limited data are available regarding the efficacy and safety of anlotinib compared with chemotherapy. To investigate the efficacy and safety of anlotinib compared with traditional chemotherapy in patients with epidermal growth factor receptor (EGFR)-positive advanced LUAD. We conducted a retrospective study of 83 EGFR mutation-positive patients with advanced LUAD between 2011 and 2022. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints, whereas the objective response rate (ORR) and disease control rate (DCR) were the secondary endpoints. Anlotinib-related adverse events (AEs) were recorded to evaluate the safety of anlotinib. 39 patients with LUAD received anlotinib and 44 patients with LUAD received chemotherapy were enrolled in the study. Patients treated with anlotinib exhibited longer PFS (11.2 vs 4.5 months, P < .01) and OS (18.8 vs 15.8 months, P < .05) than patients treated with chemotherapy. There were no significant differences in ORR (7.9% vs 20.5%, P = .129) or DCR (100% vs 93.2%, P = .120) between the two groups. Anlotinib-related AEs grading 3-4 level were observed in 2 (5.1%) patients, no anlotinib-related death was recorded. Cox regression analyses of PFS and OS showed that brain metastases and age < 30 years at diagnosis had negative effects on clinical outcomes. Anlotinib is effective and safe in patients with EGFR-positive advanced LUAD. Patients without brain metastases had better clinical outcomes.
Assuntos
Adenocarcinoma de Pulmão , Receptores ErbB , Indóis , Neoplasias Pulmonares , Quinolinas , Humanos , Masculino , Feminino , Indóis/uso terapêutico , Indóis/efeitos adversos , Indóis/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Quinolinas/administração & dosagem , Pessoa de Meia-Idade , Receptores ErbB/genética , Receptores ErbB/metabolismo , Idoso , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Estudos Retrospectivos , Adulto , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Resultado do Tratamento , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Estadiamento de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversosRESUMO
Non-Hodgkin's lymphoma (NHL) is the most common type of Gastrointestinal (GI) lymphoma with known complications such as bleeding, obstruction and perforation. In this article we present a 59-year-old male patient diagnosed with Peripheral T cell Lymphoma - Not Otherwise Specified (PTCL-NOS) with GI involvement was started on chemotherapy. On day 2 post completion of first cycle of chemotherapy, patient had presented to the emergency department with sudden onset abdominal pain and distension. On evaluation, he was diagnosed with multiple perforations in the small bowel. Patient underwent exploration with primary repair of few perforations and ileal resection with double barrel ileostomy. Chemotherapy plays an important role in the management of NHL. One well-known NHL consequence, intestinal perforation, can happen at the time of initial presentation or after starting chemotherapy. Surgeons should be aware of possibility of such complications and high-risk factors for perforation. At present, there is no role for elective surgery in GI lymphoma and is mainly reserved for complications like uncontrolled bleeding, obstruction or perforation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Perfuração Intestinal , Linfoma de Células T Periférico , Tomografia Computadorizada por Raios X , Humanos , Perfuração Intestinal/diagnóstico , Perfuração Intestinal/etiologia , Masculino , Pessoa de Meia-Idade , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Vincristina/uso terapêutico , Doxorrubicina/uso terapêutico , Ciclofosfamida/uso terapêutico , Ciclofosfamida/efeitos adversos , Prednisona/uso terapêuticoRESUMO
BACKGROUND: Autologous stem cell transplantation (ASCT) is a pivotal treatment for lymphoma patients. The BeEAM regimen (Bendamustine, Etoposide, Cytarabine, Melphalan) traditionally relies on cryopreservation, whereas the CEM regimen (Carboplatin, Etoposide, Melphalan) has been optimized for short-duration administration without the need for cryopreservation. This study rigorously compares the clinical and safety profiles of the BeEAM and CEM regimens. METHODS: A controlled, randomized clinical trial was conducted with 58 lymphoma patients undergoing ASCT at the International Medical Center (IMC) in Cairo, Egypt. Patients were randomly assigned to either the BeEAM (n = 29) or CEM (n = 29) regimen, with an 18-month follow-up period. Clinical and safety outcomes were meticulously compared, focusing on time to engraftment for neutrophils and platelets, side effects, length of hospitalization, transplant-related mortality (TRM), and survival rates. RESULTS: The findings demonstrate a significant advantage for the CEM regimen. Neutrophil recovery was markedly faster in the CEM group, averaging 8.5 days compared to 14.5 days in the BeEAM group (p < 0.0001). Platelet recovery was similarly expedited, with 11 days in the CEM group versus 23 days in the BeEAM group (p < 0.0001). Hospitalization duration was substantially shorter for CEM patients, averaging 18.5 days compared to 30 days for those on BeEAM (p < 0.0001). Furthermore, overall survival (OS) was significantly higher in the CEM group at 96.55% (95% CI: 84.91-99.44%) compared to 79.31% (95% CI: 63.11-89.75%) in the BeEAM group (p = 0.049). Progression-free survival (PFS) was also notably superior in the CEM group, at 86.21% (95% CI: 86.14-86.28%) versus 62.07% (95% CI: 61.94-62.20%) in the BeEAM group (p = 0.036). CONCLUSION: The CEM regimen might demonstrate superiority over the BeEAM regimen, with faster neutrophil and platelet recovery, reduced hospitalization time, and significantly improved overall and progression-free survival rates. Future studies with longer duration and larger sample sizes are warranted. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov under the registration number NCT05813132 ( https://clinicaltrials.gov/ct2/show/NCT05813132 ). (The first submitted registration date: is March 16, 2023).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cloridrato de Bendamustina , Carboplatina , Citarabina , Etoposídeo , Transplante de Células-Tronco Hematopoéticas , Linfoma , Melfalan , Condicionamento Pré-Transplante , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Masculino , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Adulto , Linfoma/terapia , Linfoma/mortalidade , Linfoma/tratamento farmacológico , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Adulto Jovem , Adolescente , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVE: Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib. METHODS: Pharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents. RESULTS: A total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference). CONCLUSIONS: Capivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors.
Assuntos
Modelos Biológicos , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Pirróis/farmacocinética , Pirróis/administração & dosagem , Paclitaxel/farmacocinética , Paclitaxel/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Pirimidinas/farmacocinética , Pirimidinas/administração & dosagem , Fulvestranto/farmacocinética , Fulvestranto/administração & dosagem , Relação Dose-Resposta a Droga , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Idoso de 80 Anos ou mais , Administração Oral , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagemRESUMO
This single-arm phase 2 trial (ChiCTR2100046715) examined previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) who received four cycles of paclitaxel with carboplatin every 3 weeks. Toripalimab was infused intravenously every 3 weeks for 12 months, or until disease progression or intolerable toxicity. Radiotherapy that encompassed the primary lesions and metastases commenced in the third cycle. The median progression-free survival time was 9.8 months (95% confidence interval [CI]: 6.8-not estimable) in the intent-to-treat population, failing to meet the pre-specified primary endpoints. Secondary endpoints included an objective response rate of 45.5%, a disease control rate of 57.6%, and a median duration of response of 11.5 months (interquartile range, 6.4-15.0). The 1-year progression-free survival and overall survival rates were 41.9% (95% CI: 27.7-63.5) and 69.7% (95% CI: 55.7-87.3), respectively. Lymphopenia was the most frequent grade ≥3 adverse event (82%), and an esophageal fistula developed in three patients (9.1%). No treatment-related deaths occurred. In prespecified exploratory biomarker analysis, higher densities of CD8 + T cells, CD11c+ dendritic cells, and CD68+ macrophages correlated with improved tumor response and prognosis. Radiotherapy supplementation to first-line chemo-immunotherapy for treatment-naive advanced ESCC demonstrated some antitumor activity and manageable safety profiles, warranting further randomized controlled trials.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Masculino , Feminino , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/mortalidade , Pessoa de Meia-Idade , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Paclitaxel/uso terapêutico , Paclitaxel/administração & dosagem , Carboplatina/uso terapêutico , Carboplatina/administração & dosagem , Intervalo Livre de Progressão , Quimiorradioterapia/métodos , AdultoRESUMO
BACKGROUND: The combination of immunotherapy and antiangiogenic therapy has shown potential in the treatment of numerous malignant tumors, but limited evidence was available for soft tissue sarcomas (STS). Therefore, the aim of the present study is to assess the efficacy and safety of immunotherapy in conjunction with antiangiogenic therapy in patients diagnosed with advanced STS (aSTS). METHODS: The study enrolled patients with aSTS from January 2014 to October 2022. Eligible participants had previously received anthracycline-based chemotherapy, presented with an anthracycline-resistant sarcoma subtype, or were ineligible for anthracycline treatment due to medical conditions. Following enrollment, these patients received a combination of immunotherapy and antiangiogenic therapy. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS), while the secondary endpoints included the disease control rate (DCR), overall survival (OS), and the incidence of adverse events. RESULTS: Fifty-one patients were included in this cohort study. The median duration of follow-up was 15.8 months. The ORR and DCR were 17.6%, and 76.5%, respectively. The median PFS (mPFS) was 5.8 months (95% CI: 4.8-6.8) for all patients, and the median OS had not been reached as of the date cutoff. Multivariate analysis indicated that Eastern Cooperative Oncology Group performance status of 0-1 and ≤ second-line treatment were positive predictors for both PFS and OS. Patients with alveolar soft part sarcoma or clear cell sarcoma had longer mPFS (16.2 months, 95% CI: 7.8-25.6) when compared to those with other subtypes of STS (4.4 months, 95% CI: 1.4-7.5, P < 0.001). Among the observed adverse events, hypertension (23.5%), diarrhea (17.6%), and proteinuria (17.6%) were the most common, with no treatment-related deaths reported. CONCLUSION: The combination of immunotherapy and antiangiogenic agents showed promising efficacy and acceptable toxicity in patients with aSTS, especially those with alveolar soft part sarcoma or clear cell sarcoma.
Assuntos
Inibidores da Angiogênese , Imunoterapia , Sarcoma , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/administração & dosagem , Adulto , Sarcoma/tratamento farmacológico , Sarcoma/terapia , Sarcoma/mortalidade , Sarcoma/patologia , Idoso , Imunoterapia/métodos , Imunoterapia/efeitos adversos , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Progressão , Adulto Jovem , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversosRESUMO
BACKGROUND: TCbHP (taxane + carboplatin + trastuzumab + pertuzumab) is the preferred neoadjuvant therapy regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no consensus exists regarding whether specific populations may be exempt from carboplatin, allowing for de-escalation to the THP (taxane + trastuzumab + pertuzumab) regimen. Additionally, the optimal number of cycles for neoadjuvant THP remains unclear. We compared the efficacy and safety of neoadjuvant TCbHP and THP regimens, providing clinicians with a nuanced perspective to guide their treatment regimen selection. METHODS: This multicenter real-world study included patients with HER2-positive breast cancer undergoing neoadjuvant TCbHP or THP between March 2019 and February 2023. Efficacy was assessed through the pathological complete response (pCR) rate, while safety was evaluated through monitoring adverse events. RESULTS: Among 220 patients, 103 received 6 cycles of TCbHP (TCbHP×6), 83 received 6 cycles of THP (THP×6), and 34 received 4 cycles of THP (THP×4). The TCbHP×6 cohort exhibited a 66% pCR rate compared with 53% in the THP×6 cohort (P = 0.072). Subgroup analysis revealed that in patients aged ≤ 50 years, those with hormone receptor (HR)-negative status, and those with clinical stage T2, the pCR rate of the TCbHP×6 regimen was significantly higher than the THP×6 regimen (P < 0.05). The TCbHP×6 cohort reported higher frequencies of any-grade adverse events (99% versus 86.7%) and grade 3-4 events (49.5% versus 12%) than the THP×6 cohort. Propensity score matching identified 27 patient pairs between the THP×6 and THP×4 cohorts, indicating a significantly higher pCR rate for the THP×6 regimen than the THP×4 regimen (63% versus 29.6%, P = 0.029). CONCLUSIONS: The TCbHP×6 regimen is favored for individuals aged ≤ 50 years and those aged > 50, ≤60 years with HR-negative status or clinical stage T2-4. For patients in compromised general condition or lacking the specified indications, the THP×6 regimen emerges as a lower-toxicity alternative with satisfactory efficacy. To ensure treatment efficacy, a minimum of 6 cycles of neoadjuvant THP is required.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Carboplatina , Terapia Neoadjuvante , Receptor ErbB-2 , Taxoides , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Terapia Neoadjuvante/métodos , Carboplatina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/metabolismo , Pessoa de Meia-Idade , China/epidemiologia , Adulto , Taxoides/administração & dosagem , Seguimentos , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêutico , Prognóstico , Estudos Retrospectivos , Idoso , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagemRESUMO
PURPOSE: Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting. METHODS: In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety proï¬le were measured and analyzed. RESULTS: In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia. CONCLUSIONS: Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.
Assuntos
Neoplasias Esofágicas , Junção Esofagogástrica , Receptor de Morte Celular Programada 1 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Junção Esofagogástrica/patologia , Junção Esofagogástrica/efeitos dos fármacos , Idoso , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Intervalo Livre de Progressão , China , População do Leste AsiáticoRESUMO
BACKGROUND: Immune-checkpoint inhibitors are now used more commonly in combination than monotherapy as the first-line choice in patients with unresectable advanced melanoma. Nevertheless, for cases that progressed after the initial combination therapy, the subsequent regimen option can be very difficult. Herein, we reported the efficacy and safety of a triple combination regimen in Chinese unresectable advanced melanoma patients who had poor responses to the first-line immune therapy. METHODS: We reviewed the clinical profiles of patients diagnosed with stage IIIC-IV melanoma between June 1, 2020, and September 30, 2023. The patients who failed the prior immune therapies and received anti-PD-1 mono antibody plus interferon(IFN)-alpha 1b and anlotinib hydrochloride as the second-line therapy were enrolled in the retrospective analysis. Additionally, we examined the exhaustion of T-cells using mIHC staining in available tumor samples. RESULTS: Fifty-five patients were included in this study. The median follow-up period was 13.6 months. The objective response rate evaluated by the investigators was 9.1%(1CR, 4PR). The disease control rate was 47.3%. The median overall survival was 17.6 months, and the median progression-free survival was 2.8 months. The adverse events rate of any grade was 100%. Grade 3 or 4 irAEs were observed in 29.1% of cases. Multiplex immunohistochemical staining revealed an increased trend of TIM3 expression on tumor-infiltrating T cells in patients without objective response. CONCLUSION: PD-1 monoclonal antibody plus interferon-alpha 1b plus anlotinib showed acceptable tolerability and anticancer benefits in Chinese metastatic melanoma patients as a second-line therapy.