RESUMO
OBJECTIVES: No head-to-head trials had been performed to estimate the relative effectiveness of poly ADP-ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). We aimed to perform a systematic review and network meta-analysis to evaluate the comparative effectiveness of various systemic treatment agents for patients with mCRPC. METHODS: A comprehensive literature search was conducted for abstracts and full-text articles from the database's inception through April 27, 2023. The study concentrated on assessing radiographic progression-free survival (rPFS) for both overall and homologous recombination repair mutation (HRRm) population, with overall survival (OS) as the secondary measure. Under the Bayesian framework, the overall effect was pooled using the fixed-effects model in base case analysis. Scenario analysis using restricted mean survival time (RMST) methods was performed to test the robustness of the results. RESULTS: Nine studies with 6,830 patients and 8 unique treatment options were included. Network meta-analysis demonstrated that talazoparib in combination with enzalutamide (TALA + ENZA; overall population, hazard ratio [HR], 0.20; 95% credible interval [CrI]: 0.16-0.26; RMST, 3.51; 95% confidence interval [CI] 2.46-4.60; HRRm population, HR, 0.15; 95% CrI: 0.09-0.23; RMST, 4.14; 95% CI 2.84-5.39) was superior to other treatments in the first-line setting in terms of rPFS. The results of Bayesian framework and RMST models showed consistent efficacy ranks. When extrapolated to overall survival benefit, within the Bayesian framework, olaparib plus abiraterone acetate and prednisone (OLAP + AAP) achieved the highest OS benefit for the overall population, which was not statistically significant when compared to TALA + ENZA. However, TALA + ENZA achieved the highest OS benefit at 3 years by applying RMST. CONCLUSIONS: We suggest that talazoparib in combination with enzalutamide is probably a preferred treatment agent for the overall population and HRRm patients with mCRPC. Given the limitations of network framework and the modeling assumptions undertaken to finalize the analyses, results should be cautiously interpreted.
Assuntos
Antagonistas de Receptores de Andrógenos , Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Acetato de Abiraterona/uso terapêutico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Teorema de Bayes , Benzamidas/uso terapêutico , Metanálise em Rede , Nitrilas , Feniltioidantoína/uso terapêutico , Feniltioidantoína/análogos & derivados , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidadeRESUMO
PURPOSE: The treatment of the advanced non-small cell lung cancer (NSCLC) with KRAS mutation has been closely paid more attention. The aim of this study is to investigate the efficacy of different first-line regimens in advanced KRAS-mutated non-small cell lung cancer. METHODS: In our retrospective study, we collected patients with advanced NSCLC with KRAS mutation in Zhejiang Cancer Hospital between January 2015 and May 2023. We analyzed the benefit of different first-line therapy according to theraputic methods and the differential effect of the same treatment method among KRAS-mutated subtypes. We divided the patients into group A (A1, chemotherapy alone; A2, immunotherapy alone) and group B (B1, chemotherapy plus immunotherapy; B2, chemotherapy combined with antiangiogenic therapy; B3, chemotherapy combined with immunotherapy plus antiangiogenic therapy). The Kaplan-Meier survival curve was used to reflect the PFS and OS of different methods. The objective response rate (ORR) and the disease control rate (DCR) were used to evaluated the response. RESULTS: We enrolled 227 patients including eighty-two with KRAS G12C mutation. The ORR and DCR of first-line treatment in the overall population were 32.2% and 80.6% respectively. The median PFS was 6.7 months and the median OS was 17.4 months for the overall population. The PFS of the Group B was significantly better than that of the Group A (7.7 months vs 5.4 months, P = 0.003), while no significant difference in OS was observed (19.4 months vs 15.0 months, P = 0.077). In the Group B, chemotherapy combined immunotherapy with antiangiogenic therapy showed better PFS than chemotherapy plus immunotherapy (14.1 months vs 7.7 months, P = 0.049), and OS also showed that tendency of difference (31.9 months vs 19.3 months, P = 0.158). There was no statistically significant difference between KRAS G12C and non-G12C mutation according to first-line treatment methods, whereas patients with TP53 co-mutation showed a better survival benefit (OS, 23.7 vs 12.5 months, P = 0.023). CONCLUSION: In the first-line treatment, combination regimen has advantages over single regimen. Among them, chemotherapy combined with immunotherapy plus antiangiogenic therapy can achieve significant efficacy benefits.
Assuntos
Inibidores da Angiogênese , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Masculino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Imunoterapia/métodos , Adulto , Inibidores da Angiogênese/uso terapêutico , Estimativa de Kaplan-Meier , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: The PanaMa trial demonstrated significant benefit in progression-free survival with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. Here, we report health-related quality of life (HRQOL) analyses from the PanaMa trial. METHODS: HRQOL outcomes were evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression/death. HRQOL outcomes were mean and individual changes in EORTC QLQ-C30 from baselines (before induction therapy and before maintenance therapy) to each cycle of treatment. Comparative analyses were performed by randomisation status and treatment arm for induction- and maintenance-therapy, respectively. The trial is registered with clinicaltrials.gov (NCT01991873). RESULTS: At least one HRQOL questionnaire was completed by a total of 349/377 (93%) patients who received induction therapy, and by 237/248 (96%) patients who were randomised and received maintenance therapy. During induction therapy, most HRQOL dimensions remained stable or showed improvement, while appetite loss and diarrhoea significantly deteriorated. During maintenance therapy, HRQOL dimensions remained stable, while those that deteriorated during induction therapy showed significant improvement, without significant differences between the treatment arms. CONCLUSION: Maintenance therapy improves HRQOL dimensions that initially deteriorated during induction therapy while stabilising HRQOL in other dimensions. The addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer prolongs progression-free survival without negative impact on HRQOL.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Panitumumabe , Leucovorina/uso terapêutico , Qualidade de Vida , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fluoruracila/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Combination treatments with immuno-oncology (IO) agents and IO agents plus a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) have been approved for first-line treatment of patients with metastatic renal cell carcinoma (mRCC). No direct comparisons have been performed among these treatment options. We performed a systematic review and network meta-analysis to compare and rank the available regimens for first-line treatment in terms of survival benefit and efficacy. In accordance with the Preferred Reporting Items for Systematic Review statement, a systematic search of reported studies was performed in MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE up to May 31, 2019. Network meta-analysis models were adjusted using the Bayesian method. Four randomized clinical trials, with a total of 3758 patients, met the inclusion criteria. Considering systemic therapy, 1880 patients had received sunitinib and 550, 432, 442, and 454 patients had received ipilimumab plus nivolumab (ipi + nivo), pembrolizumab plus axitinib (pembro + axi), avelumab plus axitinib (avelu + axi), and atezolizumab plus bevacizumab (atezo + bev). No difference was found in overall survival between ipi + nivo and pembro + axi for the intention to treat population (hazard ratio [HR], 1.34; 95% credible interval [CrI], 0.92-1.97). No difference was found in progression-free survival among the treatments. The overall response rate (ORR) was superior with pembro + axi and avelu + axi compared with the ORR with the other treatments (atezo + bev vs. pembro + axi: HR, 0.66; 95% CrI, 0.52-0.84; ipi + nivo vs. pembro + axi: HR, 0.73; 95% CrI, 0.59-0.90; atezo + bev vs. avelu + axi: HR, 0.55; 95% CrI, 0.43-0.71; avelu + axi vs. ipi + nivo: HR, 1.66; 95% CrI, 1.31-2.12), with no differences across them (HR, 1.21; 95% CrI, 0.95-1.53). In the present indirect comparison, for an intention to treat population, we found no survival differences between pembro + axi and ipi + nivo. All treatments showed better progression-free survival compared with sunitinib that was similar among them. The combination of an IO agent (pembrolizumab or avelumab) and axitinib seemed to be the most effective therapy for the ORR.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Prognóstico , Taxa de SobrevidaRESUMO
PURPOSE: Considering the recent publication of the results of several clinical trials for metastatic clear cell renal cell carcinoma (mRCC), we performed a systematic review and meta-analysis of randomized studies comparing standard first-line VEGFR-targeted therapy to immune checkpoint inhibitors-based combinations for mRCC patients. METHODS: 3960 patients from 5 randomized clinical trials where available for evaluation. RESULT: In the all-comers population, immunotherapy-based combinations were able to decrease the risk of death over the standard of care by 26% (HR 0.74; 95% CI 0.60-0.92; p = 0.006), to decrease the risk of progression by 21% (HR 0.79; 95% CI 0.72-0.86; p < 0.00001), and to increase the relative risk of response by 40% (HR 1.40; 95% CI 1.11-1.77; p = 0.006). For poor/intermediate-risk patients, the risk of death is decreased by 41% and the risk of progression by 27%. CONCLUSIONS: The benefit of immunotherapy-based combinations in mRCC patients is independent from the IMDC risk group, but it is stronger for poor/intermediate-risk patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: In a phase III study, maintenance pemetrexed showed superior survival over placebo (PARAMOUNT) for patients with advanced non-squamous non-small cell lung cancer (NSCLC) who completed 4 cycles of pemetrexed plus cisplatin (PC) induction therapy, with low incidence of treatment-emergent adverse events (TEAEs) generally associated with pemetrexed. Prior analyses did not account for toxicities carried over from induction; thus, the current analysis was developed to understand toxicities that may be attributed to pemetrexed maintenance versus PC induction, and how treatment duration affects toxicity. PATIENTS AND METHODS: Selected clinically relevant TEAEs were explored in 2 analyses: assessing induction versus maintenance treatment in PARAMOUNT, and comparing PC from PARAMOUNT with toxicity data from a previous phase III study that established the role of PC in front-line therapy of non-squamous NSCLC (JMDB trial). RESULTS: In PARAMOUNT, the incidence of most drug-related TEAEs was higher during induction than maintenance, for both the pemetrexed and placebo randomized populations. The majority of TEAEs during maintenance, except renal events, were carried over from induction with no change in severity from the end of induction; the incidence of TEAEs associated with pemetrexed maintenance was low. The cross-trial analysis showed that 6 cycles of PC in JMDB compared with 4 cycles in PARAMOUNT increased grade 1/2 fatigue (34.1% vs. 25.0%), anemia (24.0% vs. 13.5%), and renal events (11.8% vs. 3.6%). CONCLUSIONS: Safety data presented here support the favorable risk benefit of 4 cycles of PC followed by maintenance pemetrexed in patients with advanced non-squamous NSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anemia/induzido quimicamente , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Fadiga/induzido quimicamente , Humanos , Quimioterapia de Manutenção/efeitos adversos , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Pemetrexede/administração & dosagem , Pemetrexede/efeitos adversos , Indução de Remissão , Estudos Retrospectivos , Vômito/induzido quimicamenteRESUMO
BACKGROUND/AIM: First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. PATIENTS AND METHODS: This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9 months. RESULTS: Median overall survival and PFS were 30.7 and 15.1 months, respectively. The overall response rate was 83 %. Weight loss ≤5 %, ECOG PS = 0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. CONCLUSION: Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.
Assuntos
Adenocarcinoma/mortalidade , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma de Células Grandes/mortalidade , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , SobreviventesRESUMO
BACKGROUND: The approval of new therapies for metastatic castration-resistant prostate cancer (mCRPC), including the oral agents abiraterone acetate and enzalutamide, has altered the standard of care for patients with mCRPC. Little information exists regarding the sequences in which new therapies for mCRPC with evidence of survival benefits are used. OBJECTIVE: To describe the sequence of medication use for patients with mCRPC as observed in 3 healthcare data sets. METHODS: Three healthcare claims data sets were used to identify patients with mCRPC who had no previous use of and were newly initiating 1 of the 2 oral study drugs (ie, abiraterone acetate or enzalutamide). The index date was the first study drug claim after September 1, 2012. Patients were followed until the data cutoff or until being lost to follow-up. Descriptive statistics summarized the proportion of patients receiving 1 line of therapy versus ≥2 lines of therapy. The use of a corticosteroid and the mean monthly pharmacy costs of abiraterone acetate or enzalutamide during the follow-up period were compared between the cohorts. RESULTS: A total of 3525 patients with mCRPC were identified from data set 1, 499 patients from data set 2, and 1949 patients from data set 3. The first-line use of abiraterone acetate was observed in 74%, 82%, and 80% of data sets 1, 2, and 3, respectively, and the first-line use of enzalutamide was seen in 26%, 18%, and 20%, respectively, of these same populations. The concomitant use of corticosteroids was observed in patients receiving first-line abiraterone acetate and in patients receiving first-line enzalutamide in all 3 data sets. After September 2012, abiraterone acetate was the most frequently administered therapy for mCRPC among the 2 oral agents, abiraterone acetate and enzalutamide. The monthly pharmacy costs associated with abiraterone acetate were significantly lower than those associated with enzalutamide in all 3 data sets. CONCLUSIONS: Based on the data used in this study, abiraterone acetate was more frequently administered for patients with mCRPC than enzalutamide. The concomitant use of corticosteroids was common in patients receiving first-line abiraterone acetate or first-line enzalutamide therapy. Patients receiving abiraterone acetate had significantly lower monthly pharmacy costs than patients receiving enzalutamide. These findings may facilitate the estimation of the budgetary impact of a treatment mix for population health and for managed care stakeholders.
RESUMO
PURPOSE: To evaluate clinical outcomes of first-line immunomodulatory therapy (IMT) and prednisone alone or late IMT in Vogt-Koyanagi-Harada disease. METHODS: Retrospective cohort study of 152 patients with Vogt-Koyanagi-Harada disease evaluated in a referral uveitis clinic in Chile from 1985 to 2011. Medical records of these patients were reviewed. Demographic data, clinical evaluation, type of treatment, functional outcomes, glucocorticoid (GC) dose and complications were recorded. Multivariate logistic regression was used to identify prognostic factors of poor response to GC. RESULTS: There were no significant differences between first-line IMT group and prednisone alone/late IMT group in terms of visual acuity (VA) improvement, complications and GC sparing effect. There was a trend for a higher frequency of systemic adverse effects leading to discontinuation of treatment in patients receiving IMT than in those receiving prednisone (14.6% and 6.5%, respectively). The subgroup of patients with poor response to GC who showed functional improvement had a significantly earlier time to IMT initiation than the patients who had no improvement. We identified following prognostic factors of poor response to GC: VA ≤ 20/200, fundus depigmentation, chronic disease and tinnitus at diagnosis. Patients with a prognostic factor (excluding tinnitus) and VA improvement had an earlier IMT initiation than those who had worse functional outcome. CONCLUSION: There were no differences in outcomes between first-line IMT and prednisone alone/late IMT in the entire VKH group. However, in a subset of patients, there was a significant better functional outcome with earlier IMT initiation.