Survival outcomes of double- and triple-sequential targeted therapy in patients with metastatic renal cell carcinoma: a retrospective comparison.
ABSTRACT: To evaluate the progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) treated with double- and triple-sequence targeted therapy (TT) using tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORi).Records of 292 patients with mRCC, treated with TT between January 2005 and July 2015, were analyzed retrospectively. Kaplan-Meier and log-rank analyses were used to calculate and compare the total PFS (tPFS) and OS when patients underwent double- or triple-TT using TKIs or mTORi.Eighty-one (27.7%) patients who underwent second-line TT were enrolled; 30 (10.3%) of whom underwent third-line TT. The tPFS and OS of double-TT using TKI-mTORi (5.4 and 30 months, respectively) were significantly better compared with TKI-TKI (0.3 and 2 months) or mTORi-TKI (2 and 6 months) (p <0.001). For triple-TT, the tPFS and OS of TKI-mTORi-TKI (22.8 and 25 months, respectively) were significantly superior compared with those for TKI-TKI-mTORi (4 and 9 months) (p <0.05).For patients with intermediate-risk according to the Heng or Memorial Sloan-Kettering Cancer Center risk models, TKI-mTORi was associated with a significantly longer tPFS and OS compared with TKI-TKI [expect for OS in the Heng group (p = 0.086)]. For the triple TT group, TKI-mTORi-TKI resulted in improved tPFS and OS compared with TKI-TKI-TKI or TKI-TKI-mTORi (p <0.05).In patients with mRCC, sequential administration of TKI-mTORi led to a significantly superior tPFS compared with any other TT sequence. By contrast, OS did not differ significantly according to TT sequence.
Project description:This retrospective register study assessed overall survival (OS) and influential factors on OS in Swedish renal cell carcinoma (RCC) patients.Using three merged national health registers, Cox proportional-hazards analysis was conducted and, in three models, it was used to assess the impact of cytokine (interferon-? and tyrosine kinase inhibitor (TKI; sunitinib or sorafenib) treatment on OS in metastatic (m)RCC.From 2000 to 2008, 8009 patients were diagnosed with RCC and 2753 with mRCC (2002-2008). Median OS in RCC patients diagnosed from 2006 to 2008 compared with 2000-2005 was not reached vs 47.9 months (P<0.001), and in mRCC patients diagnosed from 2006 to 2008 compared with 2002-2005, was 12.4 vs 9.6 months, respectively (P=0.004). Factors associated with significantly improved OS in RCC were female gender, lower age, and previous nephrectomy, and, in mRCC female gender, previous nephrectomy, and any TKI prescription (Model 1: median-adjusted OS, 19.4 months (TKI patients) vs 9.7 months (non-TKI patients); hazard ratio, 0.621; P<0.001).OS was improved in Swedish patients diagnosed with RCC and mRCC in the period 2006-2008 compared with 2000-2005 (RCC) and 2002-2005 (mRCC). Although multifactorial in origin, results suggest that increased nephrectomy rates and the use of TKIs contributed to the improvement seen in mRCC patients.
Project description:We compared progression-free survival (PFS) and overall survival (OS) among 292 metastatic renal cell carcinoma (mRCC) patients either undergoing nephrectomy (Nx, 61.6%) or not (non-Nx, 38.4%), stratified according to the MSKCC and Heng risk models, treated with either immunotherapy (IT, 45.2%) or targeted therapy (TT, 54.8%) between 2000 and 2015. During the follow-up duration of 16.6 months, PFS/OS of the Nx (6.0/30 months) and non-Nx (3.0/6.0 months) groups were significantly different despite differences among baseline parameters (p?<?0.05). The intermediate- and poor-risk patients defined using either model showed significantly longer PFS and OS in the Nx group than in the non-Nx group (p?<?0.05). After stratifying groups by systemic therapy and risk models, both the Nx and non-Nx groups showed no significant differences in intermediate and poor-risk models (p?>?0.05). In both synchronous and metachronous mRCC patients, both PFS and OS showed similar survivals; the Nx group had significantly longer PFS and OS than the non-Nx group, even after considering each systemic therapy and prognostic model. Nx showed a significant positive benefit in PFS and OS compared to no Nx upon patient stratification according to the MSKCC and Heng risk models. The metastatic type did not significantly affect survival between the two groups.
Project description:OBJECTIVE:The optimal sequencing of targeted therapies for metastatic renal cell carcinoma (mRCC) is unknown. Observational studies with a variety of designs have reported differing results. The objective of this study is to systematically summarize and interpret the published real-world evidence comparing sequential treatment for mRCC. METHODS:A search was conducted in Medline and Embase (2009-2013), and conference proceedings from American Society of Clinical Oncology (ASCO), ASCO Genitourinary Cancers Symposium (ASCO-GU), and European Society for Medical Oncology (ESMO) (2011-2013). We systematically reviewed observational studies comparing second-line mRCC treatment with mammalian target of rapamycin inhibitors (mTORi) versus vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI). Studies were evaluated for 1) use of a retrospective cohort design after initiation of second-line therapy, 2) adjustment for patient characteristics, and 3) use of data from multiple centers. Meta-analyses were conducted for comparisons of overall survival (OS) and progression-free survival (PFS). RESULTS:Ten studies reported OS and exhibited significant heterogeneity in estimated second-line treatment effects (I2?=?68%; P?=?0.001). Four of these were adjusted, multicenter, retrospective cohort studies, and these showed no evidence of heterogeneity (I2?=?0%; P?=?0.61) and a significant association between second-line mTORi (>75% everolimus) and longer OS compared to VEGF TKI (>60% sorafenib) (HR?=?0.82, 95% CI: 0.68 to 0.98) in a meta-analysis. Seven studies comparing PFS showed significant heterogeneity overall and among the adjusted, multicenter, retrospective cohort studies. Real-world observational data for axitinib outcomes was limited at the time of this study. CONCLUSIONS:Real-world studies employed different designs and reported heterogeneous results comparing the effectiveness of second-line mTORi and VEGF TKI in the treatment of mRCC. Within the subset of adjusted, multicenter observational studies, second-line use of mTORi was associated with significantly prolonged survival compared with second-line use of VEGF TKI.
Project description:To compare survival outcomes for renal embolization (RE) to cytoreductive nephrectomy (CN) and no primary renal treatment (NT) among patients with synchronous metastatic renal cell carcinoma (mRCC) treated using either targeted therapy (TT) or immunotherapy (IT).The median follow-up duration was 81.3 months, with a duration of first-line treatment of 3.5 months. Among the 211 patients, the median PFS and OS were 4.4 and 10.6 months. Specifically for patients receiving TT (124 patients), the PFS and OS were 5.5 and 12.0 months. An intervention effect was identified only for OS, with a median OS of 20.1, 8.8 and 9.3 months for CN, RE and NT, respectively. After stratification by risk classification, CN provided a significant benefit on OS, compared to RE and NT, for patients with an intermediate risk (MSKCC). For those with a poor risk (Heng criteria), NT provided better survival than PFS (p=0.003), and a comparable survival to RE (p > 0.05).Retrospective analysis of 211 patients, 87 treated with IT and 124 with TT, retrieved from our RCC database. Patients' risk factors for survival was evaluated using the Heng and MSKCC criteria, with only patients with an intermediate or poor survival risk included in the analysis. Between-group comparisons were evaluated with respect to progression-free survival (PFS) and overall survival (OS).The differential effect of CN and RE on OS appears to be modulated by risk classification. In patients with a poor risk, RE should be implemented after careful consideration of comorbidities and life expectancy.
Project description:Purpose:This study aimed to compare progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) in Heng intermediate-risk patients with metastatic renal cell carcinoma (mRCC) treated with first-line immunotherapy (IT) or targeted therapy (TT). Materials and Methods:From 2000 to 2017, a total of 186 intermediate-risk mRCC patients treated with first-line IT (n=64, 34.4%) or TT (n=122, 65.6%) were retrospectively evaluated for PFS, OS, and CSS using the Kaplan-Meier method with log-rank test and Cox proportional hazards models for their risk factors with a p-value for significance of <0.05. Results:During a median 5.08-month of systemic treatment and 92.22 months of follow-up, the median PFS, OS, and CSS were 5.16, 18.44, and 19.04 months, respectively. The comparison of baseline characteristics between the two groups showed a significantly higher rate of T3-4 stages, a lower rate of high nuclear grades, shorter follow-up, longer treatment durations, lesser rates of cytoreductive nephrectomy, a lower objective response rate, and no cases of complete response in the TT group compared with the IT group (p<0.05). The survival comparisons between the two groups showed that PFS was significantly different, whereas OS and CSS were not significantly different. The multivariate analyses showed that synchronous metastatic type(hazard ratio [HR], 2.285), IT (HR, 1.746), and treatment-free interval <1 year (HR, 1.926) were significant factors for PFS, whereas none of the risk factors were significant for OS or CSS. Conclusions:TT significantly prolonged PFS compared with IT, whereas long-term survival was not significantly different in intermediate-risk mRCC patients.
Project description:Introduction: Sequential therapy with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) is effective in some patients with metastatic renal cell carcinoma (mRCC) progressed from or were intolerant to a prior TKIs. Anlotinib is a multi-kinase inhibitor targeting VEGFR1/2/3, PDGFR and FGFR, which has demonstrated efficacy and safety in first-line treatment of mRCC. This study assessed the potential of anloitnib as second-line treatment for patients with mRCC after prior one VEGFR-TKI. Methods: This is a single-arm, open-label, phase 2 study. Patients progressed after or were intolerant to sorafenib or sunitinib were enrolled. Anlotinib was administrated orally 12 mg once daily for 14 days every 3 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), safety and quality of life (QoL). Results: Forty three patients were enrolled and 42 received anlotinib, of whom 32 progressed after and 10 were intolerant to sorafenib or sunitinib. Median PFS were 14.0 months (95% CI 8.3-20.3) and 8.5 months (95% CI 5.6-16.6) for overall population and patients progressed after a previous VEGFR-TKI, respectively. Median OS was 21.4 months (95% CI 16.0-34.5), confirmed ORR and DCR were 16.7 and 83.3% in overall population. The most common adverse events included diarrhea (47.6%), hypertension (45.2%), hand and foot syndrome (42.9%), and fatigue (40.5%). Grade 3 hematological adverse events occurred in four cases, while no grade 4 hematological adverse events was observed. Conclusions: Anlotinib showed promising efficacy as well as favorable safety as second-line treatment for patients with mRCC. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02072044.
Project description:The objective response rate (ORR) of tyrosine kinase inhibitors (TKIs) therapy in metastatic renal cell cancer (mRCC) patients was not satisfactory. Effective indicator of mRCC patient selection for TKI therapy is urgently needed. The function of tumor infiltrating B lymphocytes (TIBs) in tumor immune elimination is still unclear. We aim to investigate the prognostic and predictive value of TIBs for TKI therapy in mRCC patients in this study. 108 eligible patients treated with TKI were enrolled in this study. TIBs was estimated by immunohistochemical staining of CD19 in the resected tumor, and its relationship with clinicopathological features, clinical outcomes and CD8+ tumor infiltrating T lymphocytes (CD8+ TILs) were evaluated. Associations between the expression level of CD19 and CD8+ TILs associated cytotoxic effectors were also assessed in public databases. Results showed TIBs positive infiltration predicted better therapeutic response to sunitinib (p = 0.006), longer overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p = 0.028) in mRCC patients. Combining TIBs and International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) model showed a better predict value of OS in TKI-treated mRCC patients than IMDC model alone. We also found a positive correlation between TIBs and CD8+ TILs (p < 0.001). Patients with both cells high infiltration showed markedly better OS compared with those infiltrated by CD8+ T cells alone (p = 0.015). To conclude, TIBs density was not only an independent prognostic factor for mRCC patients, but also a predictive marker for TKI therapy response. It may potently enhance the antitumor effect by recruiting and activating CD8+ TILs in mRCC.
Project description:To explore the efficacy and safety of pazopanib in a 'real-world' setting in unselected patients, as data regarding unselected patients with metastatic clear-cell renal cell carcinoma (ccRCC) treated with first-line pazopanib are limited.We reviewed records of patients with metastatic ccRCC treated with first-line pazopanib from 1 November 2009 through to 1 November 2012. Cox models were fitted to evaluate the association of progression-free survival (PFS) and overall survival (OS) with patient co-variables.In all, 88 patients were identified; 74 were evaluable for response: two (3%) had a complete response, 27 (36%) a partial response, 36 (49%) had stable disease and nine (12%) had progressive disease. The median PFS was 13.7 months [95% confidence interval (CI) 8.7-18.3]. PFS was correlated with a Karnofsky Performance Status score of <80 [hazard ratio (HR) 3.26, P < 0.001] and serum lactate dehydrogenase of >1.5 × upper limit of normal (HR 3.25, P = 0.014). The median OS was 29.1 months (95% CI 20.2-not reached). The OS was correlated with brain metastasis (HR 2.55, P = 0.009), neutrophilia (HR 1.179, P = 0.018), and anaemia (HR 3.51, P < 0.001). There were no treatment-related deaths. In all, 53 patients received second-line therapy [vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) in 22 patients, mammalian target of rapamycin inhibitors (mTORi) in 22 patients, and other therapy in nine patients]; the median PFS was 8.6 months (95% CI 3.3-25.7) with VEGFR-TKI and 5 months (95% CI 3.5-15.2) with mTORi (P = 0.41); the median OS was 19.9 months (95% CI 12.9-not reached) and 14.2 months (95% CI 8.1-not reached), from initiation of second-line VEGFR-TKI or mTORi, respectively (P = 0.37).In this retrospective study, first-line pazopanib confirmed its efficacy in metastatic ccRCC. Trends for longer PFS and OS were seen with VEGFR-TKI compared with mTORi after first-line pazopanib.
Project description:OBJECTIVE:This study aimed to determine the prognostic factors of progression-free survival (PFS) and overall survival (OS) in non-nephrectomized patients with synchronous metastatic renal cell carcinoma (mRCC) receiving first-line vascular endothelial growth factor (VEGF)-targeted therapy or immunotherapy. METHODS:Of 70 patients, 57 (81.4%) were treated with targeted therapy, including 5 (7.1%) with previous immunotherapy and 13 (18.6%) with immunotherapy only. The medical records of patients were retrospectively reviewed and analyzed to determine factors of PFS and OS using the Cox proportional hazards model with a statistical significance p-value <0.05. RESULTS:The median treatment and follow-up periods were 3.9 and 30.9 months, respectively. Disease progression was reported in 90.0% of patients, with an objective response rate and clinical benefit rate of 26.1% and 76.8%, respectively. The lung (77.1%) was the most common site of metastasis. Multivariable analysis showed that poor Heng risk (hazard ratio [HR]: 2.37) and liver metastasis (HR: 2.34) were significant prognostic factors for PFS, and female sex (HR: 2.13), poor Heng risk (HR: 3.14), and liver metastasis (HR: 2.78) were significant prognostic factors for OS (p < 0.05). A subset analysis of risk factors among patients without previous history of immunotherapy also showed poor Heng risk (HR 2.92 and HR 4.24 for PFS) and liver metastasis (HR 2.87 and HR 4.81 for OS) as significant factors for both PFS and OS (p<0.05). CONCLUSION:Poor Heng risk, sex, and liver metastasis were associated with survival outcomes after first-line systemic therapy in patients with non-nephrectomized synchronous mRCC.
Project description:There is an unmet need to determine factors predictive of clinical benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC). We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as predictors of response rate, progression free survival (PFS) and overall survival (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI).Regulatory approval was obtained. A single center retrospective chart review of mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics, smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria), NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF therapy ?6 months or <6.42 patients were evaluated with median age of 61 years (range, 24-85). Pretherapy NLR < 3 and ?3 was seen in 19 (45%) and 23 (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF inhibitors for a duration of ?6 months and <6 months, respectively. 12 (29%), 22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease based on Heng criteria, respectively. Multivariable analysis showed pretherapy NLR ?3 was predictive of shorter PFS and OS when treated with ICI with median 3.08 months and 13.50 months, respectively, versus 15.57 months and not reached for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF therapy <6 months was predictive of increased likelihood of benefit from ICI therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months, respectively, in cases with prior anti-VEGF therapy for ?6 months and <6 months.Pretherapy NLR <3 and duration of prior anti-VEGF therapy of <6 months, are independent statistically significant predictors of longer PFS and OS with ICI therapy in mRCC. Validation is required in a larger sample size with multi-institutional collaboration.