Evaluation of disease‐free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: A trial‐level meta‐analysis

Harshman, Lauren C.; Xie, Wanling; Moreira, Raphael Brandão; Bossé, Dominick; Ares, Gustavo J. Ruiz; Sweeney, Christopher J.; Choueiri, Toni K.

doi:10.1002/cncr.31154

Cited by 41 publications

(34 citation statements)

References 43 publications

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“…This data suggests a suppressive role of angiogenesis on T cell-inflammation and may support further development of VEGFR2-TKI in combination or sequential therapy with ICI in earlier stage ccRCC. In clinical trials in non-metastatic ccRCC, perioperative systemic treatment with VEGFR2-TKI was not shown to increase overall survival versus surgery alone [57–59]. Benefit from ICI in the adjuvant and neoadjuvant setting has been observed in multiple cancers including NSCLC, breast cancer and melanoma and multiple phase III clinical trials evaluating ICI in ccRCC in both adjuvant and neoadjuvant settings are ongoing [60–64] (NCT03024996, NCT03142334, NCT03055013).…”

Section: Discussionmentioning

confidence: 99%

BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma

et al. 2019

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BackgroundClinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed death 1/ligand one antibodies.MethodsIn this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and Chi-square test (or Fisher’s Exact test). The Kaplan–Meier method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS) in all patients and the subsets of patients with clinical benefit or primary resistance. Cox’s regression model was used to evaluate the correlation between survival endpoints and variables of interest. To explore clinical factors in a larger, independent patient sample, The Cancer Genome Atlas (TCGA) was analyzed. RNAseq gene expression data as well as demographic and clinical information were downloaded for primary tumors of 517 patients included within TCGA-ccRCC.ResultsOf 90 patients, 38 (42.2%) had primary resistance and 52 (57.8%) had clinical benefit. Compared with the cohort of patients with initial benefit, primary resistance was more likely to occur in patients with worse ECOG performance status (p = 0.03), earlier stage at diagnosis (p = 0.04), had no prior nephrectomy (p = 0.04) and no immune-related adverse events (irAE) (p = 0.02). In patients with primary resistance, improved OS was significantly correlated with lower International Metastatic RCC Database Consortium risk score (p = 0.02) and lower neutrophil:lymphocyte ratio (p = 0.04). In patients with clinical benefit, improved PFS was significantly associated with increased BMI (p = 0.007) and irAE occurrence (p = 0.02) while improved OS was significantly correlated with overweight BMI (BMI 25–30; p = 0.03) and no brain metastasis (p = 0.005). The cohort TCGA-ccRCC was examined for the correlations between gene expression patterns, clinical factors, and survival outcomes observing associations of T-cell inflammation and angiogenesis signatures with histologic grade, pathologic stage and OS.ConclusionsClinical characteristics including performance status, BMI and occurrence of an irAE associate with outcomes in patients with ccRCC treated with immunotherapy. The inverse association of angiogenesis gene signature with ccRCC histologic grade highlight opportunities for adjuvant combination VEGFR2 tyrosine kinase inhibitor and immune-checkpoint inhibition.

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Section: Discussionmentioning

confidence: 99%

BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma

et al. 2019

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“…However, some ongoing clinical trials may provide evidence for the future adoption of adjuvant therapy such as new tyrosine kinase inhibitors and nivolumab. One study suggested that full-dose sunitinib could improve DFS in a subset analysis (51, 52). Therefore, we could expect the clinical results of several trials involving adjuvant new TKIs or combined with immune checkpoint inhibitors in the following years.…”

Section: Discussionmentioning

confidence: 99%

Construction and Validation of a 9-Gene Signature for Predicting Prognosis in Stage III Clear Cell Renal Cell Carcinoma

Jin

et al. 2019

Front. Oncol.

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Purpose: Aim of this study was to develop a multi-gene signature to help better predict prognosis for stage III renal cell carcinoma (RCC) patients.Methods: Fourteen pairs of stage III tumor and normal tissues mRNA expression data from GSE53757 and 16 pairs mRNA expression data from TCGA clear cell RCC database were used to analyze differentially expressed genes between tumor and normal tissues. Common different expressed genes in both datasets were used for further modeling. Lasso Cox regression analysis was performed to select and build prognostic multi-gene signature in TCGA stage III kidney cancer patients (N = 122). Then, the multi-gene signature was validated in stage III renal cancer cases in Fudan University Shanghai Cancer Center (N = 77). C-index and time-dependent ROC were used to test the efficiency of this signature in predicting overall survival.Results: In total, 1,370 common different expressed genes were found between tumor and normal tissues in both datasets. After Lasso Cox modeling, nine mRNAs were finally identified to build a classifier. Using this classifier, we could classify stage III clear cell RCC patients into high-risk group and low-risk group. Prognosis was significantly different between these groups in discovery TCGA cohort, validation FUSCC cohort and entire set (All P < 0.001). Multivariate cox regression in entire set (N = 199) revealed that risk group classified by 9-gene signature, age of diagnosis, pN stage and ISUP grade were independent prognostic factor of overall survival in stage III kidney cancer patients.Conclusion: We developed a robust multi-gene classifier that can effectively classify stage III RCC patients into groups with low and high risk of poor prognosis. This signature may help select high-risk patients who require more aggressive adjuvant target therapy or immune therapy.

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“…To address this clinical need, multiple trials have investigated the addition of systemic therapy after surgery in nonmetastatic disease based on effectiveness in the metastatic setting [4]. However, despite over 13 randomized trials testing adjuvant systemic therapies in the last 40 years [5], there has been only one positive study. In this trial highlight, we discuss the recent controversy over the adjuvant use of targeted therapies and highlight the ongoing trials of perioperative immune checkpoint blockade with a focus on the PROSPER RCC Study.…”

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confidence: 99%

The Future of Perioperative Therapy in Advanced Renal Cell Carcinoma: How Can We Prosper?

et al. 2019

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Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.

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Evaluation of disease‐free survival as an intermediate metric of overall survival in patients with localized renal cell carcinoma: A trial‐level meta‐analysis

Cited by 41 publications

References 43 publications

BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma

BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma

Construction and Validation of a 9-Gene Signature for Predicting Prognosis in Stage III Clear Cell Renal Cell Carcinoma

The Future of Perioperative Therapy in Advanced Renal Cell Carcinoma: How Can We Prosper?

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