MP69-09 THE CLINICAL BENEFIT OF METASTASECTOMY IN METASTATIC RENAL CELL CARCINOMA IN THE ERA OF TARGETED MOLECULAR THERAPY.

TPS4601 Background: In the cytokine era cytoreductive nephrectomy (CN) has been shown to increase survival in patients (pts) with metastatic renal cell carcinoma (mRCC). Efficacy of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib has been demonstrated. It is unclear if similar survival benefit could be achieved without CN with TKIs since most of pts enrolled into phase III trials had undergone CN. Methods: A total of 270 mRCC pts will be randomized to receiveCN followed by TKIs vs upfront TKIs without CN. Patients will receive pazopanib 800 mg orally daily or sunitinib 50 mg daily, 4 weeks on/ 2 weeks off. The choice of TKI will be done according to investigator’s clinical practice. Primary objective: to compare clinical benefit, as measured by overall survival (OS), provided by CN followed by TKIs vs upfront TKIs in pts with mRCC. Secondary objectives: i) to compare clinical benefit, as measured by progression-free survival (PFS) and response rate (RR) provided by CN followed by TKIs vs upfront TKIs; ii) Safety; iii) Exploratory analyses: evaluation of the predictive role of circulating tumor cells count and circulating tumor DNA at baseline, before and after surgery (in pts undergoing CN), 24 weeks after randomization and at the time of disease progression. Key inclusion criteria: Favorable or intermediate MSKCC or Heng prognostic risk group; histological diagnosis of RCC with a clear-cell component; resectable asymptomatic mRCC with primary tumor in place; up to three different metastatic sites; ≥ 3 metastatic lesions. Key exclusion criteria: Widespread disease ( > or = 4 metastatic organ sites); disease suitable of metastasectomy ( < 3 lesions confined at one organ site). Statistical plan: The sample size was calculated in order to compare 5-year OS between subjects randomized to receive CN followed by TKIs and those randomized to receive upfront TKIs. A total of 191 deaths will yield 80% power to detect a hazard ratio of 1.5 of upfront TKIs vs CN followed by TKIs with an overall type 1 error of 0.05 (two-sided log-rank test). Such a HR corresponds to an increase in the 5-year OS, from an anticipated value of 10% for TKIs to 21.5% for CN followed by TKIs. To date 10/270 pts have been enrolled. Clinical trial information: NCT02535351.

Download Full-text

RENAL CELL CARCINOMA 2005: NEW FRONTIERS IN STAGING, PROGNOSTICATION AND TARGETED MOLECULAR THERAPY

The Journal of Urology ◽

10.1097/01.ju.0000165693.68449.c3 ◽

2005 ◽

Vol 173 (6) ◽

pp. 1853-1862 ◽

Cited By ~ 231

Author(s):

JOHN S. LAM ◽

OLEG SHVARTS ◽

JOHN T. LEPPERT ◽

ROBERT A. FIGLIN ◽

ARIE S. BELLDEGRUN

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Molecular Therapy ◽

Targeted Molecular Therapy

Download Full-text

Correlates of clinical benefit from immunotherapy and targeted therapy in metastatic renal cell carcinoma: comprehensive genomic and transcriptomic analysis

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000953 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000953

Author(s):

Nazli Dizman ◽

Yung Lyou ◽

Nicholas Salgia ◽

Paulo Gustavo Bergerot ◽

JoAnn Hsu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Clinical Benefit ◽

Renal Cell ◽

Treated Patient ◽

Transcriptomic Analysis ◽

Genomic Profiling ◽

Patient Cohort ◽

Promoter Mutations

BackgroundThe clinical significance of tumor-specific genomic alterations in metastatic renal cell carcinoma (mRCC) is emerging, with several studies suggesting an association between PBRM1 mutations and response with immunotherapy (IO). We sought to determine genomic predictors of differential response to vascular endothelial growth factor–tyrosine kinase inhibitors (VEGF-TKIs) and IO.MethodsConsecutive patients who underwent genomic profiling were identified; patients receiving either VEGF-TKIs or IO were included. Clinical tumor-normal whole exome sequencing and tumor whole transcriptome sequencing test were performed using a Clinical Laboratory Improvement Amendments (CLIA)-certified assay (Ashion Analytics; Phoenix, Arizona, USA). Genomic findings were compared between patients with clinical benefit (CB; complete/partial response or stable disease for >6 months) and no clinical benefit (NCB) in VEGF-TKI-treated patient cohort and IO-treated patient cohort.Results91 patients received genomic profiling and 58 patients received VEGF-TKI and/or IO therapy. 17 received sequenced treatment involving both VEGF-TKI and IO, resulting in 32 patients in the IO cohort and 43 patients in the VEGF-TKI cohort. The most commonly used IO and VEGF-TKIs were nivolumab (66%) and sunitinib (40%). The most frequently detected alterations in the overall cohort were in VHL (64%), PBRM1 (38%), SETD2 (24%), KDM5C (17%) and TERT (12%). TERT promoter mutations were associated with NCB in the IO cohort (p=0.038); transcriptomic analysis revealed multiple differentially regulated pathways downstream of TERT. TERT promoter mutations and PBRM1 mutations were found to be mutually exclusive. While PBRM1 mutations were more prevalent in patients with CB with IO and VEGF-TKIs, no statistically significant association was found.ConclusionsOur analysis found that TERT promoter mutations may be a negative predictor of outcome with IO and are mutually exclusive with PBRM1 loss-of-function mutations.

Download Full-text

Activity of retreatment with sorafenib for metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.404 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 404-404 ◽

Cited By ~ 5

Author(s):

M. Nozawa ◽

N. Matsumura ◽

M. Yasuda ◽

Y. Okuda ◽

H. Uemura

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Clinical Benefit ◽

Renal Cell ◽

Objective Response ◽

Interleukin 2 ◽

Severe Toxicity ◽

Sorafenib Therapy ◽

Significant Difference

404 Background: Treatment options for metastatic renal cell carcinoma (mRCC) have increased. Complete remission is, however, rarely seen and patients are treated with multiple sequential therapies. We assessed clinical activity of sorafenib rechallenge after progressing on other therapies. Methods: Patients with mRCC who received a second course of sorafenib therapy after failure of prior sorafenib and other agents were retrospectively identified. RECIST-defined objective response rate and progression-free survival (PFS) and toxicity were analyzed. Results: Fourteen patients with mRCC who were retreated with sorafenib were identified and twelve patients were assessable for this study. 92% were male. Median age at first systemic therapy was 63 years. Prior nephrectomy was performed in 92% of patients. 42% of patients had favorable or intermediate risk, 17% poor, and the rest not available per MSKCC criteria. Eighty-three percent of patients were treated with other agents before initial sorafenib therapy, including 75% interferon-alpha (IFN-alpha), 50% interleukin-2 (IL-2), and 17% sunitinib. First sorafenib therapy began a median of 9.0 months after the diagnosis of mRCC and produced a clinical benefit (PR + SD) rate of 75% and a median PFS of 5.0 months. 67% of patients discontinued initial sorafenib for disease progression and 33% for adverse events. Interval between discontinuation of initial sorafenib and rechallenge was a median of 7.6 months. During the intervening period, 50% of patients were treated with sunitinib, 33% with everolimus, 25% with VEGFR1 vaccine, and others. Clinical benefit rate of 67% and a median PFS of 4.3 months were obtained on sorafenib rechallenge. There was no significant difference in outcome to sorafenib rechallenge based on duration between sorafenib treatments or number or type of intervening treatments. No new severe toxicity was observed during rechallenge. Conclusions: Sorafenib rechallenge has potential to achieve clinical benefits, is well-tolerated, and may be considered after multiple sequential therapies in select mRCC patients. No significant financial relationships to disclose.

Download Full-text