Long-Term Response to Sunitinib Therapy for Metastatic Renal Cell Carcinoma

BackgroundSunitinib achieves objective response and prolongs progression-free survival (PFS) in patients with metastatic renal cell carcinoma (RCC). A subset of patients achieves long-term responses. The characteristics of patients who achieved long-term response (defined as patients achieving ongoing complete response [CR] or remaining progression free for > 18 months while receiving sunitinib) are reported.Patients and MethodsA database of 186 patients treated with sunitinib alone (n = 89) or in combination (n = 97) in 9 clinical trials was reviewed; all had 1 year or more follow-up from sunitinib start to data cutoff for analysis. Median PFS was 10.8 months (95% CI, 8.3-13.3); median overall survival (OS) was 30.4 months (95% CI, 21.5-36.8 months) for the 186 patients. Thirty-four patients were identified as long-term responders because they either had durable CR or remained progression free while receiving sunitinib for > 18 months.ResultsBest response for 34 long-term responders was CR in 3 patients, partial response (PR) in 24 patients, and stable disease in 7 patients. The median duration of sunitinib therapy was 24.9 months (range, 18.1-73.9 months). The median PFS among the long-term responders was 17.4 months (95% CI, 7-29.9 months) at a landmark PFS analysis performed after 18 months from treatment start. Univariate analysis from the 186 patients identified bone metastasis, lung metastasis, and intermediate/poor risk groups as adverse prognostic factors for long-term response.ConclusionSunitinib achieves long-term response in a subset of patients with metastatic RCC. Lack of bone metastasis or lung metastasis and good MSKCC risk status may predict long-term response.     

Relationship Between Thymidine Kinase 1 Expression and Trifluridine/Tipiracil Therapy in Refractory Metastatic Colorectal Cancer: A Pooled Analysis of 2 Randomized Clinical Trials

Background

High thymidine kinase 1 (TK1) activity increases the incorporation of trifluridine (FTD) into DNA; thus, FTD antitumor activity is likely to increase in patients with high tumoral TK1 activity. To date, no established predictive biomarker to indicate the clinical benefit of FTD/tipiracil (TPI) has been identified. We aimed to determine the relationship between TK1 expression and FTD/TPI efficacy in refractory metastatic colorectal cancer.

Active Smoking Is Associated With Worse Prognosis in Metastatic Renal Cell Carcinoma Patients Treated With Targeted Therapies

Background

Smoking increases the risk of developing renal cell carcinoma (RCC) but the effect of tobacco consumption on survival outcome of patients with metastatic RCC (mRCC) treated with targeted therapies has not been well characterized.

Single-Agent Gemcitabine vs. Carboplatin-Gemcitabine in Advanced Breast Cancer: A Retrospective Comparison of Efficacy and Safety Profiles

Background

Single-agent gemcitabine is a moderately effective compound in metastatic breast cancer (mBC) treatment. Carboplatin is frequently used in addition to gemcitabine to improve tumor responses, but with an unclear effect on survival outcomes. In this study we evaluated the antitumor efficacy and safety profiles of gemcitabine and carboplatin-gemcitabine in mBC patients.

Sunitinib in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to International Metastatic Renal Cell Carcinoma Database Consortium Risk Group

Background

Sunitinib malate, a targeted tyrosine kinase inhibitor, is standard of care for metastatic renal cell carcinoma (mRCC) and serves as the active comparator in several ongoing mRCC clinical trials. In this analysis we report benchmarks for clinical outcomes on the basis of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups for patients treated with sunitinib for mRCC in a first-line setting.

Surrogate End Points and Postprogression Survival in Renal Cell Carcinoma: An Analysis of First-Line Trials With Targeted Therapies

Our end point was to determine the correlations between progression-free survival (PFS), postprogression survival (PPS), response rate (RR), and disease control rate (DCR) (RR + stable disease) and overall survival (OS) in first-line trials of renal cell carcinoma (RCC) treated with targeted therapies and to identify a potential surrogate for OS. Data were collected from first-line phase III randomized trials in RCC. Linear regression was undertaken to evaluate the correlations between end points and a potential surrogate end point for OS. Six randomized trials were identified containing a total of 7 treatment arms. The nonparametric Spearman rank correlation coefficients (r_s) between PFS, PPS, and RR/DCR and OS are 0.869, and 1, 0.96/1 (all P < .0001), respectively. There is a strong relationship between differences (Δ) in DCR and ΔOS (r_s = 1). The slope of the regression line is 0.3963 ± 0.0019, indicating that a novel drug producing a 10% increase for DCR will yield an estimated absolute 3.9% increase in OS. In first-line trials including novel targeted agents for RCC, PFS is a relatively flawed surrogate end point because of PPS influence. Improvement in DCR is strongly associated with improvement in median OS. In this population, DCR may be an appropriate surrogate for OS.     

Sunitinib Rechallenge in Patients With Metastatic Renal Cell Carcinoma

BackgroundSunitinib has been the standard of care for patients with metastatic renal cell carcinoma (mRCC). However, nearly all patients will eventually develop resistance. Before the introduction of novel agents, few treatment options remained after sunitinib failure. Sunitinib rechallenge is a strategy based on the presumption that resistance might be only temporary. The aim of this analysis was to evaluate the efficacy and safety of sunitinib rechallenge in patients with mRCC.Patients and MethodsPatients who had undergone sunitinib rechallenge (SU2) at the Medical University of Vienna from 2010 to 2017 were identified for the present retrospective study. The primary endpoint was the treatment duration with rechallenge (TD^SU2). The secondary endpoints included the treatment duration with upfront sunitinib (TD^SU1), progression-free survival (PFS^SU1 and PFS^SU2), overall survival (OS^SU1 and OS^SU2), the objective response rate in both settings (ORR^SU1 and ORR^SU2), and toxicity.ResultsA total of 31 patients were eligible. The median TD^SU2 was 7.2 months, and the median TD^SU1 was 17.8 months. The median OS^SU1 and OS^SU2 was 57.9 months and 14.7 months, respectively. The median PFS^SU1 and PFS^SU2 was 14.2 months and 5.6 months, respectively. The ORR^SU1 and ORR^SU2 was 34% and 16%, and another 48% and 42% achieved stable disease (SD), respectively. Fatigue and hypertension were the most common adverse events.ConclusionsSunitinib rechallenge appears to benefit patients in later treatment lines. With the abundance of novel treatment options available, this approach might appear less relevant. However, novel agents are not yet available everywhere. Thus, sunitinib rechallenge could be an additional strategy to improve the outcomes of patients with mRCC.     

Second-Line Treatment Outcomes After First-Line Sunitinib Therapy in Metastatic Renal Cell Carcinoma

This study was conducted to evaluate the treatment outcomes associated with common second-line targeted therapies given after first-line sunitinib for metastatic renal cell carcinoma (mRCC). The sample comprised patients with mRCC (n = 257) who were receiving second-line everolimus, sorafenib, or temsirolimus between April 1, 2008, and February 29, 2011, after first-line sunitinib treatment. The patients were followed-up from the start of second-line treatment until treatment failure (defined as advancement to a third-line therapy or to mortality) or the last observation in the medical and pharmacy databases. Treatment failure was observed in 38.5% (n = 99) of cases: 20.2% of patients (n = 52) advanced a line of treatment; and 18.3% of patients (n = 47) died. Kaplan-Meier analysis indicated a statistical difference in time to treatment failure among the 3 second-line targeted therapies (log-rank test, P = .045). The estimated 1-year cumulative probabilities of treatment failure were 49.9% for everolimus, 68.4% for sorafenib, and 71.4% for temsirolimus. In a multivariate Cox proportional hazards model, a higher adjusted risk of treatment failure vs. everolimus was observed for both temsirolimus (hazard ratio [HR] 2.05 [95% CI, 1.26-3.35]; P = .004) and sorafenib (HR 1.77 [95% CI, 1.02-3.07]; P = .043). The results of this real-world data analysis suggest that the risk of second-line treatment failure after first-line sunitinib was significantly higher with temsirolimus and sorafenib compared with everolimus.     

Contemporary Cytoreductive Nephrectomy Provides Survival Benefit in Clear-cell Metastatic Renal Cell Carcinoma

IntroductionA recent randomized trial questioned the role of cytoreductive nephrectomy in clear-cell metastatic renal cell carcinoma (ccmRCC). We reassessed the effect of cytoreductive nephrectomy on survival in a contemporary population-based ccmRCC cohort.Patients and MethodsWithin the Surveillance, Epidemiology, and End Results database (2010-2015), we focused on patients with ccmRCC. The primary endpoint consisted of overall mortality. Univariable and multivariable Cox regression models were applied in the overall cohort and in patients who underwent targeted therapy. Sensitivity analyses included 1:1 propensity score matching, 3- and 6-month landmark analyses, incremental survival benefit analyses, and metastases number and location-based stratifications.ResultsOf 4062 patients with ccmRCC, 2241 (55.1%) received targeted therapy; cytoreductive nephrectomy was performed in 2226 (54.8%) patients and 1168 (52.1%) patients in the overall and targeted therapy cohorts, respectively. Cytoreductive nephrectomy was associated with lower overall mortality in the overall cohort (median survival, 30 vs. 9 months; hazard ratio [HR], 0.43; P < .001), as well as in the targeted therapy cohort (median survival, 28 vs. 12 months; HR, 0.49; P < .001). In sensitivity analyses, cytoreductive nephrectomy was associated with lower overall mortality after 1:1 propensity score-matching (HR, 0.49; P < .001), in 3- and 6-month landmark analyses (HR, 0.49; P < .001 and HR, 0.51; P < .001, respectively), in metastases number and location-based stratifications, except for exclusive liver metastases, as well as in all incremental benefit analyses.ConclusionCytoreductive nephrectomy is associated with better survival in patients with ccmRCC, including those exposed to targeted therapy, after adjustment for multiple potential confounders.     

Real-world Experience With Sunitinib Treatment in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to Risk Score

BackgroundADONIS is an ongoing observational study in 9 European countries, designed to evaluate treatment patterns/outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with first-line sunitinib and/or second-line axitinib post sunitinib. We present an evaluation of sunitinib efficacy by risk group, in the real-world setting examined in ADONIS.Patients and MethodsPatients were enrolled at the start of first-line sunitinib treatment or second-line axitinib post sunitinib treatment. Evaluation of sunitinib efficacy was assessed by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center risk criteria.ResultsFor all patients in this analysis (N = 467), the median progression-free survival was 23.8 months (95% confidence interval [CI], 16.5-28.5 months), 11.8 months (95% CI, 8.1-17.4 months), and 4.6 months (95% CI, 2.5-7.7 months) for IMDC favorable-, intermediate-, and poor-risk groups, respectively. The median overall survival was 97.1 months (95% CI, 46.3 months-not evaluable [NE]), 33.5 months (95% CI, 20.5-46.6 months), and 10.0 months (95% CI, 4.5-19.8 months) for the respective risk groups. Data on individual risk factors were available for a subgroup of patients, allowing analysis by intermediate risk by 1 versus 2 risk factors. When including this subgroup (n = 120), the median overall survival for IMDC favorable-, intermediate-1, and intermediate-2 risk factors was 21.6 months (95% CI, 16.3 months-NE), 20.5 months (15.5 months-NE), and 15.1 months (4.1 months-NE), respectively.ConclusionsFor patients overall and by risk-group stratification, survival estimates were aligned with previously published data. In patients with intermediate-1 risk, overall survival was very similar to patients with favorable risk. However, further exploration of outcome data from different sources is needed to confirm these observations.     

Metastatic Clear-cell Renal Cell Carcinoma With a Long-term Response to Sunitinib: A Distinct Phenotype Independently Associated With Low PD-L1 Expression

BackgroundLong-term responders (LTRs) are defined by at least 18 months of response to sunitinib in metastatic clear-cell renal cell carcinoma (ccRCC). Well-described by clinical studies, the phenotype of these tumors has never been explored.Patients and MethodsIn a retrospective and multicenter study, 90 ccRCCs of patients with metastatic disease were analyzed. Immunohistochemistry (carbonic anhydrase IX, vascular endothelial growth factor, c-MET, programmed death-ligand 1 [PD-L1], and PD-1) and VHL status were performed. Progression-free survival and overall survival were calculated from sunitinib introduction and from progression. LTRs and their corresponding tumors were compared with others using univariate and multivariate analysis.ResultsTwenty-eight patients were LTRs. They had a median progression-free survival of 28 months versus 4 months for other patients (P < .001). Similarly, LTRs had a median overall survival of 49 months versus 14 months (P < .001), even from progression (median, 21 vs. 7 months; P = .029). They were associated with a favorable or intermediate risk (International Metastatic Renal Cell Carcinoma Database Consortium model) (P = .007) and less liver metastasis (P = .036). They experienced more frequent complete or partial responses at the first radiologic evaluation (P = .035). The corresponding ccRCCs were associated with less nucleolar International Society for Urological Pathology grade 4 (P = .037) and hilar fat infiltration (P = .006). They were also associated with low PD-L1 expression (P = .02). Only the International Metastatic Renal Cell Carcinoma Database Consortium model and PD-L1 expression remained significant after multivariate analysis (P = .014 and P = .029, respectively).ConclusionPrimary tumor characteristics of LTRs were studied for the first time and demonstrated a different phenotype. Interestingly, they were characterized by low expression of PD-L1, suggesting a potentially lower impact of targeted immunotherapy in these patients.     

Patients with Metastatic Renal Cell Carcinoma with Long-Term Disease-Free Survival After Treatment with Sunitinib and Resection of Residual Metastases

A complete response (CR) to therapy in patients with metastatic renal cell carcinoma (RCC) is rare but has been achieved in a minority of patients using high-dose interleukin-2. Surgical CR after partial response to immunotherapy in metastatic RCC has been anecdotally reported, although the low overall response rate to cytokines precludes this procedure in the majority of patients. Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity. Clinical efficacy has been demonstrated, with high objective response rates observed in a variety of solid tumor types, including RCC. Herein, we report 2 cases of patients with cytokine-refractory metastatic RCC who received sunitinib and achieved sufficient decrease in tumor burden to permit subsequent surgical resection, resulting in long-term CR.     

Trabectedin as a Single-Agent Treatment of Advanced Breast Cancer After Anthracycline and Taxane Treatment: A Multicenter,Randomized, Phase II Study Comparing 2 Administration Regimens

BackgroundThe purpose of this study was to assess the efficacy and safety of trabectedin for advanced breast cancer.Patients and MethodsIn an open-label, phase II, multicenter study, women with advanced breast cancer previously treated with ≤ 2 lines of chemotherapy for advanced disease, including both anthracyclines and taxanes, were randomized (1:1) to 3-hour infusions of trabectedin 1.3 mg/m² once every 3 weeks (1/3 treatment arm) or 0.58 mg/m² every week for 3 of 4 weeks (3/4 treatment arm). The primary end point was objective response. Secondary end points included time to progression (TTP), progression-free survival (PFS), and overall survival (OS).ResultsFifty-two women (median age, 50 years; median chemotherapy agents, 4) were enrolled. Relative trabectedin dose intensities were 81% and 76% in the 1/3 and 3/4 treatment arms, respectively. Objective response rates were 12% (3 of 25) and 4% (1 of 27), respectively. Stable disease was observed in 14 (56%) and 11 (41%) patients in the 1/3 and 3/4 treatment arms, respectively, with median durations of 3.5 and 3.7 months. Median TTP and PFS were higher in the 1/3 treatment arm (3.1 months each) than in the 3/4 treatment arm (2.0 months each). At a median follow-up of 7 months in both treatment arms, median OS was not reached in the 1/3 treatment arm and was 9.4 months in the 3/4 treatment arm. The most frequent drug-related adverse events in the 1/3 and 3/4 treatment arms, respectively, were alanine aminotransferase (ALT) level increases (68% vs. 63%), nausea (56% vs. 59%), and asthenia (56% vs. 48%). Neutropenia and increases in ALT levels were the most frequent grade 3/4 events. Both types of events were usually transient and reversible.ConclusionIn the population studied, trabectedin showed a manageable safety profile for both regimens analyzed. There were higher objective response rates and a longer PFS in the 1/3 treatment arm compared with the 3/4 treatment arm.     

Tolerance of Sunitinib in Dialyzed Patients With Metastatic Renal Cell Carcinoma

The use of sunitinib in dialysis patients is poorly described but is of clinical importance. We report 2 cases of patients receiving sunitinib for metastatic renal cell carcinoma while undergoing dialysis. The first patient is undergoing hemodialysis and, though responding to sunitinib, is having significant fatigue and hypertension. The second patient underwent peritoneal dialysis and also had significant problems with hypertension. The tolerance of sunitinib in the setting of dialysis can be challenging as these interventions can have synergistic side effects. Close monitoring for toxicity and dosage manipulations might be required if such therapy is attempted.     

Clinical Relevance of Gene Copy Number Variation in Metastatic Clear Cell Renal Cell Carcinoma

Background

Gene copy number variations (CNVs) have been reported to be frequent in renal cell carcinoma (RCC), with potential prognostic value for some. However, their clinical utility, especially to guide treatment of metastatic disease remains to be established. Our objectives were to assess CNVs on a panel of selected genes and determine their clinical relevance in patients who underwent treatment of metastatic RCC.