Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials

Background

We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months.

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.     

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.     

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.

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.     

Effect of Changes in Skeletal Muscle Mass on Oncological Outcomes During First-Line Sunitinib Therapy for Metastatic Renal Cell Carcinoma

Background

Sarcopenia is a state of degenerative skeletal muscle wasting induced by cancer cachexia.

Objective

To evaluate the prognostic impact of changes in skeletal muscle mass (SMM) during first-line sunitinib therapy on oncological outcomes in metastatic renal cell carcinoma (mRCC).

Patients and Methods

Sixty-nine patients were evaluated retrospectively. The skeletal muscle index (SMI) was calculated based on computed tomography images obtained before the initiation (pre-treatment SMI) and after two cycles of sunitinib treatment (post-treatment SMI). The change in SMM was evaluated based on the value of ΔSMI, which was calculated as [(posttreatment SMI – pretreatment SMI)/ pretreatment SMI]?×?100. Oncological outcomes were compared between patients with ΔSMI <0 (SMM decrease) and ΔSMI ≥0 (SMM maintenance).

Results

A decrease in SMM was observed in 38 patients (55.1%). Progression-free survival (PFS) and overall survival (OS) after sunitinib therapy initiation were significantly shorter in patients with ΔSMI <0 than in those with ΔSMI ≥0 (median PFS: 9.53 vs. 28.4 months, p?<?0.0001; OS: 19.8 vs. 52.6 months, p?=?0.0001). ΔSMI was an independent predictive factor for PFS (HR 3.25, 95% CI 1.74–6.29, p?=?0.0002) and OS (HR 4.53, 95% CI 2.15–10.5, p?<?0.0001). The objective response rate was significantly lower in patients with ΔSMI <0 than in those with ΔSMI ≥0 (23.7% vs. 51.6%, p?=?0.0164).

Conclusion

Decreased SMM during first-line sunitinib therapy can be an effective marker of outcome prediction for mRCC.

     

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.     

Correlation of c-MET Expression with PD-L1 Expression in Metastatic Clear Cell Renal Cell Carcinoma Treated by Sunitinib First-Line Therapy

Background

Clear cell renal cell carcinoma (ccRCC) is highly metastatic. Cabozantinib, an anti-angiogenic tyrosine kinase inhibitor that targets c-MET, provided interesting results in metastatic ccRCC treatment.

Objective

To understand better the role of c-MET in ccRCC, we assessed its status in a population of patients with metastatic ccRCC.

Patients and Methods

For this purpose, tumor samples were analyzed for c-MET expression by immunohistochemistry (IHC), for c-MET copy number alterations by fluorescence in situ hybridization (FISH), and for c-MET mutations by next generation sequencing (NGS) in a retrospective cohort of 90 primary ccRCC of patients with metastases treated by first-line sunitinib. The expression of c-MET was correlated with pathological, immunohistochemical (VEGFA, CAIX, PD-L1), clinical, and molecular criteria (VHL status) by univariate and multivariate analyses and to clinical outcome using Kaplan-Meier curves compared by log-rank test.

Results

Of ccRCC, 31.1% had low c-MET expression (absent to weak intensity by IHC) versus 68.9% with high expression (moderate to strong intensity). High expression of c-MET was associated with a gain in FISH analysis (p=0.004), sarcomatoid component (p=0.037), and PD-L1 (p<0.001) after logistic regression. No difference was observed in clinical outcomes.

Conclusion

This study is the first to analyse c-MET status in metastatic ccRCC. The high expression of c-MET in the majority of ccRCC and its independent association with PD-L1 expression, may suggest a potential benefit from combining c-MET inhibitors and targeted immunotherapy.

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Acalculous Cholecystitis in a Patient with Metastatic Renal Cell Carcinoma Treated with Sunitinib

A 62-year-old woman was treated with sunitinib as a second-line therapy for metastatic clear-cell renal carcinoma. She was given oral sunitinib 50 mg once daily, 4 weeks on followed by 2 week off. During the fourth week of her first cycle, the patient was admitted to our hospital because of an acute-onset, right upper quadrant pain associated with nausea and vomiting. She was diagnosed with acute acalculous cholecystitis, which was treated with broad-spectrum antibiotics, and sunitinib therapy was discontinued. A follow-up computed tomography scan of the abdomen revealed a complete resolution of gallbladder changes. Our patient did not have major risk factors for developing an acalculous cholecystitis except for a relative immunosuppressed state secondary to her advanced renal cancer. The Naranjo Adverse Drug Reaction Probability Scale score for this event was 5, indicating a probable association of the event with sunitinib. Because the use of sunitinib is expanding in clinical practice, we want to alert the oncology community about this uncommon and life-threatening complication in patients receiving sunitinib or another agent with antiangiogenic activity.     

Efficacy and Toxicity of Sunitinib in Metastatic Renal Cell Carcinoma Patients in Egypt

Background: To evaluate our results in terms of response, survival and toxicity profile of sunitinib amongEgyptian patients with metastatic renal cell carcinoma. Materials and Methods: Between January 2010 andDecember 2013, 44 patients with metastatic renal cell carcinoma who received sunitinib at an oncology centerof Cairo university hospitals were enrolled in this retrospective analysis. Results: The median age of the patientswas 53 years, 22 (50%) having localized disease at presentation ,while the remaining half of the patients presentedwith metastasis. At a median follow up of 19 months, 9 (21%) patients achieved partial remission, while diseasewas reported stable in 20 cases (45%) and progressive in 7 (16%), 4 (9%) being lost to follow up, and 4 (9%)had discontinued therapy due to toxicity. The median overall survival was 23 months (95%CI 15.2 - 30.9), whileprogression free survival was 12 months (95%CI 11.6 - 12.3). The most commonly reported non hematologicalgrade 3 adverse events included mucositis (15.9%), hand-foot syndrome (13.6%), and fatigue (9%), while thepredominant grade 3 or 4 laboratory abnormalities were neutropenia (6.8%), followed by anemia in 4.5% ofpatients. Conclusions: Our efficacy data were comparable to the published literature in terms of progressionfree survival and overall survival , while toxicity profile is different from Asian and western countries. However,sunitinib adverse events were manageable and tolerable in most of our Egyptian patients     

转移性肾细胞癌分子靶向治疗研究进展

肾细胞癌是泌尿系统肿瘤中常见的恶性肿瘤,发病率约5～10/10万。转移性肾细胞癌在以细胞因子为基础的治疗失败后,尚无明确的二线治疗措施。随着对乏氧诱导因子(hypoxia-inducible factor,HIF)相关蛋白的研究,转移性肾细胞癌分子靶向治疗研究成为热点。本文综述较有前景的靶向药物,包括Bevacizumab(贝伐单抗)、Sorafenib(索拉非尼)、Sunitinib(舒尼替尼)、AG-013736、Vatalanib(PTK787)、Thalidomide(沙利度胺)及Temsirolimus(CCI-779)。     

Clinical Effectiveness of Second-line Sunitinib Following Immuno-oncology Therapy in Patients with Metastatic Renal Cell Carcinoma: A Real-world Study

BackgroundLimited data exist on the clinical effectiveness of second-line (2L) vascular endothelial growth factor (receptor) targeted inhibitor (VEGF(R)i) sunitinib after first-line (1L) immuno-oncology (IO) therapy for patients with metastatic renal cell carcinoma (mRCC) in real-world settings.MethodsA retrospective cohort study among adult patients with mRCC treated with 2L sunitinib following 1L IO was conducted from select International mRCC Database Consortium (IMDC) centers. All analyses were performed overall and by 1L ipilimumab + nivolumab (IPI+NIVO) or 1L IO+VEGF(R)i. Median overall survival (mOS) and time-to-treatment discontinuation (mTTD) in 2L were estimated using Kaplan-Meier analysis. The 2L objective response rate (ORR) (complete/partial response) was reported.ResultsAmong 102 patients on 2L sunitinib, mean age was 61.3 years. IMDC risk scores at 2L initiation was available for 83 patients: 8 (9.6%) were favorable, 45 (54.2%) were intermediate, and 30 (36.1%) were poor risk. The 1L consisted of IPI+NIVO in 62 (60.8%), IO+VEGF(R)i therapy in 27 (26.5%), and IO monotherapy in 13 (12.7%) patients. Among all patients, mOS was 15.6 months (95% confidence interval [CI], 9.8-21.7), with a 1-year OS rate of 57.5% (95% CI, 45.2-68.0). mTTD was 5.4 months (95% CI, 4.2-7.2) and ORR was 22.5%.ConclusionDespite availability of effective 1L therapies in recent years, 2L sunitinib continues to have clinical activity after failure of 1L IO. Further studies on optimal treatment sequencing after 1L IO progression are needed.     

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.     

Factors Prognostic for Survival in Japanese Patients Treated with Sunitinib as First-line Therapy for Metastatic Clear Cell Renal Cell Cancer

Background: Factors predictive of survival have been identified in Western patients with metastatic clearcell renal cell carcinoma (mCCRCC) treated with sunitinib. Less is known, however, about factors predictiveof survival in Japanese patients. This study evaluated factors prognostic of survival in Japanese patients withmCCRCC treated with first-line sunitinib. Materials and Methods: This retrospective study evaluated 46consecutive Japanese mCCRCC patients treated with sunitinib as first line therapy. Clinical and biochemicalmarkers associated with progression-free survival (PFS) were analyzed, with prognostic factors selected by uniandmultivariate Cox regression analyses. Results: Univariate analysis showed that factors significantly associatedwith poor PFS included Memorial Sloan-Kettering Cancer Center poor risk scores, International MetastaticRCC Database Consortium poor risk and high (>0.5 mg/dl) serum C-reactive protein (CRP) concentrations(p<0.001 each). Multivariate analysis showed that high serum CRP was independently associated with poorerPFS (p=0.040). Six month disease control rate (complete response, partial response and stable disease) in responseto sunitinib was significantly higher in patients with normal (≤0.5 mg/dl) than elevated baseline CRP (p<0.001).Conclusions: CRP is a significant independent predictor of PFS for Japanese patients with mCCRCC treatedwith first-line sunitinib. Pretreatment CRP concentration may be a useful biomarker predicting response tosunitinib treatment.     

Adjuvant Therapy for Renal Cell Carcinoma

In the past few years, several targeted therapies have been approved by the U.S. Food and Drug Administration for the treatment of advanced renal cell carcinoma. This has led to an improvement in the progression-free survival and quality of life for these patients. Nevertheless, the use of these and other therapies in the adjuvant setting has failed to demonstrate a clear benefit. Immune therapies and hormonal or targeted therapies have been studied in this indication, and there are clinical trials currently enrolling patients with high risk of relapse. This article reviews the available data and the ongoing trials exploring the role of adjuvant therapy for kidney cancer.