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.

     

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.     

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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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.     

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.     

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.     

Sarcomatoid Renal Cell Carcinoma: Clinical Outcome and Survival After Treatment With Sunitinib

BackgroundRenal tumors with sarcomatoid changes are aggressive malignancies with poor prognosis. Immunotherapy and chemotherapy have provided little benefit. The efficacy of treatments targeting the vascular endothelial growth factor pathway is unclear because of the lack of clinical trial data and the small number of published series.Patients and MethodsWe reviewed the clinical records of 23 consecutive patients with advanced sarcomatoid renal cell carcinoma who were treated with sunitinib in our center. Overall survival (OS), progression-free survival, and response rate were evaluated. We also studied the effect on clinical outcome of performance status, prognostic risk group, and proportion of sarcomatoid component.ResultsMedian OS was 15.7 months (95% confidence interval [CI], 5.0-21.2). Median progression-free survival was 5.7 months (95% CI, 3.2-12.6). Seven patients (30%) had an objective response, 5 patients (22%) had stable disease, and 11 (48%) had progressive disease. The median survival of the 13 (56.5%) patients with performance status of 0 to 1 was 20.9 months (95% CI, 9.7-63.3) whereas the medial survival of the 10 (43.5%) patients with performance status of 2 to 3 was 5.0 months (95% CI, 1.1-16.5). Objective responses were observed only among the 13 (56.5%) patients with performance status of 0 to 1. Heng prognostic risk group and percentage of sarcomatoid component did not influence outcome.ConclusionSunitinib shows efficacy in advanced renal tumors with sarcomatoid differentiation particularly in patients with good performance status. Appropriate patient selection and risk-directed treatment remains essential in this aggressive disease.     

Clinical Outcomes of First-line Sunitinib Followed by Immuno-oncology Checkpoint Inhibitors in Patients With Metastatic Renal Cell Carcinoma

BackgroundThe present retrospective, longitudinal cohort study assessed the association between the first-line sunitinib treatment duration and clinical outcomes with second-line immuno-oncology (IO) therapy among patients with metastatic renal cell carcinoma (mRCC).Patients and MethodsA total of 161 patients with mRCC who had been treated with first-line sunitinib and subsequent IO therapy from select International mRCC Database Consortium centers were included. The overall survival, time to next therapy, time to treatment discontinuation, and real-world physician-assessed best response measured from IO therapy initiation were analyzed and compared between patients treated with first-line sunitinib for ≥ 6 months and those treated for < 6 months.ResultsThe 116 patients treated with sunitinib for ≥ 6 months tended to be older and to have a better International mRCC Database Consortium risk than the 45 patients treated for < 6 months (favorable, 36% vs. 8%, P = .001; intermediate, 59% vs. 70%, P = .21; poor, 5% vs. 22%, P = .007). The receipt of sunitinib for ≥ 6 months versus < 6 months was associated with longer survival (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.21-0.87; P = .02). No significant association was observed between the first-line sunitinib duration and second-line IO outcomes, including the time to next therapy (HR, 0.89; 95% CI, 0.52-1.51; P = .66), time to treatment discontinuation (HR, 0.85; 95% CI, 0.54-1.34; P = .49), and tumor response (odds ratio, 0.73; 95% CI, 0.22-2.49; P = .62).ConclusionsWe found no statistically significant association between the first-line sunitinib duration and clinical outcomes with second-line IO therapy. Patients receiving first-line sunitinib for ≥ 6 months compared with < 6 months was associated with better overall survival, although potential unadjusted confounders could have been present. These findings support the paradigm that previous therapy will not dictate the effectiveness of subsequent immunotherapy.     

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.

First-Line Treatments for Metastatic Clear Cell Renal Cell Carcinoma: An Ever-Enlarging Landscape

Treatment paradigm for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the recent decades. From cytokines, interleukin-2 and interferon-α to tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, during the last decade, combinations of immune checkpoint inhibitors have taken over first-line treatment of mccRCC. These combinations are approved based on results from large phase III clinical trials, all of which used sunitinib as the comparator. These trials include CheckMate214 (ipilimumab plus nivolumab), KEYNOTE 426 (pembrolizumab plus axitinib), JAVELIN Renal 101 (avelumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), and the CLEAR study (lenvatinib and pembrolizumab). Results from these studies constitute milestones for newer therapeutic approaches in mccRCC. The broadening spectrum of treatment options for patients with mccRCC with multiple first-line options currently available also means that treating physicians will need to consider each option carefully, balance clinical factors, financial considerations, and weigh toxicity profiles of each drug before deciding the optimal treatment regimen for each individual patient. We describe each frontline treatment option in detail through this review to aid the decision-making process.     

Prognostic Impact of the Components of Progressive Disease on Survival After First-Line Tyrosine Kinase Inhibitor Therapy for Metastatic Renal Cell Carcinoma

Background

According to the Response Evaluation Criteria in Solid Tumors (RECIST) classification, progressive disease (PD) is defined as target lesion growth (TLG), unequivocal non-target lesion growth (NTLG), or new lesion appearance (NLA). The prognostic impact of the components of PD in tyrosine kinase inhibitor (TKI) therapy for metastatic renal cell carcinoma (mRCC) remains unknown.

Objective

We retrospectively evaluated the prognostic impact of these PD components on survival in patients with mRCC after first-line TKI therapy.

Patients and Methods

Patients were divided into three groups (TLG, NTLG, and NLA) based on the components of PD. Progression-free survival (PFS) and overall survival (OS) after first-line TKI therapy were compared between groups using the Kaplan-Meier method and log-rank test. The predictive impact of the PD components was evaluated using multivariate analyses.

Results

Among the 116 patients included, 80 (69.0%) had TLG, 18 (15.5%) NTLG, and 69 (58.6%) NLA. The mean PFS and OS were shorter for patients with TLG than those without TLG (PFS, 7.1 vs. 11.6 months, p?=?0.0071; OS, 18.2 vs. 25.5 months, p?=?0.0091). TLG was an independent predictor of PFS (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.02–2.51; p?=?0.0395) and OS (HR, 1.67; 95% CI, 1.02–2.83; p?=?0.040). NTLG and NLA were not associated with survival.

Conclusions

In this retrospective single-center study, patients with TLG had poor survival after first-line TKI therapy for mRCC. Thus, individual components of PD influence patient prognosis.

     

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     

Dosing Patterns,Toxicity, and Outcomes in Patients Treated With First-Line Sunitinib for Advanced Renal Cell Carcinoma in Community-Based Practices

BackgroundThis retrospective study by McKesson Specialty Health (MSH)/US Oncology Network (USON) evaluates dosing patterns of first-line sunitinib for patients with advanced renal cell carcinoma (aRCC) and its association with toxicities and clinical outcomes in community practices.Patients and MethodsPatients with aRCC who started first-line sunitinib between June 1, 2007, and May 31, 2011, were identified from 17 MSH/USON practices. Clinical data were extracted from iKnowMed electronic medical records linked to the MSH/USON pharmacy database.ResultsIn total, 134 patients were included; mean age was 63.9 years, 85% of the patients had an Eastern Cooperative Oncology Group performance score of 0 or 1, 82% had clear-cell renal cell carcinoma, and 65% had undergone nephrectomy. The median treatment duration was 4 cycles (range, 1-19). Overall, 113 patients discontinued sunitinib, mainly because of disease progression (45.1%) or toxicities (16.8%). Of all discontinuations, 77% occurred within the first 5 cycles. A total of 45 patients were dose-reduced, mostly because of toxicities (93%); 67% of all dose reductions occurred in the first 3 cycles. The objective response rate was 16.4%, median overall survival (OS) was 15.5 months, and progression-free survival (PFS) was 7.5 months. Multivariate analysis showed that OS and PFS were associated with sunitinib treatment duration.ConclusionsPatients with aRCC from community practices undergo sunitinib dose reductions more frequently because of toxicities and discontinue therapy sooner than in clinical trials. Clinical outcomes were inferior to those reported in clinical trials, potentially because of shorter duration of therapy. Sunitinib therapy optimization remains an important challenge in community practices.     

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.     

Surgical Treatment of Metastatic Renal Cell Carcinoma

The survivals of 174 patients who underwent nephrectomy forrenal cell carcinoma were analyzed to evaluate the influenceof the surgical treatment of metastases on their prognosis.For 34 of the 174 patients, surgical resections of the metastaseswere performed concurrently with nephrectomy. For 38 patients,44 surgical resections of metastases were performed in the follow-upperiod after nephrectomy. Apparently curative resections ofmetastases, at the time of nephrectomy or after nephrectomy,were significantly correlated with good survivals after surgery,irrespective of the number of metastatic foci. Aggressive surgicaltreatment was beneficial in patients with a longer tumor-freeperiod after nephrectomy or with stable disease for about sixmonths after surgical treatment, although this might simplybe a reflection of a longer natural disease course in this specificgroup of patients.