Faisal Mehmud

Randomized, Controlled, Double-Blind, Cross-Over Trial Assessing Treatment Preference for Pazopanib Versus Sunitinib in Patients With Metastatic Renal Cell Carcinoma: PISCES Study

PURPOSE Patient-reported outcomes may help inform treatment choice in advanced/metastatic renal cell carcinoma (RCC), particularly between approved targeted therapies with similar efficacy. This double-blind cross-over study evaluated patient preference for pazopanib or sunitinib and the influence of health-related quality of life (HRQoL) and safety factors on their stated preference. PATIENTS AND METHODS Patients with metastatic RCC were randomly assigned to pazopanib 800 mg per day for 10 weeks, a 2-week washout, and then sunitinib 50 mg per day (4 weeks on, 2 weeks off, 4 weeks on) for 10 weeks, or the reverse sequence. The primary end point, patient preference for a specific treatment, was assessed by questionnaire at the end of the two treatment periods. Other end points and analyses included reasons for preference, physician preference, safety, and HRQoL. RESULTS Of 169 randomly assigned patients, 114 met the following prespecified modified intent-to-treat criteria for the primary analysis: exposure to both treatments, no disease progression before cross over, and completion of the preference questionnaire. Significantly more patients preferred pazopanib (70%) over sunitinib (22%); 8% expressed no preference (P < .001). All preplanned sensitivity analyses, including the intent-to-treat population, statistically favored pazopanib. Less fatigue and better overall quality of life were the main reasons for preferring pazopanib, with less diarrhea being the most cited reason for preferring sunitinib. Physicians also preferred pazopanib (61%) over sunitinib (22%); 17% expressed no preference. Adverse events were consistent with each drugs known profile. Pazopanib was superior to sunitinib in HRQoL measures evaluating fatigue, hand/foot soreness, and mouth/throat soreness. CONCLUSION This innovative cross-over trial demonstrated a significant patient preference for pazopanib over sunitinib, with HRQoL and safety as key influencing factors.

Patient preference between pazopanib (Paz) and sunitinib (Sun): Results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310.

CRA4502 Background: Increasingly pt reported outcomes are being added to traditional efficacy outcomes to understand the clinical relevance of toxicity differences between therapies. This study investigated if tolerability differences were significant enough to lead a patient to prefer continuing their treatment with Paz or Sun. METHODS Pts with mRCC were randomized 1:1 to receive as first line treatment blinded 800mg Paz for 10 weeks followed by a 2-week washout and then 50mg Sun for 10 weeks (4/2 weeks schedule) or vice versa. Pts were stratified based on ECOG performance status (0 vs 1) and number of metastatic sites (0/1 vs 2+). The primary endpoint, patient preference assessed at 22 weeks, was compared using Prescotts test (α=0.10). At least 102 of 160 planned pts were required to complete the preference questionnaire to provide 80% power to detect a preference for one drug over another of 50% vs 30% with 20% expressing no preference. Other endpoints included physician preference, safety, QoL, pharmacokinetics and biomarkers. RESULTS Of 168 randomized pts, 126 completed the preference questionnaire. In the protocol-driven primary analysis (n=114), Paz was preferred by 70% of pts, Sun by 22% and 8% had no preference. After adjusting for a modest sequence effect, the difference in preference was 49% [90% CI 37.0 - 61.5% p <0.001] in favor of Paz. All pre-planned sensitivity analyses conducted were statistically significant in favor of Paz, including one which imputed Sun for all unavailable pt preference data. The most common reasons for Paz preference were better QoL and less fatigue. 60% of physicians preferred Paz vs 21% for Sun vs 19% no preference. Adverse events (AE) were in line with known profiles for both drugs. Pts on Paz had fewer dose reductions (13% vs 20%) and interruptions (6% vs 12%) vs Sun, mostly due to AE. There was less fatigue on Paz as assessed by FACIT-Fatigue; treatment difference of 2.49, p=0.002. Investigator assessed response (RECIST 1.1) was 22% with Paz vs 24% with Sun, p=0.87. CONCLUSIONS This innovative trial design clearly demonstrates the better tolerability of Paz compared to Sun.

Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first-line sunitinib: a medical chart review across ten centers in five European countries

Angiogenesis inhibitors have become standard of care for advanced and/or metastatic renal cell carcinoma (RCC), but data on the impact of adverse events (AEs) and treatment modifications associated with these agents are limited. Medical records were abstracted at 10 tertiary oncology centers in Europe for 291 patients ≥18 years old treated with sunitinib as first‐line treatment for advanced RCC (no prior systemic treatment for advanced disease). Logistic regression models were estimated to compare dose intensity among patients who did and did not experience AEs during the landmark periods (18, 24, and 30 weeks). Cox proportional hazard models were used to explore the possible relationship of low‐dose intensity (defined using thresholds of 0.7, 0.8, and 0.9) and treatment modifications during the landmark periods to survival. 64.4% to 67.9% of patients treated with sunitinib reported at least one AE of any grade, and approximately 10% of patients experienced at least one severe (grade 3 or 4) AE. Patients reporting severe AEs were statistically significantly more likely to have dose intensities below either 0.8 or 0.9. Dose intensity below 0.7 and dose discontinuation during all landmark periods were statistically significantly associated with shorter survival time. This study of advanced RCC patients treated with sunitinib in Europe found a significant relationship between AEs and dose intensity. It also found correlations between dose intensity and shorter survival, and between dose discontinuation and shorter survival. These results confirm the importance of tolerable treatment and maintaining dose intensity.

Angiogenesis inhibitor therapies for advanced renal cell carcinoma: Toxicity and treatment patterns in clinical practice from a global medical chart review

The aim of this study was to assess the treatment patterns and safety of sunitinib, sorafenib and bevacizumab in real-world clinical settings in US, Europe and Asia. Medical records were abstracted at 18 community oncology clinics in the US and at 21 tertiary oncology centers in US, Europe and Asia for 883 patients ≥18 years who had histologically/cytologically confirmed diagnosis of advanced RCC and received sunitinib (n=631), sorafenib (n=207) or bevacizumab (n=45) as first-line treatment. No prior treatment was permitted. Data were collected on all adverse events (AEs) and treatment modifications, including discontinuation, interruption and dose reduction. Treatment duration was estimated using Kaplan-Meier analysis. Demographics were similar across treatment groups and regions. Median treatment duration ranged from 6.1 to 10.7 months, 5.1 to 8.5 months and 7.5 to 9.8 months for sunitinib, sorafenib and bevacizumab patients, respectively. Grade 3/4 AEs were experienced by 26.0, 28.0 and 15.6% of sunitinib, sorafenib and bevacizumab patients, respectively. Treatment discontinuations occurred in 62.4 (Asia) to 63.1% (US) sunitinib, 68.8 (Asia) to 90.0% (Europe) sorafenib, and 66.7 (Asia) to 81.8% (US) bevacizumab patients. Globally, treatment modifications due to AEs occurred in 55.1, 54.2 and 50.0% sunitinib, sorafenib and bevacizumab patients, respectively. This study in a large, global cohort of advanced RCC patients found that angiogenesis inhibitors are associated with high rates of AEs and treatment modifications. Findings suggest an unmet need for more tolerable agents for RCC treatment.

Overall Survival Endpoint in Oncology Clinical Trials: Addressing the Effect of Crossover - The Case of Pazopanib in Advanced Renal Cell Carcinoma

Objective: To identify the issues of using overall survival (OS) as a primary endpoint in the presence of crossover and the statistical analyses available to adjust for confounded OS due to crossover in oncology clinical trials. Methods: An indirect comparison was conducted between pazopanib and sunitinib in advanced renal cell carcinoma. Statistical adjustment methods were used to estimate the true comparative effectiveness of these treatments. Recently, a head-to-head trial comparing pazopanib and sunitinib was completed. This provided the opportunity to compare the OS treatment effect estimated for pazopanib versus sunitinib using indirect comparison and statistical adjustment techniques with that observed in the head-to-head trial. Results: Using a rank-preserving structural failure time model to adjust for crossover in the pazopanib registration trial, the indirect comparison of pazopanib versus sunitinib resulted in an OS hazard ratio (HR) of 0.97, while an unadjusted analysis resulted in an OS HR of 1.96. The head-to-head trial reported a final OS HR of 0.92 for pazopanib versus sunitinib. Conclusion: This case study supports the need to adjust for confounded OS due to crossover, which enables trials to meet ethical standards and provides decision makers with a more accurate estimate of treatment benefit.

Development and Validation of a Prognostic Nomogram for Progression-Free Survival in Patients with Advanced Renal Cell Carcinoma Treated with Pazopanib

Objective: To develop and validate a prognostic nomogram for predicting the probability of 12-month progression-free survival (PFS) for patients receiving first-line pazopanib for advanced renal cell carcinoma (RCC). Methods: Statistical modeling was performed with data from 557 pazopanib-treated patients in the phase 3 COMPARZ trial. A multivariable Cox model was fit using known prognostic indicators. Variables included neutrophil count, serum levels of albumin and alkaline phosphatase, time from diagnosis to treatment, and bone metastases. Data from the pazopanib arm of a placebo-controlled phase 3 trial were used for validation. Results: The model included ten prognostic variables and was plotted as a nomogram for predicting the probability of 12-month PFS. Calibration plots suggested reasonable correspondence between predicted probabilities and actual proportions of PFS. The concordance index for 12-month PFS was 0.625. Significant associations (p < 0.05) were observed between PFS and bone metastases, time from diagnosis to treatment, albumin, and alkaline phosphatase. Albumin and alkaline phosphatase appeared to be influential predictors. Conclusion: The nomogram predicts, with reasonable accuracy, PFS in patients with advanced RCC receiving pazopanib, based on their baseline clinical characteristics.

Development and internal validation of a prognostic nomogram for overall survival in patients with advanced renal cell carcinoma (aRCC) treated with pazopanib (PAZ).

380 Background: PAZ, an oral multikinase inhibitor, demonstrated significant improvement in PFS over placebo in patients with aRCC in a randomized, phase III trial (J Clin Oncol 2009:29; 475). The purpose of this study was to develop and internally validate a prognostic nomogram based on the outcome data from phase III trial for predicting the probability of 12-month OS for treatment-naïve and cytokine-pretreated aRCC patients who received PAZ. METHODS Statistical modeling was performed on a dataset consisting of 281 patients from the PAZ arm of the phase III trial. Missing values were first imputed using multiple imputation with chained equations. A Cox proportional hazards regression model was fit using routinely available predictors thought to be prognostic based on clinical judgment. These predictors included the neutrophil count relative to ULN, platelet count relative to ULN, LDH relative to ULN, alkaline phosphatase relative to ULN, corrected calcium, albumin, hemoglobin, ECOG performance status, months from diagnosis to treatment, number of metastatic sites, and presence of lung, liver and bone metastases. Bootstrap-corrected estimates of discrimination and calibration in the small were calculated following 1,000 resamples. The Cox model was plotted as a nomogram. RESULTS A prognostic nomogram was developed and internally validated for predicting the probability of 12-month OS in aRCC patients based on a Cox regression model using 13 predictor variables. Calibration plots suggested reasonable correspondence between predicted probabilities and actual proportions of OS. The bootstrap-corrected concordance index, a measure of discrimination, was 0.70. When examining the nomogram, albumin appeared to have the greatest potential influence on predicted OS. Months from diagnosis to treatment and corrected calcium level seemed to be the next most potentially influential predictors. CONCLUSIONS The nomogram predicts with reasonable accuracy and should facilitate treatment decision making for patients with advanced renal cell carcinoma. Validation in a separate dataset is planned.