Real-world Effectiveness and Safety of Pazopanib in Patients With Intermediate Prognostic Risk Advanced Renal Cell Carcinoma (2019)

Type of publication:
Journal article

Author(s):
Procopio G.; Bamias A.; Schmidinger M.; Hawkins R.; Sanchez A.R.; Estevez S.V.; *Srihari N.; Kalofonos H.; Bono P.; Pisal C.B.; Hirschberg Y.; Dezzani L.; Ahmad Q.; Rodriguez C.S.; Jonasch E.

Citation:
Clinical Genitourinary Cancer; Jun 2019; vol. 17 (no. 3), p. e526-e533

Abstract:
Introduction: The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778).
Patients and Methods: Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients.
Result(s): Three hundred sixty three and 343 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS >= 2 (vs. PS < 2). All-grade treatment-related adverse events occurred in approximately 63% of patients, and the safety profile among older and younger patients was similar.
Conclusion(s): Outcomes with pazopanib in intermediate-risk patients suggest that patients can be further stratified by number of risk factors (1 vs. 2) and Eastern Cooperative Oncology Group PS (< 2 vs. >= 2) to more accurately predict outcomes.Patients with intermediate-risk advanced renal cell carcinoma are a heterogeneous population, having either 1 or 2 risk factors. It is unclear whether all patients in this risk category should be treated similarly. A secondary analysis of the PRINCIPAL study of pazopanib found that
patients can be stratified by number of risk factors and Eastern Cooperative Oncology Group performance status to more accurately predict outcomes.

Real-world Effectiveness and Safety of Pazopanib in Patients With Intermediate Prognostic Risk Advanced Renal Cell (2018)

Type of publication:
Conference abstract

Author(s):
Procopio G.; Bamias A.; Schmidinger M.; Hawkins R.; Sanchez A.R.; Estevez S.V.; *Srihari N.; Kalofonos H.; Bono P.; Pisal C.B.; Hirschberg Y.; Dezzani L.; Ahmad Q.; Rodriguez C.S.; Jonasch E.

Citation:
Annals of Oncology (2018) 29 (suppl_8): p.313

Abstract:
Introduction: The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778). Patients and Methods: Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediaterisk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients.
Result(s): Three hundred forty-three and 363 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS >= 2 (vs. PS < 2). All-grade treatment-related adverse events occurred in approximately 63% of patients, and the safety profile among older and younger patients was similar.
Conclusion(s): Outcomes with pazopanib in intermediate-risk patients suggest that patients can be further stratified by number of risk factors (1 vs. 2) and Eastern Cooperative Oncology Group PS (< 2 vs. >= 2) to more accurately predict outcomes. Patients with intermediate-risk advanced renal cell carcinoma are a heterogeneous population, having either 1 or 2 risk factors. It is unclear whether all patients in this risk category should be treated similarly. A secondary analysis of the PRINCIPAL study of pazopanib found that patients can be stratified by number of risk factors and Eastern Cooperative Oncology Group performance status to more accurately predict outcomes.

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study) (2019)

Type of publication:
Journal article

Author(s):

Schmidinger M.; Bamias A.; Procopio G.; Hawkins R.; Sanchez A.R.; Vazquez S.; *Srihari N.; Kalofonos H.; Bono P.; Pisal C.B.; Hirschberg Y.; Dezzani L.; Ahmad Q.; Jonasch E.; Gimeno R.A.; Herranz U.A.; Ardavanis A.; Ashraf S.A.; Barone C.; Bella S.R.; Belz H.; Companario E.B.; Bolling C.; Bothe K.; Carteni G.; Espinosa J.C.; Clausse M.; Confente C.; Coskun H.; Herrero G.C.; Demey W.; D’hondt R.; Santasusana M.D.; Doshi G.; Elkiran E.; Facchini G.; Fein L.; Calvo O.F.; Flaherty A.; Fountzilas G.; Fruehauf J.; Diaz E.G.; Garcia R.; Dominguez R.G.; Ghosn M.; Glorieux P.; Goebell P.J.; Gutierrez L.G.-A.; Gonzalez M.; Green N.B.; Arnau M.G.; Harich H.-D.; Hegele A.; Perez C.H.; Herrmann E.; Horniniger W.J.; Hutson T.E.; Janetschek G.; Kalantari H.; Klausmann M.; Kolin M.; Krause S.; Kroening H.; Sorrosal J.J.L.; Lazaro M.; Lema M.; Lema M.L.; Lin J.; Lueck A.; Lybaert W.; Magi A.; Marina V.A.; Rey J.P.M.; Matus G.; Melear J.; Gonzalez B.M.; Milella M.; Montalar J.; Ferrandis J.M.; Nathan P.; Nechushtan H.; Nusch A.; Ojamaa K.; Oksuzoglu B.; Ozkan M.; Papazisis K.; Passalacqua R.; Pe’er A.; Gracia J.L.P.; Pichler A.; Pokker H.; Porta C.; Rauchenwald M.; Richardet M.E.; Richey S.L.; Garcia J.M.R.; Rudolph R.; Sabbatini R.; Salmon J.-P.; Lobera C.S.; Sarid D.L.; Saylors G.B.; Schrijvers D.; Schulze M.; Sevilay A.; Shumaker G.G.; Siemer S.; de Prado y Otero D.S.; Stoiber F.; Rodriguez C.S.; Varela M.S.; Vasanthan S.; Estevez S.V.; Vehling-Kaiser U.; Vogelzang N.; Weiss H.; Whenham N.; Wyendaele W.; Yildiz R.; Yucel I.; Zarba J.J.; Zarkar A.; Zhong W.; Ziem P.

Citation:
The Oncologist; Apr 2019; vol. 24 (no.4); p. 491-497

Abstract:
BACKGROUND Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC).SUBJECTS, MATERIALS, AND METHODS Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups.RESULTS Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2-12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. CONCLUSION PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. IMPLICATIONS FOR PRACTICE PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months.

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Prospective, multinational, observational study of real-world treatment outcomes with pazopanib in patients with advanced or metastatic renal cell carcinoma (PRINCIPAL study) (2018)

Type of publication:
Conference abstract

Author(s):
Schmidinger M.; Procopio G.; Hawkins R.E.; Sanchez A.R.; Vazquez S.; *Srihari N.; Kalofonos H.; Bamias A.; Bono P.; Pisal C.B.; Hirschberg Y.; Dezzani L.; Ahmad Q.I.; Jonasch E.

Citation:
Journal of Clinical Oncology; May 2018; vol. 36 (no. 15)

Abstract:
Background: PRINCIPAL (NCT01649778) was the largest prospective real-world effectiveness and safety study of pazopanib (PAZ) in patients (pts) with renal cell carcinoma (RCC). Method(s): Pts with advanced and/or metastatic clear cell RCC were enrolled within 30 days of initiating firstline PAZ. Follow-up data on progression, survival, and safety was collected approximately every 3 months until death, consent withdrawal, or loss to follow-up, for up to 30 months. Primary efficacy end points were median overall survival (mOS), median progression-free survival (mPFS), and overall response rate (ORR). Safety measures included frequency of adverse events (AEs), serious AEs, and AEs of special interest. Result(s): Among 657 pts who received >=1 dose of PAZ, 76.3% completed the study (33.0% completed 30 months of follow-up and 43.2% died). Median enrollment age was 66 years, with 57.2% aged >=65 years. 4.1%, 62.6%, and 33.3% of pts were grouped as favorable, intermediate, or poor risk by Heng criteria, respectively. Most pts (84%) initiated treatment at 800 mg, and the median treatment time with or without dose interruption was 6.9 and 7.6 months, respectively. mPFS and mOS are shown in the Table. Among the measurable disease population (n = 168), ORR was 30.3%, median duration of response was 11.0 months (95% confidence interval [CI] 8.6-14.6), and time to response, evaluated every 3 months, was 3.0 months (95% CI 2.9-3.1). Most pts had an AE (74.0%) that led to dose  adjustment/interruption in 49.3% and treatment discontinuation in 14.6%. The most frequent ( > 10%) drug-related AEs were hypertension (20.9%), diarrhea (11.3%), and increased alanine aminotransferase (11.0%). Conclusion(s): Realworld effectiveness and safety outcomes in the PRINCIPAL study were consistent with clinical trials and support the first-line use of PAZ across all risk groups of pts with advanced or metastatic RCC.

Comparison of clinical outcomes with firstline pazopanib in clinical trial eligible and non-clinical trial eligible patients with renal cell carcinoma (2018)

Type of publication:
Conference abstract

Author(s):
Jonasch E.; Procopio G.; Hawkins R.E.; Sanchez A.R.; Vazquez S.; *Srihari N.; Kalofonos H.; Bamias A.; Bono P.; Pisal C.B.; Hirschberg Y.; Dezzani L.; Ahmad Q.I.; Schmidinger M.

Citation:
Journal of Clinical Oncology; May 2018; vol. 36 (no. 15)

Abstract:
Background: Although pazopanib (PAZ) has been evaluated in clinical trials of patients (pts) with renal cell carcinoma (RCC), limited real-world data on the effectiveness and safety of PAZ exist. The PRINCIPAL study (NCT01649778) assessed the effectiveness and safety of first-line PAZ in a real-world setting. Method(s): In this nonrandomized, prospective study, pts with advanced and/or metastatic clear cell RCC were enrolled in PRINCIPAL within 30 days of initiating first-line PAZ. Data on progression, survival, and safety were collected approximately every 3 months (mos) until death, consent withdrawal, or loss to follow-up, for up to 30 mos. Pts in PRINCIPAL were separated into two groups based on key eligibility criteria from the Phase III COMPARZ trial (Motzer et al. NEJM. 2013;369:722). Key clinical trial eligible (CTE) criteria included no prior systemic therapy, presence of measurable disease per RECIST 1.1, Karnofsky performance status >=70, adequate organ system function, no history or clinical evidence of central nervous system metastases, and no coronary or cerebral artery disease at baseline. CTE pts were compared to non-CTE (NCTE) pts. Clinical effectiveness (ie, median overall survival [mOS], median progression-free survival [mPFS], and overall response rate [ORR]), adverse event (AE) measures, and relative dose intensity (RDI) were assessed in both pt populations. Result(s): Of the 657 enrolled pts who received >=1 dose of PAZ, 97 (14.8%) were CTE and 560 (85.2%) were NCTE. RDI >=85% was achieved in 70.1% and 56.6% in the CTE and NCTE populations, respectively. Effectiveness was similar in the CTE and the NCTE populations (mPFS, 9.6 vs 10.7 mos; ORR, 33.0% vs 29.8%; mOS, 26.3 vs 32.9 mos). Serious AEs were reported by 23.7% of CTE and 28.2% of NCTE pts. AEs led to dose adjustment/interruption in 83.5% and 95.2%, respectively, and AEs led to treatment discontinuation in 8.2% of the CTE and 15.5% NCTE pts. Conclusion(s): The results of the PRINCIPAL study suggest that first-line PAZ for pts with advanced or metastatic RCC remains effective and safe in a real-world setting, showing similar outcomes to those reported in large randomized clinical trials.