Abstract
Background/Aim: Pazopanib is a tyrosine kinase inhibitor (TKI) approved as first-line treatment for renal cell carcinoma (RCC). Although pazopanib efficacy and safety have been established in phase III studies, real-world data are limited. The aim of this study was to evaluate pazopanib efficacy, duration of responses and safety, as first-line treatment in patients with advanced/metastatic RCC with favorable-intermediate prognosis.
Patients and Methods: This single-arm prospective Greek observational study evaluated 59 patients treated with first-line pazopanib as indicated, and who were followed-up every 3 months for 2 years, or until disease progression. The primary objective was to evaluate the efficacy of first-line pazopanib treatment in patients with favorable-intermediate prognosis metastatic RCC at 9 months from treatment onset.
Results: The primary composite efficacy point (complete response, partial response, or stable disease at 9 months) was reached by 30.5% [95% confidence interval (CI)=19.2-43.9%] of patients, with 27.1% (95% CI=16.4-40.3%) of patients demonstrating stable disease. Best overall response was complete response in 5.1% (3/59 patients), partial response in 22% (13/59 patients), and stable disease in 35.6% (21/59 patients). Median progression-free survival was 17.7 (95% CI=9.15-26.25) months and declined with the International Metastatic Renal Cell Carcinoma Database Consortium progressive risk (24.5 and 6.97 months for favorable- and intermediate-risk, respectively; p=0.012). The cumulative overall survival rate was 95% after 9 (95% CI=89.8-100.0%) months and 24 (95% CI=89.8-100.0%) months. Median overall survival was not reached. Overall, 234 adverse events were reported in 55 patients, of which the most common were malignant neoplasm progression, diarrhea, and hypertension.
Conclusion: These data demonstrate that pazopanib is well-tolerated and effective as first-line treatment in patients with favorable-intermediate risk metastatic RCC in real-life conditions in Greece.
Introduction
Pazopanib is a multiple tyrosine kinase inhibitor that has been approved as a first-line treatment of renal cell carcinoma (RCC), and as second-line treatment, following cytokine therapy, for advanced/metastatic RCC (mRCC) (1). The efficacy and safety profile of pazopanib has been established in the phase III studies VEG105192 (pazopanib vs. placebo) (2), and COMPARZ (pazopanib vs. sunitinib) (3). Pazobanib has also been shown to improve the health-related quality of life (1). The SPAZO study validated the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model for first-line pazopanib in mRCC and confirmed its effectiveness and safety (4). Real-world data on pazopanib as a first-line treatment for mRCC have been reported (1), however data from the everyday clinical setting in Greece are still very limited (5). The present study evaluated the efficacy, and duration of responses, as well as the safety profile of first-line pazopanib treatment in patients with mRCC with favorable and intermediate prognosis in the Greek clinical setting.
Patients and Methods
Study design and setting. This was a single-arm prospective non-interventional observational study to evaluate the on-label efficacy, tolerability and safety of first-line pazopanib as per everyday clinical practice in Greece, as per local regulations. Adult consenting patients with favorable/intermediate prognosis mRCC, as per the IMDC model (4), who were receiving pazopanib as a first-line treatment up to 3 months prior to the enrollment were recruited at 13 sites from 20th November 2017 until 12th February 2019. Fifty-nine eligible patients received first-line treatment with pazopanib as per the treating physician’s judgement and were followed up at 3-month intervals for 2 years, or until disease progression. Upon disease progression, survival data were collected every 6 months until the end of the study (last data collection: 25 January 2021).
Endpoints and assessments. The primary endpoint was the proportion of patients with no disease progression at 9 months of first-line treatment with pazopanib. Secondary endpoints included time to progression, uninterrupted treatment duration with first-line pazopanib, duration of response per risk group, overall response rate, complete response (CR) rate, partial response (PR) rate, median progression-free survival (PFS) according to the Response Evaluation Criteria for Solid Tumors (v1.1) (6). Due to the observational nature of this study, efficacy assessments were performed on the intention to treat (ITT) population (N=59). Safety findings are reported by preferred term as per MedDRA version 22.0 (7). The percentage of patients who received subsequent treatments following discontinuation of pazopanib, and the duration of treatment were also explored.
Statistical analysis. The statistical analysis here was performed based on evaluable datasets from the ITT and safety populations. The ITT population was considered the patient population representing the total number of patients who had at least one evaluation for the primary efficacy endpoint. The safety dataset was the patient population that received at least one dose of pazopanib. Missing data were not replaced by other values, and the primary endpoint was calculated based on the data recorded to the last available observation/event. A statistical power calculation was omitted. The sample size was representative of the general population, based on the disease incidence and the expected recruitment rate within the enrollment period. Descriptive analysis was performed for evaluating time under pazopanib treatment. Time-to-event outcomes were descriptively analyzed and graphically presented by means of Kaplan–Meier survival estimates. Multivariate analysis was performed according to the Cox regression model. Probability testing between PFS risk groups was performed using the log rank test (Mantel–Cox). Missing data were not subjected to data imputation and the primary endpoint was calculated based on the data recorded to the last available observation. All statistical calculations were performed using R version 3.4.0 (http://www.r-project.org) and IBM-SPSS v24.0 (IBM, Armonk, NY, USA) statistical software.
Results
Patients and baseline characteristics. The study outcomes were analyzed in a population that included 59 patients. The ITT population (N=59) constituted the safety population since the patients had already commenced pazopanib treatment prior to enrollment. Patient demographics and clinical characteristics at baseline are outlined in Table I. At initial diagnosis, 67.8% (40/59) of the total patient population had RCC stage III/IV, with a median time of diagnosis of 2.0 [interquartile range (IQR)=0.0-4.0] years, and with predominant histology of clear-cell RCC in 76.3% (45/59). Metastatic disease included local in 38.9%, lymph node in 35.6%, pulmonary in 49.2%, bone in 27.1%, liver in 18.6%, adrenal gland in 11.9%, and peritoneal/retroperitoneal in 8.5% and was diagnosed at a median of 1.00 (IQR=0.0-2.0) months, with a median of 2.0 (IQR=1.0-3.0) localized metastatic lesions.
Patient demographics and clinical characteristics at baseline (intention to treat population).
Concurrent medical conditions, and patient distribution per IMDC risk classification and risk factors, are summarized in Table II. Most (83.1%) patients received at least one concomitant medication other than pazopanib, and the most reported concomitant medications received by at least 20% of the patients were: Hydroxymethylglutaryl-CoA reductase inhibitors, selective beta blockers, thyroid hormones and dihydropyridine derivatives, in 32.2%, 28.8%, 27.1% and 25.4% of the patients, respectively. Main procedures prior to study enrollment included: nephrectomy in 81.4%, of which 71.2% (42/48) was total; metastasectomy in 10.2% (6/59); and radiotherapy for metastatic disease in 8.5% (5/59).
Concurrent medical conditions, and risk stratification per International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria.
Clinical outcomes. Out of the 19 evaluable patients at 9 months of first-line treatment with pazopanib, the primary composite efficacy endpoint of non-progressive disease was 30.5% (95% CI=19.2-43.9%), with 27.1% (95% CI=16.4-40.3%) of patients achieving SD (Table III). Nine patients were not evaluated, i.e., no evaluation was performed at the specific visit (9 months), or evaluation was awaited at the time of the analysis, or unknown, or no evaluation by Response Evaluation Criteria for Solid Tumors was performed. Over the 24-month observation period, a best overall response to the treatment with pazopanib, defined as the best recorded response at any time from the initiation of study treatment until progressive disease or the end of treatment, was achieved by 62.7% (37/59) of patients. Overall, both the median time to progression (TTP) and the median PFS was 17.7 months (TTP, 95% CI=4.3-31.1 months; PFS, 95% CI=9.1-26.2 months, Figure 1), and declined with worsening IMDC risk status, for favorable median risk [TTP: 24.5 (95% CI=24.4-24.6) months; PFS: 24.5 (95% CI=24.4-24.6) months], and intermediate median risk [TTP: 10.87 months, (95% CI=3.7-18.1) months; PFS: 7.00 (95% CI=1.6-12.3) months, p=0.012].
Response to pazopanib in patients with renal cell carcinoma evaluable at 9 months of treatment.
Kaplan–Meier analysis of survival and disease progression. Cumulative progression-free survival probability median (95% confidence intervals) estimates are shown for the intention to treat population overall (A), and by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group (B).
The statistically significant factors associated with PFS were the risk classification group (p=0.009; Table IV) and the number of metastatic lesions (p=0.036). The cumulative OS rate was 95% after 9 months (95% CI=89.8-100.0%) and 24 months (95% CI=89.8-100.0%), and median OS was not reached.
Factors associated with progression-free survival.
Pazopanib dosing schedule and subsequent treatments. At baseline, 94.9%, 3.4% and 1.7% of the patients were receiving 800 mg, 600 mg, or 400 mg of pazopanib, respectively, for a median of 20 days prior to study enrollment. Most patients received up to two lines of an mRCC treatment regimen after pazopanib: 79.7% of the patients received only first-line pazopanib for a median of 3.3 (IQR=1.37-9.9) months, and 20.3% of the patients received a second line of either, nivolumab, cabozantinib, or lenvatinib plus everolimus, for a median of 3.85 (IQR=3.3-5.6) months.
Performance status. At baseline, 83% of the evaluable patients had a mean Karnofsky score of 93.22% (standard deviation=8.60%), which was overall maintained up to 24 months (95.33%, standard deviation=9.15%) post enrollment. No statistical evaluation took place due to the small number of evaluable patients at 24 months.
Safety. In total, 234 AEs in 55 patients were reported throughout the study. The most common AEs were reported by preferred term as per MedDRA version 22.0 and are listed in Table V. The most frequently reported AEs that led to treatment discontinuation were malignant neoplasm progression in 44.1%, diarrhea in 18.6%, increased transaminases in 8.5%, and increased aspartate transaminase, alanine transaminase, or fatigue in 5.1% each. Two deaths were reported without a causal relationship to pazopanib treatment.
List of most frequently* reported adverse events (safety population).
Discussion
The rising global incidence of RCC, including mRCC, necessitates further research into the efficacy of targeted therapies in the real-life clinical setting, particularly so in Greece where real-world evidence is scarce (5, 8). The demographics and clinical characteristics of the present study, in terms of age, sex, mRCC histology and risk factors, are in line with previously reported RCC epidemiological data (4, 5, 9, 10). Most study subjects had a baseline Fuhrman grade of III-IV and previous metastatic involvement, both of which may indicate a prognostically burdened patient population (11, 12).
The mean Karnofsky score was indicative of minimal frailty in regard to the treatment throughout the study period, supporting previous evidence regarding the favorable tolerability profile of treatment with pazopanib. The Karnofsky score is an indicator of survival outcomes and has been shown to correlate with PFS in real-life studies. Karnofsky score was maintained over the observation period, with a median PFS of 17.7 months, which appears to be slightly longer than previous clinical and real-world studies, some of which included treatment-naïve patients which overall show better responses than previously treated patients (2-5, 9). The median OS was not reached up to 24 months in the present study, which reflects the reported outcomes in other studies (4, 5, 8, 10, 13). Nevertheless, it should be noted that the variability of treatment duration, or other differences in operational practices or disease assessments among real-world studies might affect the attained responses (2-4, 9, 10, 13).
Reflecting other real-life studies, the reported PFS per IMDC risk group was comparable. Statistically significant differences in PFS were noted between risk subgroups, with favorable-risk patients showing improved survival outcomes and response to treatment (CR or PR) in relation to intermediate-risk patients (4, 5, 9, 14). In the SPAZO phase III study, SD and CR were attained by 43.6% and 4.6% of the patients, respectively (4). Similarly in our study, among the evaluable study population, pazopanib treatment conferred SD, PR, and CR, respectively in 35.6%, 22%, and 5.1% of patients. This study corroborated previous evidence that the majority of patients treated with first-line pazopanib attained SD (5).
Almost 80% (47/59) of patients remained on first-line treatment with pazopanib for a median of 3.3 months, prior to switching to a subsequent treatment regimen, which is comparable to other similar real-life studies with a past first-line pazopanib treatment and switching to subsequent therapies (13, 15). In agreement with the PRINCIPAL study, where 44.3% (43/97) of patients underwent pazopanib dose changes/interruptions due to safety reasons (9), in the current study pazopanib treatment was temporarily interrupted at least once in 32.2% (19/59) of patients, mainly as a result of AEs in 94.7% (18/19) of these patients. Permanent treatment discontinuation predominantly occurred due to disease progression or AEs, in 44.1% (26/59) and 18.6% (11/59) of patients, respectively.
The safety profile was manageable and similar to previous reports [reviewed in (1)]. Notably, none of the patients in the current study were diagnosed with brain metastasis, which is associated with poor survival outcomes (11). Moreover, as there are limited safety data on pazopanib-treated patients over 65 years old, the present study contributed evidence that pazopanib is well-tolerated in this patient population.
The limitations of this study are driven by the observational non-interventional study design, lack of comparison group, possible differences in data collection patterns, and routine clinical practice variations across the different participating sites, as well as missing data. Although inherently unavoidable, these limitations were addressed to some extent, with rigorous multivariate statistical analyses.
Consistent with guideline treatment recommendations and other real-world studies, the present study affirmed the efficacy and safety of first-line treatment with pazopanib in naïve patients with favorable-intermediate risk profile mRCC, in everyday clinical setting in Greece.
Acknowledgements
Medical writing services were provided by Creative Pharma & HR Services.
Footnotes
Authors’ Contributions
Conceptualization: Novartis S.A.C.I. Investigation: EB, IX, MV, CC, PM, CK, IA, AA, PP, ES, CP, PK. Data interpretation, draft manuscript preparation, critical revision, and editing: MM. Review/editing: All Authors. All Authors approved the final version of the manuscript.
Conflicts of Interest
CC: Amgen, Astra Zeneca, BMS, Genesis, Gilead, Lilly, Merck, MSD, Novartis, Pfizer, Roche; MM: Employed by Novartis (Hellas) S.A.C.I.
Funding
The study was funded by Novartis (Hellas) S.A.C.I.
- Received February 19, 2025.
- Revision received March 17, 2025.
- Accepted March 21, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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