Urological Science

: 2021  |  Volume : 32  |  Issue : 3  |  Page : 104--110

Outcomes of starting low-dose pazopanib in patients with metastatic renal cell carcinoma who do not meet eligibility criteria for clinical trials

Jun Akatsuka1, Go Kimura1, Kotaro Obayashi1, Kotaro Tsutsumi2, Masato Yanagi1, Yuki Endo1, Hayato Takeda1, Tatsuro Hayashi1, Yuka Toyama1, Yasutomo Suzuki1, Tsutomu Hamasaki1, Yoichiro Yamamoto2, Yukihiro Kondo1,  
1 Department of Urology, Nippon Medical School Hospital, Tokyo, Japan
2 RIKEN Centre for Advanced Intelligence Project, Tokyo, Japan

Correspondence Address:
Go Kimura
Department of Urology, Nippon Medical School Hospital, Tokyo 113-8603


Purpose: Eligibility for clinical trials is very strict and only patients who satisfy various criteria can enter trials. The individual use of pazopanib has not been adequately investigated. An optimal administration regimen for pazopanib in “real-world” patients with metastatic renal cell carcinoma (mRCC) is required. Our purpose was to determine the tolerability and efficacy of first-line pazopanib with a low starting dose in patients with mRCC who were ineligible for clinical trials. Materials and Methods: This study included patients with mRCC who underwent treatment with first-line pazopanib and were previously excluded from clinical trials because they did not meet the inclusion criteria. A 400 mg pazopanib starting dose is used routinely in patients with mRCC; if tolerated, dose escalation up to 800 mg may occur. Results: We identified 18 patients with mRCC who received first-line pazopanib and were previously determined ineligible for clinical trials. Pazopanib dose was escalated in 12 patients (66.6%), to 600 mg/day in 8 patients (44.4%) and to 800 mg/day in 4 patients (22.2%), and was not escalated in 6 patients (33.3%). In 3 patients (16.7%), pazopanib was discontinued owing to intolerability. The most common frequent adverse event was elevated alanine aminotransferase levels in 6 patients (33.3%), followed by a decreased platelet count in 5 patients (27.8%) and anorexia in 5 patients (27.8%). Partial response was seen in 5 patients (27.8%) and stable disease in 10 patients (55.6%); median progression-free survival was 11.9 months (95% confidence interval: 6.3–28.7 months). Conclusion: Our data indicated that a low starting dose of 400 mg pazopanib did not negatively affect treatment tolerability and efficacy in patients with mRCC ineligible for clinical trials. We found that lower starting doses may lead to better results. Additional studies are needed in a larger cohort and longer follow-up to attain authentic outcomes.

How to cite this article:
Akatsuka J, Kimura G, Obayashi K, Tsutsumi K, Yanagi M, Endo Y, Takeda H, Hayashi T, Toyama Y, Suzuki Y, Hamasaki T, Yamamoto Y, Kondo Y. Outcomes of starting low-dose pazopanib in patients with metastatic renal cell carcinoma who do not meet eligibility criteria for clinical trials.Urol Sci 2021;32:104-110

How to cite this URL:
Akatsuka J, Kimura G, Obayashi K, Tsutsumi K, Yanagi M, Endo Y, Takeda H, Hayashi T, Toyama Y, Suzuki Y, Hamasaki T, Yamamoto Y, Kondo Y. Outcomes of starting low-dose pazopanib in patients with metastatic renal cell carcinoma who do not meet eligibility criteria for clinical trials. Urol Sci [serial online] 2021 [cited 2023 Jan 31 ];32:104-110
Available from: https://www.e-urol-sci.com/text.asp?2021/32/3/104/326930

Full Text


Renal cell carcinoma (RCC) accounts for 2%–3% of all adult malignancies, representing 62,700 new cases/year and an estimated 14,240 deaths in the United States.[1] More than 70% of kidney cancers are diagnosed in the organ-limited form, and approximately 30% of kidney cancer patients present with metastasis at the time of diagnosis. In addition, approximately 30% of patients develop recurrent or metastatic disease after undergoing radical treatment for localized disease.[1],[2],[3] Currently, metastatic RCC (mRCC) is one of the most difficult malignancies to treat.

Pazopanib is an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and the c-kit.[4],[5] A randomized, double-blind, placebo-controlled phase III trial examined the safety and efficacy of pazopanib.[6] A large non-inferiority study, the COMPARZ, compared pazopanib with sunitinib as the first-line treatment for mRCC, and no statistically significant difference was found in the the progression-free survival (PFS) and overall survival (OS) between the two drugs.[7] The PISCES (Patient Preference Study of Pazozanib vs. Sunitinib in Advanced or Metastatic Kidney Cancer) trial confirmed that patients preferred pazopanib to sunitinib as it permitted a better quality of life.[8] Immuno-oncology (IO) therapy has become an essential pillar for mRCC treatment.[9],[10] However, several guidelines identify pazopanib as the first-line agent for mRCC,[11],[12] and pazopanib remains the first-line therapy for mRCC.

The dose of antitumor agents is determined from the results of phase I clinical trials.[13] Owing to safety issues, clinical trials have strict eligibility criteria. Therefore, it is not easy for patients to be accepted into clinical trials. The typical starting dose of pazopanib is 800 mg. However, in some patients with mRCC, including Japanese patients with lower body weight, the 800 mg dose of pazopanib cannot be maintained.

Effective management of treatment-related toxicity is needed to maximize the benefit of the treatment, particularly with daily oral agents.[14] Therefore, an optimal pazopanib administration regimen is required considering the adverse events (AEs) and tolerability for “real-world” Asian patients. A retrospective study was performed to assess the tolerability and efficacy of an initial low-dose pazopanib therapy for patients with mRCC patients who did not meet the eligibility criteria for clinical trials.

 Materials and Methods


A total of 21 patients with mRCC patients treated with first-line pazopanib therapy between October 2014 and April 2019 were identified. Of these, 18 patients were previously excluded from clinical trials due to ineligibility before undergoing pazopanib treatment and were included in our study. All patients provided written informed consent for mRCC treatment with pazopanib and were administered with a starting dose of 400 mg pazopanib at our institution (Nippon Medical School Hospital). If tolerated, the dose was escalated up to 800 mg. The present study included those patients who were treated with first-line pazopanib using our suggested regimen. The data on demographics, Karnofsky performance status (KPS), body surface area (BSA), Memorial Sloan-Kettering Cancer Center (MSKCC) risk category for mRCC, stage, histology, and toxicity related to pazopanib therapy were extracted from the medical records.

Based on the eligibility criteria for the COMPARZ study, the reasons why each patient was determined to be ineligible for clinical trial participation were reviewed. In our study, three major reasons for the ineligibility of each patient were defined, and these reasons were evaluated.

Host factor (KPS <70%, anemia, diabetes, and hepatitis C positivity)Oncological factor (nonclear cell pathology, multiple primary cancer, and brain metastasis)Organ functional factor (renal dysfunction, hemodialysis, and low cardiac function).


At the start of pazopanib administration and every 3–6 months thereafter, all patients underwent diagnostic monitoring of the tumor (chest, abdominal, and pelvic computed tomography scans). The response to treatment was assessed using the Response Evaluation Criteria in Solid Tumors, version 1.1, which included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Furthermore, we investigated the disease control rate (DCR). The safety profile of patients was assessed every month in accordance with the National Cancer Institute Common Toxicity Criteria for AEs, version 4.0. Based on the amount of pazopanib administered and the treatment duration, we calculated the relative dose intensity (RDI), which is the ratio of the dose intensity delivered to the standard dose (800 mg).

Statistical analysis

Statistical analysis was conducted to evaluate the PFS, OS, and time-to-treatment failure (TTF). PFS was defined as the time from the start of pazopanib treatment to PD. OS was measured from the 1st day of pazopanib exposure to the date of the last follow-up or death. TTF was defined as the time from the start of pazopanib treatment to stopping of treatment for any reason, including disease progression, treatment toxicity, or death. In our study, PFS, OS, and TTF were evaluated according to the number of major risk factors for clinical trial ineligibility. Kaplan–Meier curves were used to estimate survival distributions. The statistical analysis and all graph data were performed using JMP software, version 13.0 (SAS Institute Japan Ltd., Tokyo). The study was conducted according to the Declaration of Helsinki and was approved by the Institutional Review Board of our institution (approval number 29-11-861).


Patient characteristics

In total, 18 mRCC patients who were treated with first-line pazopanib at a starting dose of 400 mg/day were identified. The patient demographics and tumor characteristics are shown in [Table 1]. Most patients were male (77.8%); at the initiation of pazopanib therapy, the median age of patients was 69 years (range: 48–81 years of age), 4 patients (22.2%) had KPS <70%, and the median BSA was 1.6 m2 (range: 1.4–1.9 m2). Radical nephrectomy was performed in 17 patients (94.4%) before pazopanib treatment was started, and one patient (5.6%) was diagnosed via needle biopsy of the primary lesion. Of the 18 patients, 12 (66.7%) had pure clear cell carcinoma along with other histological subtypes, including papillary cells and hemodialysis-associated RCC in 4 (22.2%) and 2 patients (11.1%), respectively, including sarcomatoid changes in 3 (16.7%) patients. The most common metastatic sites were the lungs (13 patients, 72.2%), lymph nodes (6 patients, 33.3%), and bone (3 patients, 16.7%). Nine patients (50.0%) had metastatic disease in ≥2 sites. Based on the MSKCC score classification, 13 patients (72.2%) were intermediate risk and 4 patients (22.2%) were poor risk, respectively.{Table 1}

Patients were determined to be ineligible for clinical trials for several different reasons [Table 2]. The most common was renal dysfunction (9 patients, 50.0%), nonclear cell RCC (6 patients, 33.3%), and anemia (5 patients, 27.8%). The major risk factors for ineligibility were oncological factors (12 patients, 66.7%), organ functional factors (11 patients, 61.1%), and host factors (10 patients, 55.6%). Overall, eight patients (44.4%) had one major factor for ineligibility, five patients (27.8%) had two major factors, and five patients (27.8%) had three major factors. Four patients (22.2%) had a history of other malignancies, which were disease-free during our study period.{Table 2}

Toxicity and drug exposure

The outpatient physician modified the dose of pazopanib based on the patient's general condition and tolerability. During the treatment period, pazopanib dose was escalated in 12 patients (66.6%), to 600 mg/day and 800 mg/day in 8 (44.4%) and 4 patients (22.2%), respectively, whereas pazopanib dose was not escalated for 6 patients (33.3%) [Table 3]. In our cohort, the median RDI was 65.0% (range: 46.0%–91.0%).{Table 3}

All patients were evaluated for toxicity. The AEs experienced during the treatment periods are summarized in [Table 3]. Most treatment-related AEs were of mild-to-moderate severity (Grade ½). The most common AEs due to pazopanib administration were elevated alanine aminotransferase (6 patients, 33.3%), decreased platelet count (5, 27.8%), and anorexia (5, 27.8%). Overall, Grade 3 or 4 AEs occurred in 6 patients (33.3%) (proteinuria, 2 patients [11.1%]; decreased white blood cell count, 2 [11.1%]; elevated alanine aminotransferase, 1 [5.6%]; and decreased platelet count, 1 [5.6%]). Due to pazopanib toxicity, four patients (22.2%) required dose reduction or dose interruption. Five patients (27.8%) required drug discontinuation due to AEs (3 patients [16.7%]), patient's preference (1 [5.6%]), and economic issue (1 [5.6%]) [Table 3].

Treatment outcome

The median duration of treatment was 8.5 months (range: 0.1–30.6 months), and the median follow-up period was 27.2 months (range: 3.1–49.3 months). Seventeen patients (94.4%) had measurable disease. The maximum tumor shrinkage of the target lesions during the treatment periods in our cohort is shown in [Figure 1]. As the best response, 5 patients (27.8%) had PR, 10 patients (55.6%) had SD, and 2 patients (11.1%) had PD. Thus, 5 patients (27.8%) had objective response (CR + PR) and 15 patients (83.3%) had disease control (CR + PR + SD). During the treatment periods, 12 patients (66.6%) remained alive and 6 patients (33.3%) died (death was cancer related in five patients and related to other causes in the remaining patients). The median PFS was 11.9 months (95% confidence interval [CI] = 6.3–28.7 months), the median OS was not reached (NR) (95% CI = 18.0–NR), whereas the median TTF was 8.5 months (95% CI = 4.1–13.5 months) [Figure 2]a, [Figure 2]b, [Figure 2]c In the present study, the differences in PFS, OS, and TTF were not significant between the number of major risk factors for clinical trial ineligibility [Figure 3]a, [Figure 3]b, [Figure 3]c.{Figure 1}{Figure 2}{Figure 3}


Based on phase III clinical trials, pazopanib is recommended as a first-line treatment for mRCC[6] and is typically started at a dose of 800 mg once daily. However, in everyday practice for real-world patients, therapy could not be maintained because the dosage was not well tolerated due to the patients' poorer general condition and/or the occurrence of treatment-related AEs. At our institution, pazopanib at a starting dose of 400 mg in patients with mRCC was administered for its manageable profile. In this study, the tolerability and efficacy in mRCC patients who did not meet the eligibility criteria for clinical trials were evaluated. As a result, pazopanib administration as our regimen was well tolerated and effective, even in patients with poorer medical conditions.

Since pazopanib was approved by the U.S. Food and Drug Administration, only a few studies have investigated the adjustment of dosage or modified dosing regimen of pazopanib for the treatment of mRCC. Regimens that start with a full-dose regimen have been associated with several issues, especially in Asian patients and clinical trial ineligible patients. A subanalysis of the COMPARZ trial revealed the relative safety profile of pazopanib in Asian and non-Asian patients.[15] In that report, Asian patients taking pazopanib experienced higher incidences of hypertension, hematologic toxicity, abnormal liver chemistry, proteinuria, elevated blood creatinine, and hand–foot syndrome than non-Asian patients. Moreover, in Asian patients, dose reduction occurred in 54% of patients and treatment interruption occurred in 65% of patients; non-Asian patients had lower rates of dose reductions (40%) and interruptions (57%). A prospective observational study (PRINCIPAL study) assessed the outcome of pazopanib in a multinational setting showing real-world clinical data.[16] In this study, 14.8% of patients were eligible and 85.2% were ineligible for a clinical trial. Dose reduction and interruption with AEs occurred in 83.5% of eligible patients and 95.5% of those ineligible for a clinical trial.

To achieve better tolerability and outcomes, various modified regimens of molecular targeting agents, including sunitinib and everolimus, have been assessed for mRCC treatment in Japan.[17],[18],[19] Kondo et al. evaluated the treatment efficacy of an altered dosing regimen of sunitinib including the AEs profile.[17] In their study, an altered dosing regimen of sunitinib, with 2 weeks on and 1 week off, resulted in a lower incidence of dose interruption and a similar oncological outcome compared with the standard dose. Nozawa et al. reported on the real-world safety and efficacy of everolimus in patients with advanced RCC receiving treatment and concluded that some ethnic differences in the AE profile of everolimus may be present and that dose modification of everolimus might correspond with longer treatment duration in patients with advanced RCC.[18]

Our patients were Asians with a small BSA (median: 1.6 m2) and were ineligible for clinical trials. A modified regimen of pazopanib was administered, which was well tolerated. In our study, elevated aminotransferase, decreased platelet count, and anorexia were the most frequent AEs (≥20% incidence). Most AEs related to our pazopanib regimen were Grade ½. Due to pazopanib toxicity, four patients (22.2%) required dose reduction or dose interruption. Three patients (16.7%) required drug discontinuation due to AEs. With its manageable and predictable safety profile, our regimen could be useful in the treatment of mRCC patients. Pharmacodynamic profiles and overall exposure are affected by the host, oncological, and organ functional factors. Moreover, each individual differs in the prevalence of functional polymorphisms in cytochromes and other genes that affect drug absorption and metabolism.[20],[21],[22] A recent study investigated the possibility of dose optimization of pazopanib from its plasma concentration in Japanese patients with soft-tissue sarcoma and RCC. The study demonstrated that a dose of 400 mg was an effective pazopanib concentration and was effective and well tolerated in more than half of the patients.[23] The findings of the study may support our favorable efficacy and safety results, even in patients with poorer medical conditions.

Our well-tolerated regimen of pazopanib was also proven to have a good efficacy for mRCC treatment in real-world Asian patients. In the COMPARZ trial, the median PFS was 8.4 months (95% CI = 8.3–10.9 months) and the median OS was 28.3 months (95% CI = 26.0–35.5 months).[7] The PRINCIPAL study reported a median PFS and a median OS of 10.3 months (95% CI = 9.2–12.0 months) and 29.9 months (95% CI = 24.7 to NR months), respectively.[16] Similarly, a single Italian cancer center reported a median PFS and a median OS of 12.7 months (95% CI = 6.9–18.5 months) and 26.2 months (95% CI = 12.6–39.9 months), respectively.[24] Vogelzang et al. reported a median PFS and a median OS of 8.5 months (95% CI = 7.1–11.2 months) and 22 months (95% CI = 16.9–NC months), respectively.[25] [Supplementary Table 1] shows outcomes of pazopanib treatment in real-world Asian mRCC patients.[26],[27],[28] The previous studies included both eligible and ineligible patients for clinical trials. Even though the present study only included patients who were ineligible for clinical trials, who had particularly poor conditions among the real-world patients, the outcomes of efficacy and safety of this study were comparable to those reported studies.[INLINE:1]

This study has some limitations. The number of patients is small, the design was retrospective, and data on quality of life and pharmacokinetics were lacking. However, we believe our results may illuminate clues to allow for the development of a pazopanib regimen with greater tolerability and efficacy in mRCC patients and a small BSA and/or other complications. Further prospective studies, including measurements of quality of life and pharmacokinetics, in a larger cohort, are necessary to resolve these issues. Currently, the “IO era” in mRCC treatment has become globally prevalent.[9],[10] Antiangiogenic drugs, including sunitinib, pazopanib, and sorafenib, will be administered to patients with poorer medical conditions as second or later line after axitinib/IO combination therapy, in addition to patients with favorable risk as first-line therapy. Therefore, a low starting dose of pazopanib for patients with poorer general medical conditions is believed to be suitable, even in the IO era.


This study reported on pazopanib treatment at low starting doses in patients with mRCC who did not meet the eligibility criteria for clinical trials. Our data indicated that this strategy did not appear to negatively affect the outcome and instead yielded even greater treatment efficacy probably due to its good tolerability. Further study is needed to confirm these results.

Financial support and sponsorship

Go Kimura has received funding from Novartis, Ono pharmaceutical Co, BMS, Pfizer, Bayer.

Conflicts of interest

There are no conflicts of interest.


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