Pazopanib in Patients with Clear-Cell Renal Cell Carcinoma: Seeking the Right Patient

摘要

Introduction Since its early development, the vascular endothelial growth factors (VEGFRs) inhibitor pazopanib showed both activity and tolerability in patients with metastatic RCC (mRCC) (Hurwitz et al., 2009 ), results which were subsequently confirmed in the following studies. A phase II study was at first designed as a randomized discontinuation study, but lately revised to an open-label study based on week 12 response rate (RR) of 38% in the first 60 patients. Thus, the primary end-point was changed from progressive disease rate at 16 weeks post-randomization to RR (Hutson et al., 2010 ). Overall RR was 35%, median duration of response was 68 weeks, and median progression-free survival (PFS) was 52 weeks (Hutson et al., 2010 ).Pazopanib was registered based on a global randomized, placebo-controlled, phase III trial. Of the 435 patients enrolled, 233 (54%) were treatment-na?ve, while 202 (46%) were pre-treated with cytokines. Pazopanib significantly prolonged PFS in overall study population [median PFS: 9.2 vs. 4.2 months, hazard ratio (HR): 0.46, 95% CI: 0.34–0.62, p < 0.0001], in the cytokine-pretreated subpopulation, as well as in the treatment-na?ve subpopulation (median PFS: 11.1 vs. 2.8 months, HR: 0.40, 95% CI: 0.27–0.60, p < 0.0001), compared to placebo (Sternberg et al., 2010 ). Furthermore, the objective response rate (ORR) was 30% with pazopanib with a median duration of response longer than 1 year. None clinically important difference in quality of life for pazopanib vs. placebo was observed in the safety analysis (Sternberg et al., 2010 ).More recently, the phase III COMPARZ study directly compared pazopanib with sunitinib in a non-inferiority study (Escudier et al., 2014 ). Pazopanib was non-inferior to sunitinib in terms of PFS (HR: 1.05, 95% CI: 0.90–1.22—predefined upper bound of the 95% CI < 1.25), and similar in OS (HR: 0.91, 95% CI: 0.76–1.08; Motzer et al., 2013 ); ORR was higher for pazopanib, as compared to sunitinib (31 vs. 25%, p = 0.03; Motzer et al., 2013 ). In terms of safety, pazopanib-treated patients experienced less fatigue, fewer side effects, including soreness of hand/foot and mouth/throat, and were more satisfied with treatment than those who received sunitinib (Motzer et al., 2013 ; Table 1 ). Less fatigue and better overall quality of life were the most common reasons that justified the preference of pazopanib vs. sunitinib (70 vs. 22%, p < 0.01) in the PISCES study, a cross-over, double blind trial which specifically assessed the innovative endpoint of patients' preference (Escudier et al., 2014 ). Table 1 Comparison of baseline characteristics, clinical outcomes and adverse events in pivotal studies. Baseline characteristics ~(*) Clinical outcomes (95% CI) Adverse events ~(§) (% grade 3/4) Hutson et al., 2010 Median age 59.8 years Clear cell and predominantly clear cell 100% Median time since diagnosis 223 days ECOG ≤ 1 100% MSKCC Poor 2% Prior nephrectomy 91% PFS 52 (44–60) weeks ORR 34.7% Diarrhea (4%), hypertension (9%), hair depigmentation (?), nausea (<1%), anorexia (<1%), vomiting (<1%), fatigue (5%), asthenia (3%), abdominal pain (2%), headache, dysgeusia, cough, abdominal pain (3%), rash (<1%), constipation (<1%), arthralgia (<1%), back pain (<1%), dizziness (<1%), hand-foot syndrome (2%), dyspepsia (1%), alopecia (?), peripheral edema (?) Clinical chemistry ALT elevation (9%), AST elevation (6%), bilirubin elevation (<1%), hyponatremia (8%), hyperkalemia (4%), alkaline phosphatase elevation (2%), anemia (2%), creatinine elevation, lipase increased (10%), amylase increased (3%) Hematologic Leukopenia (1%), neutropenia (3%), thrombocytopenia (2%), lymphocytopenia (10%) Sternberg et al., 2010 Median age 59 years Clear cell and predominantly clear cell 100% Median time since diagnosis 15.7 months ECOG ≤ 1 100% MSKCC Poor 9% Prior nephrectomy 89% PFS 9.2 months ORR 30% (25.1–35.6%) Diarrhea (3%), hypertension (4%), hair depigmentation (<1%), nausea (<1%), anorexia (2%), vomiting (2%), fatigue (2%), asthenia (3%), abdominal pain (2%), headache (?) Clinical chemistry ALT elevation (12%), AST elevation (7%), hyperglycemia (<1%), bilirubin elevation (3%), hypophosphatemia (4%), hyponatremia (5%), hypocalcemia (5%), hypomagnesemia (3%) Hematologic Leukopenia, neutropenia (1%), thrombocytopenia (<1%), lymphocytopenia (4%) Motzer et al., 2013 Median age 61 years Clear cell and predominantly clear cell 100% KPS > 70 100% Prior nephrectomy 82% Lactate dehydrogenase ≤ 1.5 ULN 93% MSKCC Poor 12% PFS 8.4 (8.3–10.9) months ORR 31% (26.9–34.5%) Diarrhea (9%), hypertension (15%), hair depigmentation (?), nausea (2%), anorexia (1%), vomiting (2%), fatigue (10%), asthenia (3%), abdominal pain (2%), headache (3%), dysgeusia (<1%), cough, abdominal pain (2%), rash (1%), constipation (1%), arthralgia (<1%), back pain (1%), dizziness (1%), hand-foot syndrome (6%), dyspepsia, alopecia, peripheral edema, proteinuria (4%), weight loss (1%), stomatitis (1%), hypothyroidism (?), muco