Pazopanib Edges Sunitinib as First-Line Kidney Cancer Therapy

VIENNA – The first head-to-head comparison of pazopanib and sunitinib is likely to reshape first-line treatment for renal cell carcinoma, long dominated by sunitinib.

The phase III COMPARZ trial shows similar potency for the two angiogenesis inhibitors, but pazopanib (Votrient) had a better tolerance and safety profile, Dr. Robert Motzer reported at the European Society for Medical Oncology (ESMO) Congress.

As previously observed in indirect comparisons, hand-foot syndrome, fatigue, and mucositis were more common with sunitinib (Sutent), while pazopanib had a higher incidence of liver abnormalities. The adverse events associated with sunitinib are the ones that really affect patients’ day-to-day living, remarked Dr. Motzer of Memorial Sloan–Kettering Cancer Center in New York.

Patrice Wendling/IMNG Medical Media

This was expressed in patient-reported outcomes on four quality of life instruments, which favored pazopanib in all but 1 of 14 domains – the exception was the emotional domain of the FACT Kidney Symptom Index (FKSI-19), but this was not statistically significant.

"This trial tips the scale for the preferred treatment, in my opinion, for most patients with kidney cancer from sunitinib, which has been the reference standard, to pazopanib," he said during a press briefing.

COMPARZ (Comparing the Efficacy, Safety and Tolerability of Pazopanib vs. Sunitinib) randomized 1,110 treatment-naive patients with locally advanced or metastatic clear cell renal cell carcinoma (RCC) to pazopanib 800 mg administered daily on a continuous dosing schedule or sunitinib 50 mg given daily in a 6-week cycle of 4 weeks on, 2 weeks off.

Disease assessments were at weeks 6, 12, 18, 24, and then every 12 weeks. Patient-reported outcomes were measured at day 28 of every cycle.

The primary end point of median progression-free survival was 8.4 months for pazopanib and 9.5 months for sunitinib by independent central review (hazard ratio, 1.047), and 10.5 months vs. 10.2 months by the investigators (HR, 0.998). The upper bound of the 95% confidence interval for the hazard ratio was below 1.25, demonstrating the noninferiority of pazopanib to sunitinib, Dr. Motzer said.

The overall response rate (complete plus partial responses) was 31% for pazopanib and 25% for sunitinib (P = .03).

Median overall survival was 28.4 months vs. 29.3 months (HR, 0.908; P = .27), according to an interim analysis. The final overall survival data is anticipated in 2013, Dr. Motzer said.

Treatment-emergent hypertension, diarrhea, and nausea of any grade occurred equally in both arms. Patients given pazopanib had more hair-color changes (30% vs. 10%) and increased alanine transaminase (ALT) levels (31% vs. 18%), reflecting known increased liver toxicity, he said. In contrast, those given sunitinib experienced more fatigue (63% vs. 55%), hand-foot problems (50% vs. 29%), taste alterations (36% vs. 26%), and thrombocytopenia (34% vs. 10%).

Serious adverse events occurring in 3% or more of patients were increased ALT and increased aspartate aminotransferase (AST) in the pazopanib arm, and pyrexia and thrombocytopenia in the sunitinib arm. Fatal adverse events were reported in 2% and 3%, respectively.

Discussant Dr. Tim Eisen, who was a subinvestigator on the trial and is an oncology professor at the University of Cambridge, England, said clinicians need to consider two crucial things when selecting an RCC treatment: whether the two drugs are equally effective, and if so, which one is "softer going" on the patient.

The data show the two drugs are "equally effective" and that pazopanib "can be considered a first-line standard of care along with sunitinib," he said.

Patrice Wendling/IMNG Medical Media

Pazopanib is "easing ahead," however, in terms of tolerance and toxicity.

"Pazopanib does score in terms of having fewer side effects that matter to patients," Dr. Eisen said. "Don’t forget these are maintenance agents taken for as long as they are controlling disease, and even low-grade toxicities can be highly significant in this group."

Fatigue, stomatitis, and hand-foot syndrome all trouble patients badly, whereas elevated ALT and AST don’t usually trouble patients, if managed properly.

On the other hand, he observed that patients can feel a lot better during the 2 weeks off sunitinib, although the disease can grow, "even grow significantly, in a small proportion of patients."

Dr. Eisen cautioned that the timing of the assessments is a consideration in COMPARZ because they would tend to favor pazopanib. "For my money, this doesn’t really matter very much for the progression-free and overall survival curves as they mature ... I would not be so generous about the quality of life assessments," he said.

Patients do not feel "too chipper" after 4 weeks of sunitinib, but feel much better during the 2-week washout. Thus, "If you are looking at day 28 of each cycle, you are timing the quality of life assessments to favor pazopanib," he said.

Dr. Eisen said the hazard ratio of up to 1.25 "does cover quite a few ... scenarios, but I think it is acceptable and provides adequate power for a group of patients with a relatively uncommon disease."

During his presentation, Dr. Motzer highlighted the PISCES study, showing that patients with metastatic RCC preferred pazopanib over sunitinib by a three-to-one margin and had fewer dose reductions and interruptions.

In COMPARZ, dose reductions were reported in 44% of patients on pazopanib and 51% on sunitinib, and discontinuations because of adverse events in 24% and 19%.

Dr. Robin Wiltshire, global medical affairs lead for sunitinib for Pfizer Oncologysaid that, based on the trial design, it was possible to achieve a positive outcome, even if pazopanib had a 25% reduction in efficacy.

"Noninferiority is not the same as equal efficacy, and we’ve actually seen from the primary end point that the PFS is a month improved with sunitinib," he said in an interview.

In addition, progression-free survival has been even longer in real-world databases.

Dr. Wiltshire said COMPARZ is unlikely to cause a "major sea change in practice" and that physicians have not switched over en masse since pazopanib was approved in 2009. Physicians have treated more than 150,000 patients with sunitinib since its 2006 approval for RCC and have learned how to boost efficacy and manage its side effects.

The pharmaceutical research and advisory firm, Decision Resources, reports that angiogenesis inhibitors make up 76% of the RCC therapy market, with sunitinib accounting for more than half of sales in this class. It projects that sunitinib will account for only 14% of sales in this class by 2020, owing to high uptake of pazopanib and launch of the recently approved axitinib (Inlyta) and the investigational agent tivozanib – the first drug to break the 12-month PFS barrier in RCC.

GlaxoSmithKline sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib. Dr. Eisen reported serving as a subinvestigator on the trial.

VIENNA – The first head-to-head comparison of pazopanib and sunitinib is likely to reshape first-line treatment for renal cell carcinoma, long dominated by sunitinib.

The phase III COMPARZ trial shows similar potency for the two angiogenesis inhibitors, but pazopanib (Votrient) had a better tolerance and safety profile, Dr. Robert Motzer reported at the European Society for Medical Oncology (ESMO) Congress.

As previously observed in indirect comparisons, hand-foot syndrome, fatigue, and mucositis were more common with sunitinib (Sutent), while pazopanib had a higher incidence of liver abnormalities. The adverse events associated with sunitinib are the ones that really affect patients’ day-to-day living, remarked Dr. Motzer of Memorial Sloan–Kettering Cancer Center in New York.

Patrice Wendling/IMNG Medical Media

This was expressed in patient-reported outcomes on four quality of life instruments, which favored pazopanib in all but 1 of 14 domains – the exception was the emotional domain of the FACT Kidney Symptom Index (FKSI-19), but this was not statistically significant.

"This trial tips the scale for the preferred treatment, in my opinion, for most patients with kidney cancer from sunitinib, which has been the reference standard, to pazopanib," he said during a press briefing.

COMPARZ (Comparing the Efficacy, Safety and Tolerability of Pazopanib vs. Sunitinib) randomized 1,110 treatment-naive patients with locally advanced or metastatic clear cell renal cell carcinoma (RCC) to pazopanib 800 mg administered daily on a continuous dosing schedule or sunitinib 50 mg given daily in a 6-week cycle of 4 weeks on, 2 weeks off.

Disease assessments were at weeks 6, 12, 18, 24, and then every 12 weeks. Patient-reported outcomes were measured at day 28 of every cycle.

The primary end point of median progression-free survival was 8.4 months for pazopanib and 9.5 months for sunitinib by independent central review (hazard ratio, 1.047), and 10.5 months vs. 10.2 months by the investigators (HR, 0.998). The upper bound of the 95% confidence interval for the hazard ratio was below 1.25, demonstrating the noninferiority of pazopanib to sunitinib, Dr. Motzer said.

The overall response rate (complete plus partial responses) was 31% for pazopanib and 25% for sunitinib (P = .03).

Median overall survival was 28.4 months vs. 29.3 months (HR, 0.908; P = .27), according to an interim analysis. The final overall survival data is anticipated in 2013, Dr. Motzer said.

Treatment-emergent hypertension, diarrhea, and nausea of any grade occurred equally in both arms. Patients given pazopanib had more hair-color changes (30% vs. 10%) and increased alanine transaminase (ALT) levels (31% vs. 18%), reflecting known increased liver toxicity, he said. In contrast, those given sunitinib experienced more fatigue (63% vs. 55%), hand-foot problems (50% vs. 29%), taste alterations (36% vs. 26%), and thrombocytopenia (34% vs. 10%).

Serious adverse events occurring in 3% or more of patients were increased ALT and increased aspartate aminotransferase (AST) in the pazopanib arm, and pyrexia and thrombocytopenia in the sunitinib arm. Fatal adverse events were reported in 2% and 3%, respectively.

Discussant Dr. Tim Eisen, who was a subinvestigator on the trial and is an oncology professor at the University of Cambridge, England, said clinicians need to consider two crucial things when selecting an RCC treatment: whether the two drugs are equally effective, and if so, which one is "softer going" on the patient.

The data show the two drugs are "equally effective" and that pazopanib "can be considered a first-line standard of care along with sunitinib," he said.

Patrice Wendling/IMNG Medical Media

Pazopanib is "easing ahead," however, in terms of tolerance and toxicity.

"Pazopanib does score in terms of having fewer side effects that matter to patients," Dr. Eisen said. "Don’t forget these are maintenance agents taken for as long as they are controlling disease, and even low-grade toxicities can be highly significant in this group."

Fatigue, stomatitis, and hand-foot syndrome all trouble patients badly, whereas elevated ALT and AST don’t usually trouble patients, if managed properly.

On the other hand, he observed that patients can feel a lot better during the 2 weeks off sunitinib, although the disease can grow, "even grow significantly, in a small proportion of patients."

Dr. Eisen cautioned that the timing of the assessments is a consideration in COMPARZ because they would tend to favor pazopanib. "For my money, this doesn’t really matter very much for the progression-free and overall survival curves as they mature ... I would not be so generous about the quality of life assessments," he said.

Patients do not feel "too chipper" after 4 weeks of sunitinib, but feel much better during the 2-week washout. Thus, "If you are looking at day 28 of each cycle, you are timing the quality of life assessments to favor pazopanib," he said.

Dr. Eisen said the hazard ratio of up to 1.25 "does cover quite a few ... scenarios, but I think it is acceptable and provides adequate power for a group of patients with a relatively uncommon disease."

During his presentation, Dr. Motzer highlighted the PISCES study, showing that patients with metastatic RCC preferred pazopanib over sunitinib by a three-to-one margin and had fewer dose reductions and interruptions.

In COMPARZ, dose reductions were reported in 44% of patients on pazopanib and 51% on sunitinib, and discontinuations because of adverse events in 24% and 19%.

Dr. Robin Wiltshire, global medical affairs lead for sunitinib for Pfizer Oncologysaid that, based on the trial design, it was possible to achieve a positive outcome, even if pazopanib had a 25% reduction in efficacy.

"Noninferiority is not the same as equal efficacy, and we’ve actually seen from the primary end point that the PFS is a month improved with sunitinib," he said in an interview.

In addition, progression-free survival has been even longer in real-world databases.

Dr. Wiltshire said COMPARZ is unlikely to cause a "major sea change in practice" and that physicians have not switched over en masse since pazopanib was approved in 2009. Physicians have treated more than 150,000 patients with sunitinib since its 2006 approval for RCC and have learned how to boost efficacy and manage its side effects.

The pharmaceutical research and advisory firm, Decision Resources, reports that angiogenesis inhibitors make up 76% of the RCC therapy market, with sunitinib accounting for more than half of sales in this class. It projects that sunitinib will account for only 14% of sales in this class by 2020, owing to high uptake of pazopanib and launch of the recently approved axitinib (Inlyta) and the investigational agent tivozanib – the first drug to break the 12-month PFS barrier in RCC.

GlaxoSmithKline sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib. Dr. Eisen reported serving as a subinvestigator on the trial.

VIENNA – The first head-to-head comparison of pazopanib and sunitinib is likely to reshape first-line treatment for renal cell carcinoma, long dominated by sunitinib.

The phase III COMPARZ trial shows similar potency for the two angiogenesis inhibitors, but pazopanib (Votrient) had a better tolerance and safety profile, Dr. Robert Motzer reported at the European Society for Medical Oncology (ESMO) Congress.

As previously observed in indirect comparisons, hand-foot syndrome, fatigue, and mucositis were more common with sunitinib (Sutent), while pazopanib had a higher incidence of liver abnormalities. The adverse events associated with sunitinib are the ones that really affect patients’ day-to-day living, remarked Dr. Motzer of Memorial Sloan–Kettering Cancer Center in New York.

Patrice Wendling/IMNG Medical Media

This was expressed in patient-reported outcomes on four quality of life instruments, which favored pazopanib in all but 1 of 14 domains – the exception was the emotional domain of the FACT Kidney Symptom Index (FKSI-19), but this was not statistically significant.

"This trial tips the scale for the preferred treatment, in my opinion, for most patients with kidney cancer from sunitinib, which has been the reference standard, to pazopanib," he said during a press briefing.

COMPARZ (Comparing the Efficacy, Safety and Tolerability of Pazopanib vs. Sunitinib) randomized 1,110 treatment-naive patients with locally advanced or metastatic clear cell renal cell carcinoma (RCC) to pazopanib 800 mg administered daily on a continuous dosing schedule or sunitinib 50 mg given daily in a 6-week cycle of 4 weeks on, 2 weeks off.

Disease assessments were at weeks 6, 12, 18, 24, and then every 12 weeks. Patient-reported outcomes were measured at day 28 of every cycle.

The primary end point of median progression-free survival was 8.4 months for pazopanib and 9.5 months for sunitinib by independent central review (hazard ratio, 1.047), and 10.5 months vs. 10.2 months by the investigators (HR, 0.998). The upper bound of the 95% confidence interval for the hazard ratio was below 1.25, demonstrating the noninferiority of pazopanib to sunitinib, Dr. Motzer said.

The overall response rate (complete plus partial responses) was 31% for pazopanib and 25% for sunitinib (P = .03).

Median overall survival was 28.4 months vs. 29.3 months (HR, 0.908; P = .27), according to an interim analysis. The final overall survival data is anticipated in 2013, Dr. Motzer said.

Treatment-emergent hypertension, diarrhea, and nausea of any grade occurred equally in both arms. Patients given pazopanib had more hair-color changes (30% vs. 10%) and increased alanine transaminase (ALT) levels (31% vs. 18%), reflecting known increased liver toxicity, he said. In contrast, those given sunitinib experienced more fatigue (63% vs. 55%), hand-foot problems (50% vs. 29%), taste alterations (36% vs. 26%), and thrombocytopenia (34% vs. 10%).

Serious adverse events occurring in 3% or more of patients were increased ALT and increased aspartate aminotransferase (AST) in the pazopanib arm, and pyrexia and thrombocytopenia in the sunitinib arm. Fatal adverse events were reported in 2% and 3%, respectively.

Discussant Dr. Tim Eisen, who was a subinvestigator on the trial and is an oncology professor at the University of Cambridge, England, said clinicians need to consider two crucial things when selecting an RCC treatment: whether the two drugs are equally effective, and if so, which one is "softer going" on the patient.

The data show the two drugs are "equally effective" and that pazopanib "can be considered a first-line standard of care along with sunitinib," he said.

Patrice Wendling/IMNG Medical Media

Pazopanib is "easing ahead," however, in terms of tolerance and toxicity.

"Pazopanib does score in terms of having fewer side effects that matter to patients," Dr. Eisen said. "Don’t forget these are maintenance agents taken for as long as they are controlling disease, and even low-grade toxicities can be highly significant in this group."

Fatigue, stomatitis, and hand-foot syndrome all trouble patients badly, whereas elevated ALT and AST don’t usually trouble patients, if managed properly.

On the other hand, he observed that patients can feel a lot better during the 2 weeks off sunitinib, although the disease can grow, "even grow significantly, in a small proportion of patients."

Dr. Eisen cautioned that the timing of the assessments is a consideration in COMPARZ because they would tend to favor pazopanib. "For my money, this doesn’t really matter very much for the progression-free and overall survival curves as they mature ... I would not be so generous about the quality of life assessments," he said.

Patients do not feel "too chipper" after 4 weeks of sunitinib, but feel much better during the 2-week washout. Thus, "If you are looking at day 28 of each cycle, you are timing the quality of life assessments to favor pazopanib," he said.

Dr. Eisen said the hazard ratio of up to 1.25 "does cover quite a few ... scenarios, but I think it is acceptable and provides adequate power for a group of patients with a relatively uncommon disease."

During his presentation, Dr. Motzer highlighted the PISCES study, showing that patients with metastatic RCC preferred pazopanib over sunitinib by a three-to-one margin and had fewer dose reductions and interruptions.

In COMPARZ, dose reductions were reported in 44% of patients on pazopanib and 51% on sunitinib, and discontinuations because of adverse events in 24% and 19%.

Dr. Robin Wiltshire, global medical affairs lead for sunitinib for Pfizer Oncologysaid that, based on the trial design, it was possible to achieve a positive outcome, even if pazopanib had a 25% reduction in efficacy.

"Noninferiority is not the same as equal efficacy, and we’ve actually seen from the primary end point that the PFS is a month improved with sunitinib," he said in an interview.

In addition, progression-free survival has been even longer in real-world databases.

Dr. Wiltshire said COMPARZ is unlikely to cause a "major sea change in practice" and that physicians have not switched over en masse since pazopanib was approved in 2009. Physicians have treated more than 150,000 patients with sunitinib since its 2006 approval for RCC and have learned how to boost efficacy and manage its side effects.

The pharmaceutical research and advisory firm, Decision Resources, reports that angiogenesis inhibitors make up 76% of the RCC therapy market, with sunitinib accounting for more than half of sales in this class. It projects that sunitinib will account for only 14% of sales in this class by 2020, owing to high uptake of pazopanib and launch of the recently approved axitinib (Inlyta) and the investigational agent tivozanib – the first drug to break the 12-month PFS barrier in RCC.

GlaxoSmithKline sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib. Dr. Eisen reported serving as a subinvestigator on the trial.