Pazopanib Better Tolerated Than Sunitinib in Renal Cancer

Roxanne Nelson

October 03, 2012

October 3, 2012 (Vienna, Austria) — Sunitinib (Sutent) has been considered the reference standard for the treatment of renal cell carcinoma (RCC), but pazopanib (Votrient) is now challenging that position.

The first head-to-head comparison shows that the 2 drugs have similar efficacy, but pazopanib appears to have a better safety profile and is better tolerated than sunitinib, said lead author Robert Motzer, MD, from the Memorial Sloan-Kettering Cancer Center in New York City.

Dr. Robert Motzer

Dr. Motzer presented the study findings here at the 2012 European Society for Medical Oncology (ESMO) Congress.

The aim of this head-to-head trial "was not to show one was superior, but to show that pazopanib had similar effectiveness," said Dr. Motzer. "It was also to show that pazopanib had a better tolerance and safety profile," he added.

Both agents are options for first-line therapy in this population. "They have the same efficacy but the safety profile is different," Dr. Motzer explained. "In this era of personalized medicine, patients should be given the different options," he noted.

Pazopanib "is less troublesome for the patient, and quality of life was better," he said. "In general terms, that is the treatment of choice, in my opinion," he said.

Behind the science is a fierce battle for market share. Sunitinib was approved for use in RCC in 2006, and global sales were $1.19 billion in 2011. Pazopanib was approved for RCC in 2009, and sales were $160 million in 2011.

Similar But Different

Both agents are oral multikinase angiogenesis inhibitors and both have improved progression-free survival in patients with metastatic RCC in phase 3 trials.

Previous studies that indirectly compared the 2 drugs have shown that there is a lower incidence of fatigue, hand–foot syndrome, and stomatitis with pazopanib, and a lower incidence of liver function abnormalities with sunitinib.

First Head-to-Head Comparison

The phase 3 COMPARZ (Comparing the Efficacy, Safety, and Tolerability of Pazopanib vs Sunitinib) study involved 1110 treatment-naïve patients with clear cell metastatic RCC and measurable disease. They were randomized to receive either pazopanib 800 mg daily administered by continuous infusion or sunitinib 50 mg daily administered in 6-week cycles (4 weeks on/2 weeks off).

The primary end point was progression-free survival. On the basis of a planned 631 progression-free survival events, assessed by an Independent Review Committee (IRC), the study had an 80% power to detect the noninferiority of pazopanib to sunitinib.

Secondary end points included overall survival, overall response rate, adverse events, and quality of life.

Median progression-free survival was similar for pazopanib and sunitinib when assessed by the IRC (8.4 vs 9.5 months; hazard [HR], 1.0466) and by the investigators (10.5 vs 10.2 months; HR, 0.998). The upper bound of the 95% confidence interval for IRC-assessed progression-free survival was below 1.25, indicating pazopanib is noninferior to sunitinib.

Overall survival was 28.4 months for pazopanib and 29.3 months for sunitinib (HR, 0.91). Final survival data are expected in 2013, said Dr. Motzer.

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

Common adverse events, such as diarrhea, fatigue, nausea, and hypertension, were similar in the 2 groups. Some events occurred less often in the pazopanib group than in the sunitinib group, including hand–foot syndrome (29 vs 50 patients; HR, 0.59), dyspepsia (14 vs 24 patients; HR, 0.58), mucositis (11 vs 26 patients; HR, 0.43), hypothyroidism (12 vs 24 patients; HR, 0.50), and anemia (7 vs 19 patients; HR, 0.36).

Adverse events associated with liver function were more common the pazopanib group than in the sunitinib group, such as elevated alanine transaminase (ALT) levels (31 vs 18 patients; HR, 1.74) and elevated aspartate transaminase (AST) levels (27 vs 18 patients; HR, 1.49).

Differences in 11 of 14 quality-of-life domains were small but statistically significant, and all favored pazopanib. "We found that there was only 1 in favor of sunitinib, a tool that looked at emotional well-being, and it was not statistically significant," explained Dr. Motzer.

Diverging Opinions

Not all experts agree that pazopanib should replace sunitinib as the treatment of choice. In a discussion of the study, Tim Eisen, MD, academic clinical lead and deputy director of the cancer division at the University of Cambridge in the United Kingdom, said that there are 2 "crucial" things to consider when selecting a treatment for RCC: Are the drugs are equally effective and, if so, which one is "softer" on the patient?

Because the data show that the 2 agents are equally effective, "pazopanib can be considered a first-line standard of care along with sunitinib," Dr. Eisen said.

For an unselected population, pazopanib might be better, he pointed out. "The safety profile favors pazopanib, except for liver function abnormalities, which can be serious," he noted.

Dr. Eisen, who was a subinvestigator on the trial, agrees that pazopanib causes fewer of the adverse effects that patients have difficulty tolerating. "These are maintenance drugs, so they are taken over a long period of time.... Liver abnormalities usually don't bother patients if they are managed properly," he explained.

"The patient usually feels better off the drug, but the disease can grow in a small number of patients." This must be considered because pazopanib is administered by continuous infusion and sunitinib is administered on and off, he noted.

Dr. Eisen pointed to the PISCES trial, which was presented earlier this year at the American Society of Clinical Oncology annual meeting. Of the 126 patients who completed the PISCES questionnaire, 70% preferred pazopanib, 22% preferred sunitinib, and 8% expressed no preference. The main reasons cited were better overall quality of life and less fatigue, but patients also reported less change in food taste, less soreness in the mouth/throat, and less foot and mouth syndrome with pazopanib.

More studies are needed that reflect patient preference, Dr. Eisen noted.

Robin Wiltshire, MB ChB, global medical affairs lead at Pfizer, the manufacturer of sunitinib, is not convinced that pazopanib is going to replace sunitinib. Both drugs have been available for several years and physicians have not been switching over to any great degree, he told Medscape Medical News. "Sunitinib also has the best efficacy data in metastatic renal cell cancer," he said.

"It is important to look at the original intention of the study, which was noninferiority," Dr. Wiltshire explained.

He pointed out that the primary end point, progression-free survival, was 1 month longer with sunitinib than with pazopanib. "The way the study was designed, it was possible that it still could be positive even if pazopanib had a 25% reduction in efficacy. Noninferiority is not the same thing as being equal. That is one thing people need to understand."

"We have also seen longer progression-free survival than was seen in this study in real-world databases," Dr. Wiltshire said.

Sunitinib has been on the market for more than 6 years, which means that more than 150,000 patients have been treated with it. "Many physicians around the world have experience with it and have learned how to get the best efficacy with it," Dr. Wiltshire noted.

He pointed out that they haven't seen the full COMPARZ data yet, but "our take on the study is that it is unlikely to change clinical practice."

THE COMPARZ study was highlighted in the Best of ESMO round-up session.

Manuela Schmidinger, MD, from the Medical University of Vienna, who was not involved in the trial, said that tolerability and quality of life favored pazopanib, but the quality-of-life questionnaires were administered on day 28, which is "the worst day for sunitinib," and that the trial participants included Asian patients, and "they are known to have a lower tolerance for the off-target effects of tyrosine-kinase inhibitors."

Dr. Motzer and several of his coauthors report financial relationships with industry, including Pfizer and GlaxoSmithKline, the manufacturer of pazopanib. Dr. Eisen has disclosed no relevant financial relationships.

2012 European Society for Medical Oncology (ESMO) Congress: Abstract LBA 8. Presented October 1, 2012.