Sunitinib vs Pazopanib in Renal Cancer in NEJM

Authors Emphasize Tolerability

Nick Mulcahy

August 21, 2013

The clinical trial results of the first-ever head-to-head comparison of the first-line treatments for metastatic renal cell carcinoma (RCC) are published in this week's New England Journal of Medicine.

The study results were first presented at the 2012 European Society for Medical Oncology (ESMO) Congress and reported by Medscape Medical News at that time.

Clinicians can now closely compare the extensive data on the safety, efficacy, and tolerability of sunitinib (Sutent, Pfizer Inc), which has been considered the reference standard, and pazopanib (Votrient, GlaxoSmithKline), which reached the market later and holds a smaller share.

Both drugs are oral multikinase inhibitors. 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.

The study's lead author suggested that the data from the comparative study, which was funded and codesigned by GlaxoSmithKline, may shake up that dynamic.

"I believe pazopanib will be the preferable choice moving forward," said Robert Motzer, MD, of Memorial-Sloan Kettering Cancer Center in New York City, in a press statement.

What is the root of Dr. Motzer's opinion about pazopanib's preferability?

It is not pazopanib's survival benefits. The drug was "similar" to sunitinib in the trial in terms of efficacy, conclude Dr. Motzer and his coauthors, who include GlaxoSmithKline employees.

Pazopanib actually provided a lower median overall survival (OS) when compared with sunitinib (OS: 28.4 vs 29.3 months; hazard ratio [HR], 0.91) and lower median progression-free survival (PFS: 8.4 vs 9.5 months; HR, 1.05), but the differences were not statistically significant.

The trial's primary objective was to show noninferiority of pazopanib compared with sunitinib in terms of PFS, and that goal was met, said the authors.

Dr. Motzer has based his preference for pazopanib in other clinical findings. The safety and quality-of-life profiles "favor" pazopanib in the trial, report he and his coauthors.

"Improved quality-of-life scores were reported among the patients taking pazopanib," said Dr. Motzer. The safety profile was also "more appealing," he said.

The study's senior author made the same points about pazopanib, but less directly.

"Tolerability is a big part of the equation when drugs work equally well," said Toni Choueiri, MD, of Dana-Farber/Brigham and Women's Cancer Care, Boston, in another press statement. "If patients are going to live the same life span, why not use the one that's better tolerated?"

However, when the study was presented at ESMO, a commentator suggested that the study's health-related quality-of-life assessments were unfair to sunitinib.

Manuela Schmidinger, MD, from the Medical University of Vienna in Austria, 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." This was a reference to the fact that sunitinib was administered for 28 days followed by 14 days off, whereas pazopanib was administered continuously. Thus, the day-28 assessments would not have captured the benefits of the built-in drug holiday in sunitinib's schedule.

Safety Details

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 randomly assigned to receive either oral pazopanib 800 mg daily with continuous dosing or oral sunitinib 50 mg daily administered in 6-week cycles (4 weeks on/2 weeks off).

The objective response rates, which were a secondary outcome, were 31% for pazopanib and 25% for sunitinib (P =.03).

The median duration of treatment was 8 months in the pazopanib group and 7.6 months in the sunitinib group. The pazopanib group had fewer dose interruptions of 7 days or more when compared with the sunitinib group (44% and 49%) and fewer reductions in the dose (44% and 51%).

However, a higher proportion of patients in the pazopanib group discontinued the study drug because of adverse events compared with the sunitinib group (24% vs 20%). The higher discontinuation rate for pazopanib vs sunitinib was "primarily" due to abnormalities in liver-function tests (6% vs. 1%), write the authors.

The most common adverse events included diarrhea, fatigue, nausea, and hypertension; adverse events were similar in the 2 groups.

Some events (all grades) occurred significantly less often in the pazopanib group than in the sunitinib group, including the following: hand–foot syndrome (29% vs 50%); dysgeusia (26% vs 36%); rash (18% vs 23%); constipation (17% vs 24%); dyspepsia (14% vs 24%); stomatitis (14% vs 27%); hypothyroidism (12% vs 24%); and mucosal inflammation (11% vs 26%) — among others.

But some adverse events (all grades) occurred significantly more often with pazopanib vs sunitinib: changes in hair color (30% vs 10%); weight loss (15% vs 6%); and alopecia (14% vs 8%).

Pazopanib was better than sunitinib in terms of hematologic adverse events. All grades of leukopenia, thrombocytopenia, neutropenia, and anemia occurred significantly more often in the sunitinib group vs the pazopanib group.

However, adverse events associated with liver function were more common in the pazopanib group than in the sunitinib group, including significantly more instances of elevations in aspartate transaminase (AST) levels of grade 3 (11% vs 3%).

Also there were significantly more instances of elevations in alanine transaminase (ALT) levels of all grades with pazopanib (60% vs 43%) and of grade 3 (15% vs 4%).

At ESMO, an expert said that liver function abnormalities with pazopanib can be "quite serious." However, Tim Eisen, MD, of the University of Cambridge in the United Kingdom, also explained that pazopanib and sunitinib 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."

Quality-of-Life Results Biased?

Health-related quality of life, which was measured with 4 different instruments, was a secondary outcome of the trial and one that was emphasized by the investigators.

"Patients who received pazopanib reported less fatigue, fewer side effects such as soreness of the hand or foot and soreness of the mouth or throat, and better satisfaction with treatment than did those who received sunitinib," write the authors.

The findings here are "consistent" with the safety profile, they observe.

The authors acknowledge that the health-related quality-of-life findings assessed on day 28 of therapy could be "biased" toward pazopanib because "it may not have captured the recovery of patients in the sunitinib group during the [subsequent] 2-week drug holiday."

The authors further assess the concern by looking at hematologic adverse events at day 28 and day 42 of therapy. They note that there was recovery from sunitinib toxicity at the later date with respect to thrombocytopenia and neutropenia, but that anemia was more severe at day 42 than at day 28. This is important, they say, because other studies have shown a correlation between anemia and fatigue in cancer patients.

The authors also point to another study of health-related quality of life with pazopanib vs sunitinib, which showed that patients treated with pazopanib "reported having less fatigue, soreness of the hand or foot, and soreness of the mouth or throat than did the patients treated with sunitinib."

Dr. Motzer and a number of coauthors report financial relationships with industry, including GlaxoSmithKline, the manufacturer of pazopanib. Dr. Eisen disclosed no relevant financial relationships. Dr. Schmidinger has previously reported financial ties to industry, including both GlaxoSmithKline and Pfizer.

N Engl J Med. 2013;369:722-31. Abstract

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