Tuma, Rabiya S. PhD
Although recent FDA approvals for drugs for metastatic renal cell cancer have given patients more options for first-line treatment, it has been unclear how to decide which is best for individual patients. Data presented at this year's Genitourinary Cancers Symposium, however, help. In a preplanned analysis of the Phase III COMPARZ trial, patients who received pazopanib reported better quality of life than patients who received sunitinib. COMPARZ trial (Abstract 346).
Experts now agree that the aggregate data available is tipped toward pazopanib, but they caution that the magnitude of difference in quality of life seen in the current analysis is relatively small and the trial design may have favored pazopanib.
The primary aim of the trial, which was funded by paxopanib's manufacturer, GlaxoSmithKline, was to test whether that drug is non-inferior to sunitinib in terms of progression-free survival in patients with previously untreated metastatic renal cell cancer. The top-line data, reported at the European Society of Medical Oncology Congress last fall (OT, 1/10/13), showed the trial met its endpoint, with a median progression-free survival, by central review, of 8.4 months in 557 patients treated with pazopanib and 9.5 months in patients treated with sunitinib. The hazard ratio for progression was 1.22, which was below the prespecified boundary for non-inferiority of 1.25, indicating that pazopanib was no worse than sorafenib.
Additionally, the drugs were similar in the overall rate of serious adverse events. In the pazopanib arm, 59 percent of patients developed Grade 3 side effects, as did 57 percent of those in the sunitinib arm; 15 percent of patients in the pazopanib arm developed Grade 4 toxicity compared with 17% in the sunitinib arm.
However, the types of side effects differed significantly between the two agents. In terms of common adverse events that occurred in more than 20 percent of patients, pazopanib was associated with liver enzyme increases and hair color changes, whereas fatigue, hand-foot syndrome, taste alteration, and thrombocytopenia were more common in the sunitinib arm.
In the quality-of-life assessment, the researchers asked a subset of 927 patients about 14 different domains. The primary endpoints were fatigue, as measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and treatment side effects as measured by the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19), including diarrhea, nausea, and general side effects. Secondary endpoints included other domains in the FKSI-19 tool, the Cancer Therapy Satisfaction Questionnaire (CTSQ), and a Supplementary Quality of Life Questionnaire (SQLQ).
Patients filled out the questionnaires at baseline and on day 28 of each six-week cycle for the first six months of therapy. The response rate was high for all of the tools, averaging over 90 percent in each arm, except for the SQLQ, which was incorporated after the start of the trial and had a response rate around 85 percent.
Fatigue and Side Effects
“The two primary endpoints in quality of life were fatigue total score and treatment side effects, and both of these were statistically significantly in favor of pazopanib,” said Robert Motzer, MD, Attending Physician in the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center, who presented the data.
“Looking across the board at this broad spectrum of quality-of-life tools, there were a number of different domains that were in favor of pazopanib. In all, 11 out of 14 domains that we assessed were statistically significantly in favor of pazopanib. In contrast, none of the domains were statistically significantly in favor of sunitinib.”
Domains that favored pazopanib included physical well being on the FKSI-19 and symptoms related to hand, foot, and mouth soreness on the SQLQ. The three domains that did not show a statistically significant difference between the two arms were emotional and functional well being on the FKSI-19 and expectations of therapy on the CTSQ.
Cautions from Discussant
While Motzer and colleagues concluded that the differences in quality of life were likely to be clinically meaningful, the Discussant for the abstract, Sandhya Srinivas, MD, Associate Professor of Medicine at Stanford University Medical Center, was more cautious. She raised the concept of “minimally important difference,” which is the smallest change in a quality-of-life score that patients perceive as important. For the fatigue subscale, that difference is around three or four points, according to previous studies.
She noted that both drugs resulted in “pretty significant” fatigue, with a large drop in the mean FACIT-F score between baseline and the first assessment at day 28. But the actual difference between the two arms at that time was just a two-point change. “It really doesn't meet clinical significance,” she said.
Moreover, the interpretation of the quality-of-life data is complicated by the timing of the assessments, she continued. Pazopanib is given on a continuous basis, whereas sunitinib is give on a schedule of four weeks on, two weeks off, to give patients a chance to recover from the side effects. Therefore, assessing patients on day 28 of each cycle, just before the sunitinib break, may exaggerate the reported differences in quality of life.
Figure. ROBERT MOTZE...Image Tools
During his talk, Motzer acknowledged that although some clinicians might think the assessment timing favored pazopanib, the goal in choosing that time point was to assess patients' quality of life when they were on active therapy.
In the end though, despite Srinivas's critical comments, she said she thinks the balance now favors pazopanib: “Putting together the COMPARZ efficacy study and the PISCES patient preference data, and the quality of life data from this trial—all favoring pazopanib—I think we will certainly tip towards more use of pazopanib.”
Motzer reported being a study investigator for GlaxoSmithKline and serving as an advisor for Pfizer Inc., which makes sunitinib. Similarly for the coauthors: They report serving as consultants to both companies. Srinivas reported receiving research funds from Exelixis and Genentech.
More News from the GU Symposium in the Special Edition supplement to this issue – access it under “Archives”
© 2013 Lippincott Williams & Wilkins, Inc.