These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis.— Naomi B. Haas, MD, and colleagues
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In the phase III ECOG-ACRIN E2805 trial reported in The Lancet by Naomi B. Haas, MD, of Abramson Cancer Center, University of Pennsylvania, and colleagues, no benefit of adjuvant vascular endothelial growth factor receptor (VEGFR) inhibitor treatment with sunitinib or sorafenib (Nexavar) was observed vs placebo in patients with completely resected high-risk nonmetastatic renal cell carcinoma.1
In the double-blind trial, 1,943 patients with pathologic stage high-grade T1b or greater disease and complete resection from the National Clinical Trials Network at 226 sites in the United States and Canada were randomized between April 2006 and September 2010 to receive sunitinib (n = 647), sorafenib (Nexavar; n = 649), or placebo (n = 647) for 54 weeks. After high rates of toxicity-related treatment discontinuation were observed among the first 1,323 patients enrolled (44% of 438 sunitinib patients; 45% of 441 sorafenib patients; 11% of placebo patients), the starting dose of each drug was reduced and then individually titrated up to the original doses.
Initial treatment was sunitinib at 50 mg/d for the first 28 days of each 6-week cycle or sorafenib at 400 mg twice per day in all cycles; the starting dose was reduced to sunitinib at 37.5 mg or sorafenib at 400 mg/d for the first one or two cycles of therapy. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population.
Due to low conditional power for the primary endpoint, the Data Safety Monitoring Committee recommended in October 2014 that blinded follow-up be stopped and study results released. Median follow-up was 5.8 years.
The primary analysis showed no significant differences in disease-free survival, with a median duration of 5.8 years (interquartile range [IQR] = 1.6–8.2 years) for sunitinib (hazard ratio [HR] = 1.02, P = .8038, vs placebo), 6.1 years (IQR = 1.7 years to not estimable) for sorafenib (HR = 0.97, P = .7184, vs placebo), and 6.6 years (IQR = 1.5 years to not estimable) for placebo. Five-year disease-free survival was 54.3%, 54.0%, and 56.4%, respectively.
Among patients with clear cell histology (approximately 80% across the groups), no differences in disease-free survival were observed with sunitinib (HR = 1.02, P = .8931) or sorafenib (HR = 0.99, P = .8734) vs placebo. Although hazard ratios and interactions were not significant, hazard ratios were higher for women (1.29) than men (0.95) and for white patients (1.09) than those of another race/ethnicity (0.74; n = 164) among patients receiving sunitinib; similar outcomes were observed for women (1.30) and men (0.89) and white patients (1.06) vs those of another race/ethnicity (0.49; n = 180) receiving sorafenib.
Median overall survival had not been reached in any group. No significant difference was observed for the sunitinib group (HR = 1.17, P = .1762) or sorafenib group (HR = 0.98, P = .8577) vs placebo. Five-year overall survival was 77.9%, 80.5%, and 80.3%, respectively.
Grade ≥ 3 adverse events occurred in 63% of sunitinib patients, 72% of sorafenib patients, and 25% of placebo patients; after reduction of the starting dose, grade ≥ 3 adverse events still occurred in more than 55% of patients in the sunitinib and sorafenib groups. The most common grade ≥ 3 adverse events were hypertension (17% of sunitinib patients, 16% of sorafenib patients), hand-foot syndrome (15% and 33%), rash (2% and 15%), and fatigue (17% and 7%).
Among patients starting at reduced doses, adverse events led to discontinuation of treatment in 34% of sunitinib patients, 30% of sorafenib patients, and 10% of placebo patients.
The investigators concluded:
“Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase III study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis.” ■
Disclosure: The study was funded by the National Cancer Institute, the ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer. For full disclosures of the study authors,
The reasons for low tolerability in the adjuvant setting may relate to there being less disease present and the agents’ not exerting an antiangiogenic effect on micrometastases. In theory, patients without metastatic disease may also be less tolerant of the side effects of these agents...!-->!-->