Regorafenib Improves Overall Survival in Asian Patients With Previously Treated Metastatic Colorectal Cancer
In the phase III CONCUR trial reported in The Lancet Oncology, Li et al found that the multikinase inhibitor regorafenib (Stivarga) improved overall survival vs placebo in Asian patients with previously treated metastatic colorectal cancer. Regorafenib has been approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. In the phase III CORRECT trial that supported its approval, 111 of 760 patients were Asian, with most being Japanese.
Study Details
In this double-blind trial, 204 patients with progressive disease from 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam were randomly assigned 2:1 between April 2012 and February 2013 to receive oral regorafenib 160 mg/d (n = 136) or placebo (n = 68) on days 1 to 21 of 28-day cycles. Both groups received best supportive care. Patients had to have received at least two prior lines of treatment, including a fluoropyrimidine plus oxaliplatin or irinotecan. Previous treatment with bevacizumab (Avastin), cetuximab (Erbitux), or panitumumab (Vectibix) was allowed but not mandatory. The primary endpoint was overall survival.
The regorafenib and placebo groups were generally balanced for age (median 58 and 56 years, 30% and 15% ≥ 65 years), sex (63% and 49% male), region (China for 82% and 88%), Eastern Cooperative Oncology Group performance status (0 for 26% and 22%, 1 for 74% and 78%), main site of disease (colon in 58% and 71%), presence of KRAS mutation (34% and 26%), time from metastatic diagnosis (median 20 months in both, < 18 months in 39% and 48%), multiple metastatic sites (79% and 78%), and previous systemic treatments (overall ≥ four in 54% and 51%, ≥ four for metastatic disease in 38% and 40%). With regard to previous targeted treatment, 41% and 38% had received none, and 59% and 62% had received anti-VEGF or anti-EGFR therapies.
Improved Overall Survival
After a median follow-up of 7.4 months, median overall survival was 8.8 months (95% confidence interval [CI] = 7.3–9.8 months) in the regorafenib group vs 6.3 months (95% CI = 4.8–7.6 months) in the placebo group (hazard ratio [HR] = 0.55, P = .00016). Median progression-free survival was 3.2 months (95% CI = 2.0–3.7 months) vs 1.7 months (95% CI = 1.6–1.8 months; HR = 0.31, P < .0001).
Subgroup analysis showed a consistent effect of regorafenib in almost all subgroups. In exploratory analysis of the effect of previous targeted biologic treatment, the hazard ratio for overall survival was 0.31 (95% CI = 0.19–0.53) among 82 patients with no prior treatment and 0.78 (95% CI = 0.51–1.19) among 122 who had received at least one targeted agent.
After disease progression, 31% of patients in the regorafenib group and 43% of the placebo group received additional systemic treatment.
Adverse Events
Drug-related adverse events of any grade occurred in 97% of the regorafenib group and 46% of the placebo group, with the most common in the regorafenib group being hand-foot skin reaction (73% vs 4%) and hyperbilirubinemia (36% vs 7%). Grade ≥ 3 drug-related adverse events occurred in 55% vs 14%, with the most common being hand-foot skin reaction (16% vs 0%), hypertension (11% vs 3%), hyperbilirubinemia (7% vs 1%), hypophosphatemia (7% vs 0%), and increased alanine transaminase (7% vs 0%) or aspartate transaminase levels (6% vs 0%). Drug-related serious adverse events occurred in 9% vs 4%.
The investigators concluded: “This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting.”
Tae Won Kim, MD, of University of Ulsan College of Medicine, South Korea, is the corresponding author for The Lancet Oncology article.
The study was funded by Bayer HealthCare Pharmaceuticals. For full disclosures of the study authors, visit www.thelancet.com.
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