Concur: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Regorafenib Monotherapy in Asian Patients with Previously Treated Metastatic Colorectal Cancer (MCRC)

Introduction: Regorafenib is an oral multi-kinase inhibitor that targets pathways involved in tumor growth and progression. The CORRECT study showed that regorafenib improves overall survival (OS) in patients with mCRC who progressed after standard therapies (HR 0.77; 95%CI 0.64-0.94; one-sided p = 0.0052). Overall 15% of patients enrolled in CORRECT were Asian, mostly from Japan. CONCUR was initiated to evaluate the efficacy and safety of regorafenib in a broader group of Asian patients with mCRC.Methods: This trial was conducted in 25 centers in mainland China, Hong Kong, Taiwan, Republic of Korea, and Vietnam. Patients with Stage IV adenocarcinoma of the colon or rectum that progressed within 3 months after completing standard therapy were randomized (2:1) to receive best supportive care plus either oral regorafenib 160 mg daily or placebo during the first 3 weeks of each 4-week cycle. Patients must have received at least 2 prior treatment lines for mCRC, which included a fluoropyrimidine, oxaliplatin, and irinotecan. Prior anti-VEGF or anti-EGFR targeted therapy was allowed, but not required. Randomization was stratified by metastatic sites (single versus multiple) and time from diagnosis of metastatic disease to randomization (<18 months versus ≥18 months). Treatment was continued until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), tumor response, disease control rate (DCR), and safety. Survival was compared using a stratified log-rank test (one-sided alpha 0.2).Results: Between May 15, 2012 and January 15, 2013, a total of 204 patients were randomized to regorafenib (n = 136) or placebo (n = 68). Demographics and baseline characteristics were generally well balanced between treatment groups. The median age was 57 years, 75% of patients had an ECOG PS of 1, and 25% were ECOG PS 0. Forty-seven percent had received ≤3 treatment lines for mCRC and 41% had not received either anti-VEGF or anti-EGFR therapy. The cut-off date for this analysis was 29 November 2013. Regorafenib improved OS versus placebo, with a HR of 0.550 (95%CI, 0.395–0.765; one-sided p = 0.0002). Median OS was 8.8 months in the regorafenib group and 6.3 months with placebo. The HR for PFS was 0.311 (95%CI, 0.222–0.435; one-sided p < 0.0001) in favor of regorafenib, with median PFS times of 3.2 months and 1.7 months, respectively. The DCR was higher in the regorafenib group (52% versus 7%). The most frequent treatment-emergent NCI-CTCAE grade ≥3 adverse events in regorafenib-treated patients were hand-foot skin reaction (16%), hypertension (12%), hyperbilirubinemia (12%), elevated liver enzymes (AST 10%, ALT 8%), hypophosphatemia (9%), anemia (7%), and hyperlipasemia (7%). There were no reports of liver failure or pancreatitis.Conclusion: Regorafenib provides a statistically significant improvement in OS in Asian patients with mCRC who progressed after standard therapy. Adverse events are consistent with the known safety profile of regorafenib in Asian patients. Introduction: Regorafenib is an oral multi-kinase inhibitor that targets pathways involved in tumor growth and progression. The CORRECT study showed that regorafenib improves overall survival (OS) in patients with mCRC who progressed after standard therapies (HR 0.77; 95%CI 0.64-0.94; one-sided p = 0.0052). Overall 15% of patients enrolled in CORRECT were Asian, mostly from Japan. CONCUR was initiated to evaluate the efficacy and safety of regorafenib in a broader group of Asian patients with mCRC. Methods: This trial was conducted in 25 centers in mainland China, Hong Kong, Taiwan, Republic of Korea, and Vietnam. Patients with Stage IV adenocarcinoma of the colon or rectum that progressed within 3 months after completing standard therapy were randomized (2:1) to receive best supportive care plus either oral regorafenib 160 mg daily or placebo during the first 3 weeks of each 4-week cycle. Patients must have received at least 2 prior treatment lines for mCRC, which included a fluoropyrimidine, oxaliplatin, and irinotecan. Prior anti-VEGF or anti-EGFR targeted therapy was allowed, but not required. Randomization was stratified by metastatic sites (single versus multiple) and time from diagnosis of metastatic disease to randomization (<18 months versus ≥18 months). Treatment was continued until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), tumor response, disease control rate (DCR), and safety. Survival was compared using a stratified log-rank test (one-sided alpha 0.2). Results: Between May 15, 2012 and January 15, 2013, a total of 204 patients were randomized to regorafenib (n = 136) or placebo (n = 68). Demographics and baseline characteristics were generally well balanced between treatment groups. The median age was 57 years, 75% of patients had an ECOG PS of 1, and 25% were ECOG PS 0. Forty-seven percent had received ≤3 treatment lines for mCRC and 41% had not received either anti-VEGF or anti-EGFR therapy. The cut-off date for this analysis was 29 November 2013. Regorafenib improved OS versus placebo, with a HR of 0.550 (95%CI, 0.395–0.765; one-sided p = 0.0002). Median OS was 8.8 months in the regorafenib group and 6.3 months with placebo. The HR for PFS was 0.311 (95%CI, 0.222–0.435; one-sided p < 0.0001) in favor of regorafenib, with median PFS times of 3.2 months and 1.7 months, respectively. The DCR was higher in the regorafenib group (52% versus 7%). The most frequent treatment-emergent NCI-CTCAE grade ≥3 adverse events in regorafenib-treated patients were hand-foot skin reaction (16%), hypertension (12%), hyperbilirubinemia (12%), elevated liver enzymes (AST 10%, ALT 8%), hypophosphatemia (9%), anemia (7%), and hyperlipasemia (7%). There were no reports of liver failure or pancreatitis. Conclusion: Regorafenib provides a statistically significant improvement in OS in Asian patients with mCRC who progressed after standard therapy. Adverse events are consistent with the known safety profile of regorafenib in Asian patients.