In patients with advanced colorectal cancer who have been heavily treated with a sequence of chemotherapy regimens and/or targeted therapies, the goals of treatment on or off a clinical trial are readily definable. These patients and their managing teams are striving to extend the length of lives, maintain quality of life, provide hope in a palliative care setting, identify new active agents, and refine the optimal use of those agents either alone or as part of combination therapies. When enrolling in these trials, patients have accepted randomization to a new treatment compared with best supportive care, highlighting both the individual patient’s and the population’s needs for better outcomes. And this strategy has been successful.

Such studies have recently identified monoclonal antibodies targeting the epidermal growth factor receptor cetuximab (Erbitux) and panitumumab (Vectibix), the cytotoxic agent TAS-102, and the multitargeted tyrosine kinase inhibitor regorafenib (Stivarga) as agents that extend survival in this heavily pretreated group of people. Once these tools are identified as effective, we need to refine their use to best advantage. The ­CONCUR trial—reported by Li and colleagues¹ and reviewed in this issue of The ASCO Post—helped to do this by extending the findings from the CORRECT trial,² a study that led to the U.S. Food and Drug Administration approval of regorafenib in the setting of advanced colorectal cancer that is refractory to chemotherapy.

CORRECT vs CONCUR Trials

How does the CONCUR study extend our knowledge about the use of this new agent? The CONCUR study was conducted in patients of Asian and non-Japanese ancestry, a population that had not been enrolled in the prior phase III CORRECT trial; the CORRECT trial did enroll patients of Japanese ancestry but not individuals from other Asian countries.

In the regorafenib-treated cohort in the CORRECT vs CONCUR studies, 49% vs 38% had at least three prior treatments; 52% vs 26% had an Eastern Cooperative Oncology Group performance status of 0; 54% vs 34% of the patients’ tumors had KRAS mutations; and none vs 41% had prior exposure to biologic agents. Despite these differences in the characteristics of the treated cohorts, the toxicity profiles were nearly identical. The relative benefits for CONCUR’s less heavily pretreated group were marginally better than for the patients treated in the CORRECT trial: median progression-free survival of 2.2 vs 1.9 months and median overall survival of 8.8 vs 6.4 months.

Similar to what was seen in the CORRECT trial, the exposure to regorafenib did not lead to an earlier deterioration of quality of life compared with the cohorts randomized to placebo treatment, nor did quality of life improve during treatment in any of the four cohorts. The agent appeared active in cohorts with both KRAS wild-type and KRAS-mutated tumors.

The Next Steps

What are the next steps for regorafenib now that we have this additional information? This study suggests the potential for earlier deployment of regorafenib and its use in combination therapy. These strategies are being tested with both ­FOLFIRI (folinic acid, fluorouracil [5-FU], and irinotecan) and ­FOLFOX (folinic acid, 5-FU, oxaliplatin) in the second-line setting. Clinical experience has also suggested the need for refining the dose and schedule of regorafenib, looking at lower doses and schedules using alternating weeks of treatment and treatment-free intervals. This is related to the need for dose adjustment and dose delays in patients treated with 160 mg daily for 3 of 4 weeks.

It is clear from these two trials (as well as from the Bayer-funded ­CONSIGN registry retrospectively examining the experiences of patients treated outside a prospective phase III trial) that regorafenib has activity and utility in treating patients with advanced colorectal cancer. As we learn to use this agent better, we hope to exploit its value even more effectively. ■

Disclosure: Dr. Goldberg has been an advisor to Taiho, served on the data monitoring committee for Eli Lilly, and his institution has received research funding from Bayer.

References

1. Li J, Qin S, Xu R, et al: Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 16:619-629, 2015.

2. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303-312, 2013.

Dr. Goldberg is Physician-in-Chief, The Ohio State University Comprehensive Cancer Center—James Cancer Hospital and Solove Research Institute, Columbus.