Survival Benefit of Regorafenib Confirmed in Combined Analysis of CORRECT and CONCUR

Axel Grothey, MD

The survival benefit observed with regorafenib (Stivarga) over placebo in Asian patients who had been previously treated for metastatic colorectal cancer (mCRC) in the international phase III CORRECT trial [NCT01103323] was confirmed by the phase III CONCUR trial [NCT01584830], according to a combined analysis of data from both trials presented at the 2015 World Congress on GI Cancer.

“The studies showed that regorafenib improved overall survival in both Asian and non-Asian patients. Both trials had a similar adverse events profile,” said Axel Grothey, MD, department of Oncology, Mayo Clinic, Rochester, MN. The researchers examined the characteristics of patients and the efficacy and safety outcomes in the 2 trials. In CONCUR, only Asian patients were examined. Prior use of biologic targeted therapy was not mandatory. The CORRECT trial was comprised of a largely mixed-Caucasian population and all patients had received prior biologicals.

The CORRECT trial was comprised of 760 patients from North America, Europe, Australia, and Asia, including 100 Japanese and 4 Chinese patients, whereas CONCUR included 204 patients from Asian countries, including 172 Chinese but no Japanese patients.

In the CORRECT trial, 49% of patients had received ≥3 prior treatments, 48% of patients were ECOG PS 0 or 1, and 100% had received anti-VEGF, anti-EGFR, or both. In CONCUR, 38% of patients had received ≥3 previous treatment lines for metastatic disease, a higher proportion of patients were ECOG PS 1, and 41% of patients had no prior biologic targeted therapy.

Both trials randomly assigned patients 2:1 to regorafenib at 160 mg or placebo for the first 3 weeks of every 4-week cycle.

Both trials met the primary endpoint of OS. In CORRECT, the median OS for regorafenib-treated patients was 6.4 months vs 5.0 months in patients who received placebo (HR = 0.77, 95% CI 0.04, 0.94; P = .0052). In CONCUR, median OS was 8.8 months for patients who received regorafenib vs 6.3 months for patients who received placebo (HR = 0.55, 95% CI 0.40, 0.77; P = .00016). Progression-free survival (PFS) was also similar across the trials. Median PFS, as previously reported, was 1.9 vs 1.7 months (HR = 0.49, 95% CI 0.42, 0.58; P < .0001) in CORRECT and 3.2 vs 1.7 months (HR = 0.31, 95% CI 0.22, 0.44; P < .0001) in CONCUR with regorafenib vs placebo, respectively.

Less pre-treatment, especially with anti-VEGF or anti-EGFR agents, may explain the larger gain of overall survival observed with regorafenib in the CONCUR trial compared with the CORRECT trial.

“Exploratory subgroup analysis in CONCUR revealed the benefit in patients who had received previous targeted treatment was similar to that seen in CORRECT, in which all patients received at least one prior targeted therapy,” said Grothey.

Disease control rates were 41% vs 15% (CORRECT) and 51% vs 7% (CONCUR) with regorafenib vs placebo, respectively (all P < .0001).

Discussant Tim Maughan, MD, professor of Clinical Oncology and clinical director of research and development for the division of Surgery and Oncology at the Oxford Cancer Centre, Oxford UK, who was not involved in either trial, polled the audience: “How many of you in your practice already deliver regorafenib at less than the standard dose?” The show of hands favored a reduced dose over standard. “The safety and frequent dose modifications with regorafenib require care in patient and dose selection. Currently, there are no biomarkers to aid in this selection.”

Maughan also referred to the genetic analysis done by Grothey and pointed out that regorafenib seemed to show more benefit over placebo in patients with KRAS wild type over mutated, HR = 0.65 and 0.87, (P < .05; P = NS).

“I welcome this new active ‘last line’ option that has demonstrated comparable overall survival effects in 2 studies,” Maughan said.

The most frequently reported drug-related adverse events grade ≥3 in CORRECT were hand—foot skin reaction (HFSR, 16%), fatigue (10%), diarrhea and hypertension (7% each). In CONCUR, the most frequent drug-related grade ≥3 adverse events were HFSR (16%), hypertension (11%), hyperbilirubinemia, hypophosphatemia, and alanine aminotransferase increase (7%, each).

“The international phase 3 CORRECT trial demonstrated the clinical benefit of regorafenib in patients with previously treated metastatic colorectal cancer, and the results were confirmed by the phase 3 CONCUR trial,” Grothey concluded.

The CONCUR and CORRECT trials were sponsored by Bayer Healthcare

Grothey A, Van Cutsem E, Wagner A, et al. Characteristics and outcomes of patients enrolled in the CORRECT and CONCUR phase 3 trials of regorafenib for metastatic colorectal cancer (mCRC). Ann Oncol. 2015;26 (suppl 4; O-011).

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