Regorafenib in Patients with Antiangiogenic-Naïve and Chemotherapy-Refractory Advanced Colorectal Cancer: Results from a Phase IIb Trial

Abstract

Background Regorafenib is a multikinase inhibitor with antiangiogenic effects that improves overall survival (OS) in metastatic colorectal cancer (mCRC) after failure of standard therapies. We investigated the efficacy and safety of regorafenib in antiangiogenic therapy‐naïve chemotherapy‐refractory advanced colorectal cancer. Patients and Methods This single‐center, single‐arm, phase IIb study (NCT02465502) enrolled adults with mCRC whose disease had progressed on, or who were intolerant to, standard therapy, but who were antiangiogenic therapy‐naïve. Patients received regorafenib 160 mg once daily for 3 weeks per 4‐week cycle. The primary endpoint was progression‐free survival (PFS) rate at week 8. Results Of 59 treated patients, almost half had received at least four prior lines of therapy. Patients received a median of 86% of the planned dose. The week 8 PFS rate was 53% (95% confidence interval [CI], 39.1–64.3); median PFS was 3.5 months (95% CI, 1.8–3.6). Median OS was 7.4 months (95% CI, 5.3–8.9). Tumor response (RECIST version 1.1) was 2%, and metabolic response rate (criteria from the European Organisation for Research and Treatment of Cancer) was 41%. The most frequently reported regorafenib‐related grade ≥3 adverse events were hypertension (36%), hand–foot skin reaction (HFSR, 25%), and hypophosphatemia (24%). There were no regorafenib‐related deaths. An exploratory analysis showed that patients with grade ≥2 HFSR had longer OS (10.2 months) with regorafenib treatment versus those with grades 0–1 (5.4 months). Conclusion These findings support the antitumor activity of regorafenib in antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC. Implications for Practice The multikinase inhibitor regorafenib improved overall survival in the phase III CORRECT and CONCUR trials in heavily pretreated patients with treatment‐refractory metastatic colorectal cancer (mCRC). Exploratory subgroup analysis from CONCUR suggested that regorafenib treatment prior to targeted therapy (including bevacizumab) may improve outcomes. In this single‐center, single‐arm phase IIb study, regorafenib demonstrated antitumor activity in 59 antiangiogenic‐naïve patients with chemotherapy‐refractory mCRC. Further studies should assess the efficacy of regorafenib in this patient population, as well as explore the reasons behind improved outcomes among patients who had a metabolic response and those who developed hand–foot skin reaction.

Sorafenib-Regorafenib Sequential Therapy in Japanese Patients with Unresectable Hepatocellular Carcinoma—Relative Dose Intensity and Post-Regorafenib Therapies in Real World Practice

“…As favorable clinical factors associated with OS in regorafenib therapy, we revealed that 1M-RDI ≥ 50% (HR 0.16, 95% CI 0.05–0.50, p = 0.001) and HFSR during regorafenib therapy (HR 0.06, 95% CI 0.01–0.28, p = 0.0004) were independently associated with OS. Previous studies [23,24,25] reported that patients with metastatic colorectal cancer who were treated with regorafenib—and who experienced HFSR—showed better OS than patients without HFSR. The correlation of HRSR and survival has also been reported in the patients who enrolled the RESORCE trial [26].…”

Effect of risk factors for acneiform rash induced by anti-epidermal growth factor receptor antibody drugs on survival: a retrospective observational study

“…A characteristic side effect of regorafenib is hand-foot skin reaction. Various studies have reported on the relationship between the grade of hand–foot skin reaction caused by regorafenib and survival time [ 17 , 18 ] and the prognostic factors that affect survival time [ 18 ]. In particular, a Phase IIb study on patients with metastatic CRC treated with regorafenib reported that patients with ≥ grade 2 hand–foot skin reaction have longer survival times than patients with grade 0–1 hand–foot skin reaction [ 17 ].…”

Evolving role of regorafenib for the treatment of advanced cancers

“…Notably, in CORRECT, all patients received prior bevacizumab and 52% received prior anti-EGFR therapy versus 41% and 35%, respectively, in CONCUR, which may contribute to the greater OS benefit in CONCUR [3,4,27]. More recently, a single-arm, phase 2b study evaluating regorafenib in antiangiogenic-naïve patients with chemotherapy-refractory, advanced CRC reported a median PFS and OS of 3.5 and 7.4 months, respectively [28], consistent with CONCUR, but comparing favorably with CORRECT. In the randomized, phase 2 REVERCE study, previously treated patients with mCRC receiving regorafenib followed by cetuximab (plus irinotecan) had better survival outcomes versus cetuximab followed by regorafenib, supporting the rationale for introducing regorafenib earlier in the treatment sequence [29].…”