Regorafenib in Combination with First-Line Chemotherapy for Metastatic Esophagogastric Cancer

Abstract

Background Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first‐line chemotherapy in metastatic esophagogastric cancer. Materials and Methods Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5‐fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14‐day cycle. The primary endpoint was 6‐month progression‐free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS. Results Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single‐center phase II study (NCT01913639). The most common grade 3–4 treatment‐related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6‐month PFS was 53% (95% confidence interval [CI], 38%–71%), the objective response rate was 54% (95% CI, 37%–70%), and the disease control rate was 77% (95% CI, 67%–94%). Next‐generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum‐based chemotherapy. Conclusion Regorafenib (one week on–one week off schedule) is well tolerated in combination with first‐line FOLFOX but does not improve 6‐month PFS relative to historical control. Implications for Practice Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first‐line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD‐1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.

Regorafenib inhibits migration, invasion, and vasculogenic mimicry of hepatocellular carcinoma via targeting ID1‐mediated EMT

“…In the past 3 years, lots of studies have focused on the antiproliferation and antiapoptosis of regorafenib in HCC cells, and its mechanisms involve in the inhibition of ERK/nuclear factor kappa B activation, Bcl‐xL/Mcl‐1 ratio, and Cyclin E1/Mcl‐1 signaling pathway, and so forth 30–32 . Importantly, regorafenib was approved for refractory mCRC in 2013, and a number of recent clinical trials for regorafenib were carried out in metastatic malignancies 11–13 . Nonetheless, the role of regorafenib in HCC metastasis and related mechanisms are still unclear.…”

“…[30][31][32] Importantly, regorafenib was approved for refractory mCRC in 2013, and a number of recent clinical trials for regorafenib were carried out in metastatic malignancies. [11][12][13] Nonetheless, the role of regorafenib in HCC metastasis and related mechanisms are still unclear. In the present study, we found that regorafenib effectively refrained VM formation, migration, and invasion in HCC cells.…”

“…Regorafenib could reverse epithelial‐to‐mesenchymal transition (EMT) in mCRC 10 . In recent years, clinical trials of regorafenib in metastatic esophagogastric cancer, osteosarcoma and pancreatic cancer had been carried out 11–13 . Nonetheless, whether regorafenib inhibits HCC metastasis is poorly understood.…”

Molecular pathogenesis and emerging targets of gastric adenocarcinoma

“…They found that while the drug was safe to give with the FOLFOX regimen, there was no benefit to the PFS in this cohort. 76 There are several clinical trials underway testing the efficacy of this drug in combination with other chemotherapies for gastric cancer (NCT03722108, NCT02406170, and NCT03627728) Several other trials using antiangiogenic therapy were less successful in GC. The AVAGAST and AVATAR trials showed no additional benefit to OS with bevacizumab (anti-VEGF antibody) added to standard of care.…”

Evolving role of regorafenib for the treatment of advanced cancers

“…Studies evaluating regorafenib combined with chemotherapy in other settings have produced varied results. A phase 1, doseescalation study in pretreated patients with metastatic esophageal/GC showed promising effects on survival with regorafenib combined with paclitaxel [59], while a phase 2 study of regorafenib combined with FOLFOX failed to meet the prespecified endpoint of 6-month PFS [60]. Several other novel targeted therapies have been evaluated in clinical studies, but only trastuzumab and ramucirumab ( ± paclitaxel) have demonstrated an OS benefit in the first-and second-line setting, respectively [61,62].…”