Regorafenib and Nivolumab or Pembrolizumab Combination and Circulating Tumor DNA Response Assessment in Refractory Microsatellite Stable Colorectal Cancer

Abstract

Background Metastatic colorectal cancers (MCRCs) with microsatellite stability (MSS) are resistant to immunotherapy with programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 inhibitors. However, the addition of regorafenib to nivolumab was recently associated with a high response rate and a protracted progression‐free survival in a small cohort of MSS Japanese patients with metastatic colorectal cancer. Materials and Methods We evaluated the outcome of patients with MSS metastatic colorectal cancer who were treated on a compassionate basis with PD‐1 inhibitors in combination with regorafenib in a single U.S. center. Results A total of 18 patients were treated with a combination of regorafenib and PD‐1 inhibitors. No treatment‐related grade 3 or above toxicities were noted. Thirteen patients (69%) had progressive disease, and five patients (31%) experienced stable disease as best response. Four out of five stable diseases occurred in patients without liver metastases, whereas only 1 of 14 patients with history of liver metastases had a short disease stabilization. A rise in circulating tumor DNA (ctDNA) at the 4‐week time pointuniversally predicted tumor progression at 2 months, whereas a decline was associated with radiographic disease stabilization. Conclusions Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy‐resistant metastatic colorectal cancer. Selection for patients without history of liver metastases may identify a cohort of patients with MSS colorectal cancer with a higher likelihood of benefit from this combination. ctDNA may represent a powerful tool for predicting early therapeutic efficacy of immunotherapy in the MSS colorectal cancer population. Implications for Practice This study showed that the combination of regorafenib and nivolumab was associated with a modest clinical activity in patients with advanced microsatellite stability (MSS) metastatic colorectal cancer. This combination should be avoided in clinical practice, especially in patients with MSS colorectal cancer with liver metastases. Further investigation of regorafenib plus PD‐1 inhibitors should be considered in MSS colorectal cancer without liver metastases.

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

“…Regorafenib (80 mg) has been proven the recommended doses to add to nivolumab in the expanded cohort. Although toxicity was similar to the Japanese study REGONIVO, very modest efficacy was reported with no objective responses [122]. Intrinsic genetic differences between the Asian and the Caucasian populations have been suggested as an explanation for these heterogeneous results, though in the absence of a clear functional hypothesis [29].…”

“…Safety data were consistent across these studies highlighting that regorafenib at the dose of 160 mg was associated with a high incidence of severe adverse events [28,36,121,122]. This is not surprising in the light of the escalating flexible dosing approach currently recommended and widely adopted in the daily clinical practice.…”

“…A small population of 28 chemo refractory pMMR mCRC patients received the same regimen in a U.S. phase I/Ib trial, including 12 patients in the phase I cohort (according to dose escalation of 80 or 120 mg or 160 mg of regorafenib) and 16 patients in the expanded cohort [122].…”

The Efficacy and Safety of Regorafenib in Combination With Anti-PD-1 Antibody in Refractory Microsatellite Stable Metastatic Colorectal Cancer: A Retrospective Study

“…Many centers all over the world are adopting the combination of regorafenib and ICI with a compassionate purpose for patients. However, a recent retrospective study of 18 patients including five Asians in a USA cancer center failed to reveal comparable clinical activity of regorafenib plus nivolumab (11). The authors proposed that this combination strategy should be avoided in clinical practice especially in pMMR/MSS mCRC patients with liver metastases (11).…”

“…However, a recent retrospective study of 18 patients including five Asians in a USA cancer center failed to reveal comparable clinical activity of regorafenib plus nivolumab (11). The authors proposed that this combination strategy should be avoided in clinical practice especially in pMMR/MSS mCRC patients with liver metastases (11). Obviously, more evidence assessing this combination strategy is needed before the completion of conclusive Phase III studies.…”