First-in-human trial of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab in advanced cancer patients

Abstract

BACKGROUND. The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC). METHODS.Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC. Comprehensive genomic profiling was performed on the exceptional responder. RESULTS.Among the 27 patients enrolled the median age was 54 years. None of 19 patients treated at dose level 1 (cetuximab i.v. 200 mg/m 2 followed by 150 mg/m 2 weekly + regorafenib 80 mg daily) experienced a DLT, and 2 of 5 patients treated at dose level 2 (cetuximab i.v. 200 mg/m 2 followed by 150 mg/m 2 weekly + regorafenib 120 mg daily) experienced a DLT (grade 3 thrombocytopenia [n = 1] and grade 3 intra-abdominal bleed [n = 1]). Most common adverse events were grade 1 or 2 rash (20 patients). Of 24 evaluable patients, 11 (46%) patients had clinical benefit (stable disease > 6 cycles or partial response [PR]) (CRC n = 8, one patient each with head and neck cancer, carcinoma of unknown primary, and glioblastoma). A CRC patient, who progressed on anti-EGFR and regorafenib, achieved a PR (46% decrease per RECIST v1.1) lasting 15 months. Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI). CONCLUSION.Regorafenib 80 mg daily plus cetuximab 200 mg/m 2 loading dose, followed by 150 mg/m 2 every week is the MTD/recommended phase II dose. The combination demonstrated early signals of activity in wild-type CRC, including 1 exceptional responder with MSI high.

A phase 1b study evaluating the safety and pharmacokinetics of regorafenib in combination with cetuximab in patients with advanced solid tumors

“…17%, respectively) . Notably, although a DLT of grade 3 thrombocytopenia was reported with regorafenib plus cetuximab in the trial by Subbiah et al ., only one case of grade ≥3 platelet count decrease was reported in our study, which was observed in the context of fatal liver failure and disseminated intravascular coagulation.…”

“…A recently published phase 1 combination trial by Subbiah et al ., of regorafenib plus cetuximab in 27 patients with advanced cancer refractory to several lines of therapy, described a considerably lower dose (regorafenib 80 mg QD plus cetuximab 200 mg/m 2 loading dose, followed by cetuximab 150 mg/m 2 weekly) as the MTD . At this dose, no DLTs were observed in the 19 evaluable patients; however, two DLTs (grade 3 thrombocytopenia in a patient with glioblastoma and grade 3 intra‐abdominal bleeding in a patient with CRC) were reported in five evaluable patients at the higher dose of regorafenib 120 mg QD plus cetuximab 200 mg/m 2 loading dose followed by 150 mg/m 2 weekly.…”

“…Furthermore, in vivo preclinical data have demonstrated decreased angiogenesis and increased tumor and endothelial cell apoptosis with combined inhibition of VEGF and EGFR . In a recently published phase 1 study of regorafenib plus cetuximab in patients with metastatic cancer refractory to standard therapies, regorafenib 80 mg QD plus cetuximab 200 mg/m 2 loading dose, followed by cetuximab 150 mg/m 2 every week, was determined as the MTD and demonstrated preliminary activity in mCRC …”

Reactive oxygen species and colorectal cancer

“…Besides, the usage of bevacizumab induces the ECM remodeling which promote the drug delivery (Rahbari et al, ). Recently, the combination of multikinase VEGF inhibitor regorafenib and anti‐EGFR antibody cetuximab show a promising results in CRC treatment (Subbiah et al, ). Jung et al () indicated that through blocking ROS‐mediated VEGFR2 signaling pathways in endothelial cells (ECs), VEGF‐dependent angiogenesis was suppressed both in vitro and in vivo.…”

A Systematic Review and Meta-analysis of Retrospective Series of Regorafenib for Treatment of Metastatic Colorectal Cancer

“…In this respect, an exceptional response to regorafenib was reported in a patient with metastatic colorectal cancer and a mutation in the KDR gene encoding for VEGFR2 (32). This patient had an ongoing PR for over 9 months at the time of the report, despite being able to tolerate only a reduced dose of 40 mg. Another prolonged PR of 15 months as well as SD for over 20 months were observed in two patients participating in a phase I trial of the combination of regorafenib with cetuximab (33). Disease in both patients had previously progressed on each drug alone.…”