Multikinase Inhibitor Regorafenib Research Articles

Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial

No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01103323. Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64-0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. Bayer HealthCare Pharmaceuticals.

IS3-7 - Randomized Phase 3 Trial of Regorafenib in Patients (Patients) with Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST) Progressing Despite Prior Treatment with at Least Imatinib (IM) and Sunitinib (SU) : Grid Trial

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and...

Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial

Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326. The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7-34·4, IQR 2·5-18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7-52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring.

LBA18 - Phase 3 Correct Trial of Regorafenib in Metastatic Colorectal Cancer (MCRC): Overall Survival Update

ABSTRACT Background The CORRECT trial was conducted to evaluate the oral multikinase inhibitor regorafenib (REG) in patients (pts) with mCRC whose disease had progressed after all approved standard therapies. This trial met its primary endpoint at a pre-planned interim analysis, the results of which were presented previously (J Clin Oncol 30, 2012 [suppl; abstr 3502]). The updated overall survival (OS) data are reported here. Methods Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive best supportive care plus either REG (160 mg od po) or placebo (PL) on a 3 weeks on/1 week off schedule. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate, and disease control rate. Safety and quality of life were also evaluated. Results From May 2010 to March 2011, 760 pts were randomized (REG: 505; PL: 255). Baseline characteristics were balanced between the two arms. A descriptive updated analysis of OS was performed, based on a database cutoff of Nov 13, 2011 with 566 total events (97% of events originally required). In this analysis, the hazard ratio (HR, REG/PL) for OS was 0.79 (95% CI, 0.66-0.94, 1-sided p = 0.0038). Median OS was 6.4 months (95% CI, 5.8-7.0) in the REG arm vs 5.0 months (95% CI, 4.4-5.9) in the PL arm. OS rate at 6 and 12 months was 52.2% and 24.1% in the REG arm vs 43.1% and 17% in the PL arm, respectively. These data serve as an update to previously reported OS data from the earlier interim analysis based on 432 (74%) events, which showed a HR for OS of 0.77 (95% CI, 0.64-0.94, 1-sided p = 0.0052). Pts in the REG arm received an average of 78.9% of the planned dose, and pts in PL arm 90.2% of the planned dose. The mean treatment duration was 12.1 ± 9.7 wks (REG) and 7.8 ± 5.2 wks (PL), respectively. Incidence of treatment-emergent, REG-related adverse events was similar in subgroups by age, sex, renal function and hepatic function, whereas the incidence was higher in Asian pts (98.6%) compared with Caucasian pts (92.3%), and higher in pts with a baseline ECOG score of 0 (97.0%) compared with pts with ECOG score of 1 (88.6%). Conclusions This updated OS analysis demonstrated the robustness and consistency of the OS benefit of REG treatment over PL in pts with previously treated mCRC. Disclosure E. Van Cutsem: Received research funding from Bayer A. Grothey: Mayo Clinic received research funding and honoraria for my consulting activity from Bayer, Genentech, Sanofi, Bayer, Daiichi, Imclone. Onyx and BMS A. Sobrero: Advisory board member and has spoken at symposia for: Roche, Merck, Bayer, Amgen, Sanofi S. Siena: Advisory board member for Amgen, AstraZeneca, Bayer, Genentech, Merck-Serono, Roche, Sanofi A. Falcone: Received honoraria from Bayer for speaking, consultancy and sitting on advisory boards. Also received research support from Bayer M. Ychou: Received honoraria from Bayer for sitting on advisory board Y. Humblet: Has received honoraria from Bayer to act as consultant. Has also received research funding from Bayer O. Bouche: Received honoraria from Roche, Merck-Sereno, Amgen L. Mineur: No conflicts of interest to declare C. Barone: Received honoraria for lecturing and advisory boards from Bayer, Merck, Roche, Novartis. Received honoraria for lecturing from GlaxoSmithKline, Amgen A. Adenis: Received honoraria from Bayer (conference and research funding) J. Tabernero: No conflicts of interest to declare T. Yoshino: Received consulting fee from Takeda; honoraria from Chugai, Takeda, Yakult, Bristol-Meyers Squibb and Merck-Serono; research funding from Daiichi Sankyo, Taiho, Bayer and Imclone H-J. Lenz: No conflicts of interest to declare R. Goldberg: Research support to hip State University from Sanofi, Bayer, Myriad, Jennerex. Consulting (unpaid) for Bayer, Sanofi. Payment for a Data Safety Monitoring Board, Lilly D. Sargent: Consulting fees from the CORRECT steering committee of F. Cihon: Employee of Bayer (sponsor of the study) L. Cupit: Employee of Bayer (sponsor of the study) A. Wagner: Employee of Bayer (sponsor of the study) D. Laurent: Employee of Bayer (sponsor of the study) All other authors have declared no conflicts of interest.

Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and correlative genotype analyses. At time of PD, pts were eligible for unblinding and crossover to open-label REG. Results: Between Jan and Aug of 2011, 234 pts were screened; 199 were randomized (REG: 133, PL: 66). Pts were stratified at randomization according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms. The primary endpoint was met: median PFS was 4.8 months for REG vs. 0.9 months for PL. Hazard ratio for PFS was 0.27 (95% CI, 0.18-0.39), p<0.0001. PFS rates at 3 and 6 months were 60% and 38% for REG vs. 11% and 0% for PL. DCR was 53% (REG) vs. 9% (PL).The HR for OS was 0.77 (p=0.20) with 85% PL pts having crossed over to REG. The most common > grade 3 treatment-emergent AEs in the REG arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%). Conclusions: This randomized trial demonstrated that REG significantly improved PFS and DCR in pts with advanced GIST after failure of at least prior IM and SU. REG was well tolerated, with AEs as expected for this class and manageable with dose modifications.

6576 POSTER Phase II Safety Study of the Oral Multikinase Inhibitor Regorafenib (BAY 73-4506) as Second-line Therapy in Patients With Hepatocellular Carcinoma

6576 POSTER Phase II Safety Study of the Oral Multikinase Inhibitor Regorafenib (BAY 73-4506) as Second-line Therapy in Patients With Hepatocellular Carcinoma

7141 POSTER Phase II Trial of the Oral Multikinase Inhibitor Regorafenib (BAY 73-4506) as First-line Therapy in Patients With Metastatic or Unresectable Renal Cell Carcinoma (RCC)

7141 POSTER Phase II Trial of the Oral Multikinase Inhibitor Regorafenib (BAY 73-4506) as First-line Therapy in Patients With Metastatic or Unresectable Renal Cell Carcinoma (RCC)