Bayer HealthCare, a subgroup of Bayer AG, has reported positive data from the phase III GRID (GIST – Regorafenib In Progressive Disease) trial evaluating its investigational drug regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumour (GIST) whose disease had progressed despite prior treatment with imatinib and sunitinib.

Regorafenib significantly improved progression-free survival (PFS) over placebo (HR=0.27, p<0.0001), which means a 73 per cent reduction in the risk of progression or death. The median PFS was 4.8 months in the regorafenib arm versus 0.9 months in the placebo arm. Furthermore, regorafenib demonstrated a significantly greater disease control rate (DCR, defined as rate of partial response [PR] plus durable stable disease [SD] lasting for at least 12 weeks) compared to placebo (52.6 per cent vs. 9.1 per cent; p<0.000001). In addition, there was a positive trend in the regorafenib group in improving overall survival (OS) (HR=0.77, p=0.20). The OS results were not statistically significant, which was expected due to the cross-over design of the study.

These data will be presented as a late-breaking abstract in an oral abstract session at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois (USA) (LBA No. 10008).

“GIST continues to represent an area of unmet patient need, given the aggressive nature of the disease after resistance emerges to the standard targeted therapies,” said George Demetri, MD, director of the Ludwig Center at the Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (USA), principal investigator and chair of the Steering Committee for the GRID trial. “These data from the GRID study support regorafenib as an important advance in helping control this difficult-to-treat cancer in patients after failure of standard molecular targeted therapies.”

Additionally, new data from the phase III CORRECT (Colorectal cancer treated with regorafenib or placebo after failure of standard therapy) trial analyzing the subgroups were presented in an oral abstract session at the 2012 ASCO Annual Meeting. The study evaluated regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic colorectal cancer (mCRC) whose disease has progressed after currently approved standard therapies. The study results showed that regorafenib plus BSC significantly improved both overall survival and progression-free survival, compared to placebo plus BSC. New data from CORRECT showed a positive trend of survival benefit (OS and PFS) in the regorafenib arm across nearly all subgroups analyzed. In particular, the benefit of regorafenib was demonstrated in both patients with KRAS wild-type tumor and those with KRAS mutant tumor (Abstract No. 3502).

“These data show regorafenib’s potential across various cancer types, first in CRC and now in GIST,” said Kemal Malik, MD, Head of Global Development and member of the Bayer HealthCare Executive Committee. “We are committed to researching treatments, particularly for patients who have exhausted available therapies and urgently need new options.”

Bayer has submitted a Marketing Authorization Application to the European Medicines Agency (EMA) and a New Drug Application to the US Food and Drug Administration (FDA) for the oral multi-kinase inhibitor regorafenib for the treatment of patients with mCRC. Bayer plans the first submissions of regorafenib for marketing authorization in GIST in the second half of 2012.

GRID was a randomized, double-blind, placebo-controlled, multi-center, cross-over phase III study of regorafenib for the treatment of GIST. It randomized 199 patients whose disease had progressed despite prior treatment with imatinib and sunitinib. Patients were randomized in a 2:1 ratio to receive either regorafenib (160 mg once daily, three weeks on/one week off) plus BSC or placebo plus BSC to evaluate efficacy and safety. The primary endpoint of this trial was PFS, and secondary endpoints included OS, time to progression, disease control rate, tumour response rate, and duration of response. Patients initially randomized to placebo were allowed to cross over to open-label regorafenib once the disease progressed, which 85 per cent of the patients from the placebo arm did.

The overall safety and tolerability profile for regorafenib in the GRID study was consistent with results from previous studies. There were no new or unexpected safety concerns with regorafenib. The most common drug-related, treatment-emergent adverse events (occurring in at least 10 per cent of patients) included hand-foot skin reaction (56.1 per cent vs. 15.2 per cent), hypertension (48.5 per cent vs. 16.7 per cent), diarrhoea (40.9 per cent vs. 7.6 per cent), fatigue (38.6 per cent vs. 27.3 per cent), oral mucositis (37.9 per cent vs. 9.1 per cent), alopecia (23.5 per cent vs. 3.0 per cent), hoarseness (22.0 per cent vs. 4.5 per cent), anorexia (20.5 per cent vs. 7.6 per cent), rash maculopapular (18.2 per cent vs. 3.0 per cent), nausea (15.9 per cent vs. 9.1 per cent), constipation (15.2 per cent vs. 7.6 per cent), myalgia (13.6 per cent vs. 9.1 per cent), and voice alteration (11.4 per cent vs. 3.0 per cent) for patients receiving regorafenib as compared to placebo.

The phase III study CORRECT randomized 760 patients with metastatic colorectal cancer (mCRC) whose disease had progressed after currently approved standard therapies to receive regorafenib plus BSC or placebo plus BSC at a 2:1 ratio. Treatment cycles consisted of 160 mg of regorafenib (or matching placebo) once daily for three weeks on / one week off plus BSC. The primary endpoint of this trial was OS. Secondary endpoints included PFS, objective tumor response rate and disease control rate. The safety and tolerability of the two treatment groups were also compared. Primary efficacy and safety data for this trial were reported earlier this year at the Annual Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology (ASCO-GI) in January 2012. The results presented at ASCO 2012 included new data from the subgroup analysis, including data on the patient’s tumour KRAS mutation status.

Regorafenib is an investigational, oral, multi-kinase inhibitor targeting three key mechanisms of tumour growth and progression – angiogenesis, oncogenesis, and the tumour microenvironment. In preclinical studies, regorafenib inhibits several angiogenic VEGF receptor tyrosine kinases that play a role in tumor neoangiogenesis and lymphangiogenesis (the growth of new blood vessels and lymphatic vessels). It also inhibits various oncogenic and tumour microenvironment kinases including KIT, RET, PDGFR, and FGFR, which individually and collectively impact upon tumor growth, formation of a stromal microenvironment and disease progression. Regorafenib is currently being investigated in clinical trials for its potential to treat patients with various tumour types.

Regorafenib is an investigational agent and is not approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) or other health authorities.

In 2011, Bayer entered into an agreement with Onyx Pharmaceuticals, Inc. under which Onyx will receive a royalty on any future global net sales of regorafenib in oncology.