Elsevier

The Lancet

Volume 381, Issue 9863, 26 January–1 February 2013, Pages 295-302
The Lancet

Articles
Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(12)61857-1Get rights and content

Summary

Background

Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib.

Methods

We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01271712.

Results

From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4–9·2) for regorafenib and 0·9 months (0·9–1·8) for placebo (hazard ratio [HR] 0·27, 95% CI 0·19–0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%).

Interpretation

The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients.

Funding

Bayer HealthCare Pharmaceuticals.

Introduction

Gastrointestinal stromal tumours (GIST) are the most common sarcomas arising in the gastrointestinal tract. Worldwide, the annual incidence of GIST is about 10 cases per million people,1 corresponding to at least 8000 new cases per year in Europe. Early-stage disease can be surgically resected, but more than 40% of cases recur and metastasise.2

Cytotoxic chemotherapy, although active in other subtypes of sarcomas, is ineffective in metastatic GIST.3, 4 Elucidation of GIST molecular pathophysiology as a mutation-driven cancer has facilitated the development of targeted kinase-inhibitor therapies that have revolutionised treatment options and clinical outcomes for this malignancy.5 About 85% of GIST are caused by gain-of-function mutations in the proto-oncogene KIT,6 which encodes a tyrosine-kinase receptor. These mutations result in constitutive ligand-independent activation of KIT intracellular signalling.1, 7, 8 Roughly 8% of metastatic GIST are associated with gain-of-function mutations in the structurally similar tyrosine-kinase receptor gene PDGFRA, encoding the platelet-derived growth factor receptor α.6, 8, 9 Other rare subtypes of GIST exist that harbour no mutations in KIT or PDGFRA, but are probably driven by other mutations in genes such as BRAF, NF1, or those encoding subunits of the succinate dehydrogenase (SDH) complex.9

Imatinib mesylate, a selective tyrosine-kinase inhibitor of KIT, PDGFRA, and ABL, significantly improves clinical outcomes in GIST both as therapy for advanced metastatic disease and in the postsurgical adjuvant setting.10, 11, 12, 13 However, imatinib therapy is limited by primary resistance to the drug in about 15% of patients,5, 14, 15, 16 and more than 80% of patients eventually develop disease progression driven by secondary resistance mutations located in KIT exons.16, 17, 18, 19, 20

The first drug shown definitively to provide clinical benefit in GIST after resistance to imatinib was sunitinib malate, which has more potent activity against the wild-type KIT kinase than the first-line treatment, imatinib, and also inhibits several other signalling pathways related to tyrosine-kinase receptors, including the vascular endothelial growth factor receptors (VEGFR1 [also known as FLT1], VEGFR2 [KDR], and VEGFR3 [FLT4]), Fms-like tyrosine kinase-3 (FLT3), and the receptor encoded by the proto-oncogene RET.21, 22, 23, 24, 25 A randomised, placebo-controlled phase 3 trial assessing sunitinib in imatinib-resistant patients showed a significant improvement in median time to tumour progression for sunitinib compared with placebo (all patients also received best supportive care).26 However, clinical progression and drug resistance to sunitinib subsequently evolve, generally within 1 year of treatment, and up to now, no other effective therapy has been developed for tyrosine-kinase inhibitor-resistant GIST. Structural biology studies have explained that the smaller sunitinib molecule shows activity in patients who are imatinib-resistant because sunitinib is able to avoid steric hindrance by gatekeeper mutations that block entrance of the larger imatinib molecule to the ATP-binding pocket of the KIT protein.27

Regorafenib is a novel, oral multikinase inhibitor that blocks the activity of several protein kinases, including those involved in the regulation of tumour angiogenesis (VEGFR1–3 and TEK), oncogenesis (KIT, RET, RAF1, BRAF, and BRAFV600E), and the tumour microenvironment (PDGFR and FGFR).28 In preclinical studies, regorafenib showed antitumour activity against human GIST and other tumour models.28

After the phase 1 study that defined the safety, tolerability, and recommended dose of regorafenib in unselected patients with solid tumours,29 a phase 2 multicentre trial was designed and done under independent academic sponsorship to assess regorafenib in patients with GIST with metastatic disease, after failure of at least previous imatinib and sunitinib.30 In that phase 2 study, regorafenib showed activity against tyrosine-kinase inhibitor-resistant GIST, including some partial responses, a high occurrence of durable stable disease, and median progression-free survival (PFS) of 10 months, along with the expected incidence of grade 3 toxic effects of hypertension and hand-foot skin reaction.30 On the basis of these data and the preclinical rationale of targeting the pathogenic mutant kinases with a structurally distinct small-molecule inhibitor, we did this phase 3 trial (GIST—regorafenib in progressive disease [GRID]) to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST, progressing after failure of at least previous imatinib and sunitinib. We report the efficacy and safety results of this trial; quality-of-life data were collected and will be reported separately and a final analysis of overall survival will be done when approximately 136 events have been recorded.

Section snippets

Study design and participants

We did this randomised, placebo-controlled, multicentre, phase 3 trial at 57 hospital sites in 17 countries (Austria, Belgium, Canada, China, Finland, France, Germany, Israel, Italy, Japan, Netherlands, Poland, Singapore, South Korea, Spain, UK, and USA).

Eligibility criteria included histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib (defined as either disease progression or intolerance) and previous sunitinib (defined solely as progression to

Results

Between Jan 04, and Aug 18, 2011, 240 patients were screened and 199 patients were randomised to receive regorafenib (n=133) or placebo (n=66; figure 1). One patient randomised to the regorafenib group died before receiving study treatment. Baseline characteristics and previous treatments were much the same between the two groups, although by chance a higher proportion of patients in the placebo group had received imatinib therapy for more than 18 months than in the regorafenib group (table 1);

Discussion

When added to best supportive care, regorafenib significantly improves PFS in a population of patients with GIST with progressive disease after failure of all approved previous therapies, compared with matching placebo. Median PFS with regorafenib was more than five times that with placebo, reducing the risk of progression or death by 73%. Although the regorafenib group might have included patients with more indolent disease, we believe that the robust results argue against any such confounding

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    Primary investigators from all participating centres are listed in the appendix

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