In Refractory GIST, Regorafenib Delays Disease Progression Across All Subgroups

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Regorafenib significantly delays disease progression in virtually all subgroups of patients with GIST in the second-line setting, and may even confer benefits when continued after progression.

Peter Reichardt, MD, PhD

The multi-tyrosine kinase inhibitor regorafenib significantly delays disease progression in virtually all subgroups of patients with gastrointestinal stromal tumor (GIST) in the second-line setting, and may even confer benefits when continued after progression, according to subgroup and post-progression analyses of the phase III GRID trial presented at the ESMO 2012 Congress.

Previously, at the 2012 Gastrointestinal Cancers Symposium, investigators from the 199-patient GRID trial reported that regorafenib (Stivarga, Bayer) conveyed an almost 4-month improvement in progression-free survival (PFS) compared with placebo (J Clin Oncol. 2012;30 [suppl;abstract LBA10008]). Median PFS was 4.8 months with regorafenib versus 0.9 months with placebo. By investigator assessment, the benefit was even more pronounced; median PFS was 7.4 months and 1.7 months, respectively.

GRID randomly assigned patients (2:1) who were refractory to both imatinib and sunitinib to receive best supportive care plus either regorafenib 160 mg or placebo once daily (3 weeks on/1 week off). The primary endpoint was PFS. Upon progression, as determined by central review, the study was unblinded, and placebo recipients could cross over to receive regorafenib while those progressing on regorafenib could continue the drug if the treating physician deemed it might be beneficial.

The current exploratory analyses were presented at ESMO by Peter Reichardt, MD, PhD, of HELIOS Klinikum in Bad Saarow, Germany.

Reichardt first noted the overall impact of regorafenib on the whole population, citing the high rate of disease control, ie, response or durable stable disease for at least 12 weeks—52.6% versus 9.1% with placebo—“despite the low overall response rate with regorafenib (4.5%).”

He then reported that a positive impact on PFS was observed across virtually all pre-specified subgroups. Benefit was seen regardless of number of prior systemic therapies, geographical region, age, baseline ECOG performance score, duration of prior treatment with imatinib, or presence of KIT/PDGFRA mutation, he said.

“Interestingly, post-progression, open-label regorafenib treatment showed sustained benefit,” Reichardt reported. Continuing regorafenib after progression (n = 41) led to an additional 4.5 months of PFS; for placebo recipients who crossed over to regorafenib (n = 56), median PFS after unblinding was 5.0 months.

“This suggests that continuous kinase inhibition after progression may benefit patients by slowing tumor progression,” he said.

Overall survival rates were not statistically significantly different, as expected, since crossover occurred in the majority of the placebo arm. A method of statistical correction for crossover (rank-preserving structural failure time) did, however, demonstrate a significant beneficial impact of regorafenib on overall survival, he said.

Peter G. Maki, MD, PhD, professor of Medicine and Pediatrics at Mount Sinai School of Medicine, New York, commented that regorafenib helps meet the need for effective therapies for advanced GIST, which virtually always becomes refractory to current agents. “We would love to have more effective agents that wipe out the last few living tumor cells,” he said.

Maki said he would like to see regorafenib compared head-on with sunitinib in the second-line setting, or even with imatinib in the first-line setting. But before replacing sunitinib with regorafenib in the second line, “we need a trial to prove that regorafenib is superior,” he emphasized.

Regorafenib received FDA approval on Sept. 27, 2012 for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

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