Regorafenib: Strong Case in GIST, Less So in Colorectal Cancer

Zosia Chustecka

November 22, 2012

Pivotal clinical trial data from 2 studies of the oral targeted agent regorafenib (Stivarga, Bayer) were published online November 22 in the Lancet. The effectiveness of regorafenib is demonstrated in patients with colorectal cancer and in patients with gastrointestinal stromal tumors (GIST).

These data support the recent approval by the US Food and Drug Administration of regorafenib for patients with metastatic colorectal cancer, and the application for its use in GIST, which has just been given priority review.

In an accompanying comment, a pair of experts conclude that there is a "strong" case for regorafenib in the treatment of GIST in patients who have failed imatinib (Gleevec) and sunitinib (Sutent), which are the other approved options. However, the case for its use in metastatic colorectal cancer is "less compelling," write Tom Waddell, MD, and David Cunningham, MD, FRCP, both from the Royal Marsden Hospital, Sutton, Surrey, United Kingdom.

Paradoxically, these recommendations seem to go against the evidence; there was no overall survival benefit in the GIST trial but there was in the colorectal cancer trial.

Use in Colorectal Cancer

The metastatic colorectal cancer trial, known as CORRECT, involved 760 patients who had progressed on all approved standard therapies. These include chemotherapy (fluoropyrimidine, oxaliplatin, and irinotecan), the vascular endothelial growth-factor monoclonal antibody bevacizumab (Avastin), and, for patients who have wild-type KRAS tumors, the epidermal growth-factor receptor monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix).

Participants had progressed during or within 3 months of the last standard therapy, or had stopped taking standard therapy because of unacceptable adverse effects. They all received best supportive care and were randomized in a 2:1 ratio to receive regorafenib or placebo. The treatment regimen consisted of oral regorafenib 160 mg daily for 3 weeks, followed by a 1-week break; this was repeated as necessary.

There was a significant improvement in overall survival with regorafenib, compared with placebo (6.4 vs 5.0 months; hazard ratio [HR], 0.77; P = .0052). There was also a significant improvement in progression-free survival (1.9 vs 1.7 months; HR, 0.49; P < .0001) and disease control (41% vs 15%; P < .0001) with regorafenib.

This is the first time a significant benefit in overall survival has been seen in patients with treatment-refractory metastatic colorectal cancer treated with a small-molecule kinase inhibitor, note the study authors, headed by Axel Grothey, MD, from the Mayo Clinic in Rochester, Minnesota. (Such an effect has been seen with bevacizumab, but it is administered by intravenous infusion.)

"In view of these findings, regorafenib could be a new standard of care in late-stage metastatic colorectal cancer," the authors conclude.

"We find it difficult to agree with the authors' conclusion," Drs. Waddell and Cunningham write in their comment.

They point out that the median improvement in overall survival was only 1.4 months and in progression-free survival was only 0.2 months. "The clinical benefits are modest," they write.

There is also a price to pay for this small benefit — literally; the initial cost of the drug is $9350 per 28-day cycle. In addition, more patients in the regorafenib group experienced grade 3 or 4 toxic effects than in the placebo group (54% vs 14%), Drs. Waddell and Cunningham note. These include hand–foot skin reaction, fatigue, diarrhea, hypertension, rash, or desquamation.

The curves for progression-free survival show that more than half of the patients had progressed by the computed tomography assessment at 8 weeks, they report. "Therefore, despite receiving treatment that would now cost almost $20,000 each, many patients did not seem to derive benefit from therapy but were exposed to potentially substantial toxic effects," they add.

The case for using this drug in metastatic colorectal cancer would be "greatly enhanced by the identification of a biomarker that allows selection of the subset of patients who really benefit from regorafenib," they conclude.

The study authors report that an analysis of biomarkers is currently underway.

Strong Case in GIST

Drs. Waddell and Cunningham appear to be more impressed with the outcomes in the GIST trial, which is known as GRID (GIST – Regorafenib in Progressive Disease).

GRID, which was headed by George Demetri, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, involved 199 patients with metastatic or unresectable GIST who had progressed after treatment with imatinib and sunitinib. Patients were treated with best supportive care and randomized in a 2:1 ratio to the same regimen of regorafenib as was used in the CORRECT trial or to placebo.

There was a statistically significant improvement in progression-free survival with regorafenib, compared with placebo (4.8 vs 0.9 months; HR, 0.27; P < .0001). Drs. Waddell and Cunningham note that there was a "much earlier separation of curves" in the GIST trial than in the colorectal cancer trial.

However, in the GIST trial, there was no significant difference in overall survival, which Drs. Waddell and Cunningham explain was "probably attributable to planned extensive crossover to regorafenib" (85% of patients in the placebo group went on to take regorafenib when their disease progressed).

Nevertheless, they conclude that there is a "strong" case for the routine use of regorafenib in patients who have failed imatinib and sunitinib.

Both studies were sponsored by Bayer, the manufacturer of regorafenib. Dr. Grothey reports acting as a consultant for Genentech, Roche, Onyx, Bayer, Imclone, Bristol-Myers Squibb, and Sanofi, with honoraria from these, as well as research funding for clinical studies, all going to the Mayo Clinic. Dr. Demetri reports serving as a consultant to Novartis, Pfzier, Lilly, Infinity, GlaxoSmithKline, Plexxikon, Koltan, and Blueprint Medicines. Several coauthors of the 2 papers report being employed by Bayer or report relationships with pharmaceutical companies, as detailed in the papers. Dr. Waddell has disclosed no relevant financial relationships. Dr. Cunningham's research unit has received funding from Amgen, Roche, Celgene, AstraZeneca, Merck-Serono, and sanofi-aventis.

Lancet. Published online November 22, 2012. CORRECT abstract, GRID abstract, Comment