SAN FRANCISCO—Regorafenib prolonged overall survival in patients with advanced colorectal cancer who had disease progression on standard therapies, researchers reported here at the Gastrointestinal Cancer Symposium. The data from the phase III, randomized, placebo-controlled study (Abstract LBA385) showed that patients taking regorafenib lived 29% longer than those taking placebo.
“Regorafenib is likely to join the list of useful therapeutics for colorectal cancer,” said the study's Discussant, Herbert Hurwitz, MD, Associate Professor of Oncology at Duke University School of Medicine.
A total of 760 patients were enrolled in the company-sponsored regorafenib trial. Patients were randomly assigned, in a 2:1 fashion, to 160 mg of oral regorafenib daily for three weeks of a four-week cycle plus best supportive care or placebo plus best supportive care.
At a preplanned interim analysis, with 432 deaths, there was a 23% reduction in the risk of death with regorafenib therapy and an increase in median overall survival from 5.0 months in the placebo arm to 6.4 months with regorafenib. Both measures reached statistical significance, and the data safety monitoring board recommended closing the trial to allow for crossover, which was not included in the original trial design.
Few patients had objective responses with regorafenib treatment (1.0% in regorafenib arm versus 0.4% in placebo arm), although stable disease was common (43.8% vs. 15.3%). “The strength of this drug is more in delaying tumor progression than in inducing tumor shrinkage,” said the lead researcher, Axel Grothey, MD, Professor of Oncology at the Mayo Clinic. Therefore, he suggested, it would be worth testing regorafenib as a maintenance drug in earlier disease settings.
The Kaplan-Meier progression-free survival curves were unusual as well. The median progression-free survival was nearly identical in the two arms, at 1.9 months in the regorafenib group and 1.7 months in the placebo group. By contrast, the Kaplan-Meier curves show a clear separation for approximately half of the patients.
“These curves run together for about 50% of patients and then spread out wide, with a hazard ratio of 0.49 and a strongly significant p-value,” he said. “The median difference in progression-free survival does not fully reflect the efficacy of this drug in this patient population.”
Subgroup Benefits from Regorafenib
Asked in an interview about the shape of the curves, he said, “Whenever we see progression-free survival curves riding together so long and then splitting, it implies that only a certain subset of patients are benefiting. We are looking at a lot of different biomarkers right now in serum and tumor samples [to identify the subgroup of patients who are benefiting].” Preliminary analyses suggest that KRAS mutation status does not affect the likelihood of benefit from regorafenib.
The Chair of the Symposium Steering Committee, Richard M. Goldberg, MD, Physician-in-Chief at Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital, said, “One of the things that looks amazing about [the regorafenib progression-free survival curve] is it looks like the single-agent panitumumab curves and single-agent cetuximab curves—curves that were unprecedented when they were first published.”
As is now well known, patients whose tumors are KRAS wild-type benefit from panitumumab and cetuximab, while those with KRAS mutations do not. “I suspect there is a subset of patients who respond to regorafenib,” he continued.
Both Goldberg and Grothey cautioned, though, that it will likely be more difficult to identify the subgroup of patients benefiting from regorafenib than it was with panitumumab and cetuximab. Regorafenib, which is structurally related to sorafenib, blocks VEGF receptor, PDGF receptor, FGF receptor, KIT, RAS, and RAFs to varying degrees. By contrast, the anti-EGFR antibodies are specific for that one pathway.
“When you look at promiscuity of this drug, it clearly will not be just one target that will be a biomarker for regorafenib activity,” Grothey told OT. “I would think a more likely biomarker will be a signature, with one pathway or a combination of pathways that are activated.
In addition, he noted, some of the unusual shape of the regorafenib progression-free survival curve may be due to the very late stage of the patients enrolled in the trial – i.e., some patients enrolled may have been too sick to benefit from regorafenib.
Side Effects Tolerable
No unexpected toxicities occurred with regorafenib. The most common Grade 3 or higher side effect was hand-foot syndrome (16.6% with regorafenib vs. 0.4% with placebo) and fatigue (15.4% vs. 10.3%). Grade 3 anorexia was similar in the two groups (4.4% vs. 4.3%); however, there was one death attributed to anorexia in the regorafenib group.
Grade 3 hypertension (7.4% vs. 0.8%) and diarrhea (8.4% vs. 2.0%) were also more common in regorafenib-treated patients compared with those receiving placebo.
Grothey noted that most of these side effects could be managed with dose adjustments, and that most patients were able to remain on therapy with dose reductions until disease progression.
However, not everyone thought the side effect profile was so benign: “I would be a bit concerned about fatigue. These are end-stage patients,” said Cathy Eng, MD, Associate Professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center and the Chair of the Symposium Program Committee.
“This is a controlled trial. It would be interesting to see what happens when you use it in real life.”
Similarly, Hurwitz noted during his discussion that while none of the side effects were particularly surprising for a VEGF-based multi-targeted kinase, the toxicities do warrant more study. Some toxicities were severe enough to compromise quality of life and occasionally led to discontinuation.
Drug Development in Advanced Colorectal Cancer
In addition to demonstrating regorafnib's efficacy in colorectal cancer patients, Grothey emphasized that the trial proves that drug development is feasible in this patient population, despite a perception otherwise by some companies.
Moreover, because of the unmet need and lack of treatment options for patients who have disease progression on standard therapies, a placebo-controlled trial was feasible and ethical. The trial accrued in just 10 months, proving that patients are not averse to participating in a placebo-controlled trial in this setting.
In fact, Grothey noted during a news conference that preceded the Symposium, that when the company and investigators discussed the trial with regulators—the FDA in the United States and the EMEA in Europe—the regulators requested a trial design without crossover to allow for a better assessment of the drug's potential impact on survival.
During his discussion, Hurwitz noted that this “clean design” likely helped the trial succeed. In addition to the lack of crossover, “there was no chemotherapy to confound either efficacy or toxicity outcomes.”
That said, Hurwitz pointed out that if drugs are tested in this last-line setting and gain approval, then that might make it harder to see benefit in earlier settings. “If we use late-stage disease for drug development and approval, then the drugs will be available for regular therapy,” he said. “Thus that will make overall survival analysis in earlier lines difficult because patients could come off a trial and have the drug in question.”
Additional Trials Underway
Given the positive results of the newly reported study, investigators are planning or have already launched additional trials with regorafenib. Goldberg, for example, is leading a phase II trial testing FOLFIRI plus regorafenib in patients who have not responded to first-line FOLFOX and have KRAS mutant tumors. Twelve patients have already enrolled in the study, which aims to enroll 240 patients.
However, it remains to be seen whether regorafenib will be valuable in combination with chemotherapy, as other tyrosine kinase inhibitors have failed in that setting, Grothey noted.
Goldberg said that regardless of what happens next with regorafenib, the current results are good news for patients: “My biggest bit of enthusiasm is that it looks like we are finally going to have some new drugs after about a 10-year drought in colon cancer. Regorafenib is the most exciting drug in the pipeline, with perhaps the exception of perifosine. Those are the two that I think are most likely to be our next two approved drugs in colon cancer.”
The phase III regorafenib trial was supported by Bayer, which makes regorafenib, and some co-authors on the abstract are Bayer employees. Grothey has served as a consultant or advisor for Bayer. Goldberg has served as a consultant or advisor for Bayer and has received research funding from the company. Eng was a paid speaker at a Bayer-sponsored CME event, though she emphasizes that the topic of her talk was unrelated to regorafenib.