BARCELONA, Spain—Two new entries in the treatment of metastatic colorectal cancer were discussed here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer, each showing promise in a heavily pretreated population.
The placebo-controlled, randomized, Phase III trials were for regorafenib (CONCUR) and TAS-102 (RECOURSE).
“The good news is, both of these drugs are active, said Richard M. Goldberg, MD, Professor and Physician-in-Chief at Ohio State University James Cancer Hospital and Comprehensive Cancer Center, who was the Discussant for both trials. He called the trials “unequivocally positive.”
Goldberg congratulated the researchers for well-designed trials in appropriate populations that showed significant survival and response benefit for each drug. But toxicities for regorafenib were too high, he said, recommending dose reductions or changes in dosing strategy.
CONCUR: Regorafenib Active in Asian Patients
In the CONCUR trial of 204 patients, reported by Jin Li, MD, Professor and Director of the Department of Medical Oncology at Fudan University Shanghai Cancer Center, use of regorafenib—an oral multikinase inhibitor that targets pathways involved in tumor growth and progression—was associated with a 45 percent reduction in the risk of death in Asian patients with metastatic colorectal cancer who had disease progression after standard therapy compared with placebo. And approximately half of treated patients experienced a clinical response or stable disease.
CONCUR, which was sponsored by Bayer HealthCare Pharmaceuticals, met its response goals but not the toxicity goals. “Regorafenib needs dose and schedule refinement,” Goldberg said in his discussion of the trial, suggesting dose reductions or a one-week-on one-week-off strategy.
With a median of 10.6 weeks under treatment, about 26 percent of patients had dose reductions and 66 percent had dose interruptions. “The biggest challenge for regorafenib researchers is to find a better way to give this drug so we can exploit its benefit, because there was a relatively high rate of grade 3 and 4 toxicity,” he said. “For those of us who use regorafenib in the clinic, treatment tolerance is the biggest issue we face.”
Median overall survival was 8.8 months for regorafenib (136 patients) versus 6.3 months for patients on placebo (68 patients). Progression-free survival was 3.2 versus 1.7 months, respectively, and the disease-control rates (including complete response [CR], partial response [PR], and stable disease [SD]) were 52.0 percent versus 7.0 percent, respectively.
Li noted that CONCUR is now the second Phase III trial showing that regorafenib monotherapy improves survival in patients with metastatic colorectal cancer who have disease progression after standard therapy. The Phase III CORRECT trial (Grothey et al: Lancet 2013;381:303-312) showed that regorafenib improves overall survival in patients with metastatic colorectal cancer who have disease progression after standard therapies. Those authors said regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer that has progressed after all standard therapies.
But only 15 percent of patients enrolled in CORRECT were Asian—mostly from Japan—while all patients in CONCUR were from mainland China, Hong Kong, Taiwan, the Republic of Korea, and Vietnam.
Patients who had disease progression after at least two prior lines of standard therapy were randomly assigned to receive oral regorafenib (136 patients) or placebo (68 patients) for the first three weeks of a four-week cycle. Prior anti-VEGF or anti-EGFR was allowed but not required.
The most frequent treatment-emergent adverse effects were hand-foot skin reaction (16% of patients), hypertension (12%), hyperbilirubinemia (12%), elevated liver enzymes (AST 10%, ALT 8%), hypophosphatemia (9%), anemia (7%), and hyperlipasemia (7%). There were no reports of liver failure or pancreatitis.
“What is important [regarding serious adverse events] is that the rate with regorafenib was similar to that of placebo—31.3 percent and 26.5 percent, respectively,” Li said.
RECOURSE: TAS-102 Improves Overall Survival
In the RECOURSE trial of 800 patients with metastatic colorectal cancer, TAS-102 treatment was associated with a significant improvement in overall survival and progression-free survival compared with placebo.
The lead author, Takayuki Yoshino, MD, a medical oncologist at National Cancer Center Hospital East in Chiba, Japan, explained that the global trial was conducted in 13 countries. Median overall survival was 7.1 months for patients receiving TAS-102 (534 patients) versus 5.3 months for those on placebo (266 patients), at a median follow-up of 8.4 months.
Median progression-free survival was 2.0 versus 1.7 months, overall response rates were 1.6 percent versus 0.4 percent, and disease-control rates (CR, PR, SD) were 44.0 percent versus 16.3 percent.
This was a heavily pretreated population, he noted, as patients had at least two prior lines of standard chemotherapy and had been resistant or refractory to fluorourpyrimidines, irinotecan, oxaliplatin, bevacizumab, and cetuximab or panitumumab for patients with KRAS wild-type tumors.
Neutropenia was the major adverse event, seen in 34.9 percent of patients receiving TAS-102 and none of the placebo patients. Other adverse events included leukopenia (12.8% vs. none for placebo); anemia (16.5% vs. 2.6 %); and febrile neutropenia (3.8% vs. none).
TAS-102 is a combination of the novel oral nucleoside trifluridine and tipiracil hydrochloride, the latter an inhibitor of thymidine phosphorylase which is seen in high levels in aggressive disease, Yoshino explained.
The agent is effective against human colorectal cancer cell lines that are resistant to fluorouracil (5-FU), and a randomized Phase II study showed a significant survival advantage for TAS-102 over placebo in refractory metastatic disease (Yoshino et al: Lancet Oncology 2012;13:993-1001).
He noted that trifluridine is activated by thymidine kinase, which does not have a role in activation of 5-FU, and trifluridine is incorporated into DNA, resulting in long-lasting DNA damage, both of which may explain why it is active in tumors refractory to 5-FU.
The DNA damage may also contribute to the toxicities, however.
Commenting in a news release, ESMO spokesperson Jean Yves Douillard, MD, Professor of Medical Oncology at the Institut de Cancérologie de l'Ouest René Gauducheau in France, said, “It is good to know that the magnitude of benefit shown in the smaller Phase II trial is confirmed in the larger Phase III trial and that the results apply to Asians and Caucasians alike.”
Douillard said he would probably move this drug into an earlier line of treatment and would also combine it with either irinotecan or oxaliplatin.
The trial was sponsored by Taiho Pharmaceutical Co.
“Is TAS-102 just another 5-FU?” Goldberg asked rhetorically in his discussion. “The answer is clearly no, it is a cytotoxic antimetabolite but it also has a potential antiangiogenic effect.”
Importantly, TAS-102 is active in KRAS-mutant tumors, but Goldberg noted that it was not as active in overall survival in patients with KRAS-mutant tumors as it had appeared to be in the Phase II trial.
He said the next step for TAS-102—“besides giving it a name”—is regulatory approval in the U.S., which he said may be a challenge because it is a combination drug and the FDA looks at that differently.
He said trials combining each of these drugs with standard agents are underway.
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