SAN FRANCISCO—Previous Phase III trials have shown that FOLFOXIRI is superior to FOLFIRI in first-line metastatic colorectal cancer, and Phase II data have suggested that also remains true when bevacizumab is added to each arm. Now, Phase III results from the TRIBE trial reported here at the Gastrointestinal Cancers Symposium (Abstract 336 ) support those conclusions and demonstrate that FOLFOXIRI plus bevacizumab prolongs progression-free survival relative to FOLFIRI plus bevacizumab in previously untreated patients with metastatic colorectal cancer.
“We believe, based on these results, that FOLFOXIRI plus bevacizumab represents a new option for the treatment of metastatic colorectal cancer patients selected according to the eligibility criteria of this study,” said Fotios Loupakis, MD, PhD, from the Department of Oncology at the Istituto Toscano Tumori in Livorno, Italy.
Key eligibility criteria for the study, which was supported by Roche, included having unresectable adenocarcinoma of the colon or rectum. Patients could have received adjuvant oxaliplatin-based chemotherapy, as long as it was completed at least 12 months before their first relapse. Additionally, eligibility was restricted to patients with an ECOG performance status of zero to two for patients up to age 70; and to performance status of zero for patients between 71 and 75.
The median progression-free survival was 12.2 months for the 252 patients in the FOLFOXIRI-plus-bevacizumab arm compared with 9.7 months for the 256 patients in the FOLFIRI-plus-bevacizumab arm. The difference was statistically significant, representing a 27 percent reduction in the risk of disease progression. Moreover, landmark analysis showed that 20 percent of patients in the experimental arm remained progression-free at two years, compared with 11 percent in the control arm.
The response rate also increased significantly in the patients receiving FOLFOXIRI plus bevacizumab compared with those receiving FOLFIRI plus bevacizumab (65 vs. 53 percent).
Toxicity Increased but Tolerable
As expected, there were higher rates of adverse events in the FOLFOXIRI-plus-bevacizumab arm compared with the FOLFIRI-plus-bevacizumab arm, but the overall safety profile was not compromised, he said. The rate of serious adverse events was similar in the two arms (20.4% in the experimental arm and 19.7% in the control arm), as were fatal adverse events (2.8% and 3.5%). Treatment-related deaths were more common in the FOLFOXIRI-plus-bevacizumab arm compared with the FOLFIRI-plus-bevacizumab arm (2.4% vs. 1.6%), as were deaths within 60 days from randomization (3.6% vs. 2.7%).
In terms of Grade 3/4 toxicities, diarrhea was significantly more common in the experimental arm than in the control arm (19% vs. 11%), as were stomatitis (9% vs. 4%) and neutropenia (50% vs. 20%). However, the higher rate of neutropenia with FOLFOXIRI plus bevacizumab did not translate into a statistically significant increase in febrile neutropenia (9% vs. 6%). Five percent of patients in the experimental arm experienced Grade 3/4 neurotoxicity, while none did in the control arm.
There were more dose reductions and treatment delays in the FOLFOXIRI-plus-bevacizumab arm compared with the FOLFIRI-plus-bevacizumab arm, but the changes “did not compromise the overall dose intensity of the treatment plan,” Loupakis said.
Aggressive from Start
During the discussion, an audience member asked if there were any drawbacks to starting with such an aggressive regimen in terms of future treatment options. “I don't think we are missing any opportunities by treating patients aggressively upfront; [we are] trying to control disease as much as possible from the beginning,” Loupakis replied.
With regard to what specific options are open to patients at progression, he said that rechallenging them with the same regimen should be considered based on prior data. Additionally, patients whose tumors are KRAS- mutant can receive regorafenib, whereas patients with KRAS wild-type tumors can receive an EGFR inhibitor or aflibercept. “We have a lot of work to do, but I don't think we preclude any options by treating patients intensively in the very beginning of their disease,” he said.
Jordan Berlin, MD, Ingram Professor of Cancer Researchand Clinical Director of the Oncology Program at Vanderbilt-Ingram Cancer Center, said, “The data show very well that you can go with FOLFOXIRI plus bevacizumab. I think there are some interesting factors here—number one, it did increase the response rate. We're not surprised by that; more drugs should increase the response rate.”
However, that increase in response rate may point to a group of patients who would most benefit from the aggressive approach, he said. “At the very least, this may be a very good regimen to use prior to hepatic resection for the patients who aren't quite there, and may increase the number of patients we can take to resection.” (The rate of R0 resection is a secondary endpoint of the trial, but remains to be analyzed.)
Loupakis, who in his disclosure statement said that he is a consultant for Bayer, acknowledged that the regimen is not for all patients but emphasized that it can be used with those who fit the study entry criteria. “It will be really important to see what happens in terms of overall survival, and to see the data in light of second-line treatments, but the primary endpoint was progression-free survival,” he said.
FOLFOXIRI = folinic acid, fluorouracil, oxaliplatin, and irinotecan
FOLFIRI = folinic acid, fluorouracil, and irinotecan