Expert Point of View: Frank Sinicrope, MD

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Frank Sinicrope, MD

Frank Sinicrope, MD

FRANK SINICROPE, MD, Professor of Oncology and Co-Leader of the GI Cancer Program at the Mayo Clinic, Rochester, said CHARTA addressed whether patient outcomes can be improved with a triplet regimen plus bevacizumab (Avastin) vs a standard doublet plus bevacizumab. This was based upon the finding from the phase III TRIBE study that FOLFOXIRI (fluorouracil [5-FU]/leucovorin, oxaliplatin, irinotecan)/bevacizumab improved response rates, progression-free survival, and overall survival over FOLFIRI (5-FU/leucovorin, irinotecan)/bevacizumab. The phase II CHARTA study used FOLFOX (5-FU/leucovorin, oxaliplatin)/ bevacizumab as the control arm. 

Dr. Sinicrope emphasized that FOLFOXIRI “is not FOLFIRINOX.” FOLFOXIRI does not require a bolus infusion of fluorouracil, involves a different infusional dose and schedule, and includes irinotecan and leucovorin at lower doses than does FOLFIRINOX. 

He noted that the binary 9-month progression-free survival endpoint was statistically significant, favoring FOLFOXIRI/bevacizumab. The benefit was observed across the different subgroups, both RAS wild-type and mutated cohorts, although the study was underpowered for subgroup analyses. 

“The data related to patient age require more evaluation,” he said. “For patients aged 65 and younger, the hazard ratio was 0.57, whereas it was 0.43 for those older than age 65. And we also need to know the dose and duration of treatment. Those data are not sufficiently sorted out at this time.” 

Importantly, no significant difference in the secondary endpoint of overall survival was found, and the survival curves crossed at 28 months. The use of subsequent therapies renders this an endpoint “not ideal for front-line studies,” Dr. Sinicrope pointed out. “There was no difference in terms of number of lines of subsequent therapies, but it would be important to review the use of targeted drugs,” he added. 

Toxicity Profile 

DR. SINICROPE also found the toxicity profile interesting. Neutropenia occurred in 21% of the FOLFOXIRI/bevacizumab cohort in CHARTA but in 50% of the TRIBE cohort. This may be because CHARTA included a higher proportion of patients with a good performance status, he suggested. Three chemotherapy agents, as compared with two, “did not adversely affect quality of life and was overall fairly well tolerated,” he added. 

Despite 17% of CHARTA patients requiring a dose reduction of 25%, “this did not reduce the regimen’s efficacy,” he said encouragingly. And outcomes in CHARTA were similar to those documented in TRIBE, “showing consistency for this triplet [5-FU/leucovorin, oxaliplatin, irinotecan].” 

Unfortunately, as was also shown in TRIBE, the FOLFOXIRI regimen did not lead to greater surgical resectability of metastatic disease. “When we decide to give patients a more aggressive regimen, this is often an important objective,” he commented, “but the lack of difference may well reflect the biology of the disease, which cannot be circumvented by simply giving more cytotoxic chemotherapy.” 

“CHARTA provides further support for FOLFOXIRI plus bevacizumab as an option for first-line therapy in metastatic colorectal cancer patients, especially those with a favorable performance status,” Dr. Sinicrope concluded. “While a confirmatory phase III study would be optimal, the pursuit of novel agents or biomarker-driven studies may be of higher priority.” ■

DISCLOSURE: Dr. Sinicrope has served as an advisor to Hoffmann-La Roche Ltd. 

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