Matthew T. Seymour, MD

For patients with operable colon cancer, neoadjuvant chemotherapy resulted in numerous benefits in the FOxTROT trial but did not reach target significance for the primary endpoint. The study was presented at the 2019 ASCO Annual Meeting by Matthew T. Seymour, MD, of the University of Leeds School of Medicine and the National Institute for Health Research Clinical Research Network.¹

“There was a trend toward an improved 2-year relapse rate with neoadjuvant chemotherapy that reached the target hazard ratio (0.75) but not the predetermined significance (P = .08),” Dr. -Seymour said, explaining that the control arm achieved better outcomes than expected. “Moving 6 weeks of chemotherapy ahead of surgery, without major additions to the cost or patient burden of treatment, was safe, with less major postoperative morbidity. It significantly downstaged tumors and reduced incomplete resections. And it trended toward improved 2-year cancer control…. We believe that neoadjuvant chemotherapy can be considered a new therapeutic option for locally advanced operable colon cancer.”

FOxTROT Details

The FOxTROT trial randomly assigned 1,052 patients with operable, nonobstructed radiologically staged T3 or T4 (N0–2, M0) colon cancer to neoadjuvant chemotherapy or surgery, followed by postoperative chemotherapy, as follows:

• Neoadjuvant arm: 6 weeks of modified FOLFOX (fluorouracil, leucovorin, oxaliplatin; 72%) or capecitabine/oxalipatin -(XELOX; 28%) followed by surgery and 18 weeks of oxaliplatin/fluoropyrimidine. Patients with KRAS wild-type tumors could opt to be randomly assigned to panitumumab (or not) during preoperative treatment.
• Surgery arm: Surgery followed by 24 weeks of FOLFOX (94%) or 12 weeks of the same (6%)
• Patients with KRAS wild-type tumors allocated to the neoadjuvant arm could opt to be randomly assigned 1:1 to panitumumab (or not) during the neoadjuvant chemotherapy phase.
• Older or low-risk patients had the option of 12 weeks rather than 24 weeks of chemotherapy (6% did so), and patients had the option to choose XELOX rather than FOLFOX (28% did so).

About 98% of patients had attempted curative resection, with no difference between the arms. However, there was a striking difference between the percentage of patients who did not receive chemotherapy: 4% in the neoadjuvant arm vs 27% in the surgery arm (P < .0001).

Efficacy Analyses

At 2 years, in the intent-to-treat analysis, the 2-year rate of failure (defined as relapse or persistent disease) was 13.6% in the novel arm and 17.2% in the control arm. This result translated to a hazard ratio of 0.75 (95% confidence interval = 0.55–1.04; P = .08).

A sensitivity analysis concluded that adding panitumumab to neoadjuvant chemotherapy did not increase the rate of tumor regression. “The overall effect seen in the primary analysis is not explained by the use of panitumumab,” Dr. Seymour said. The investigators are undertaking a full analysis of an enriched biomarker population.

There were 173 patients with tumors demonstrating mismatch repair (MMR) deficiency. In these individuals, neoadjuvant chemotherapy failed to achieve the same effects as seen in MMR-proficient tumors. In MMR-deficient patients, the rate of zero tumor regression was 73.6%, compared with 26.6% in the MMR-proficient patients.

Dr. Seymour cautioned that this was a nonprespecified subgroup analysis that needs validation. However, he said, it suggests the neoadjuvant approach may be ineffective in MMR-deficient patients. ■

DISCLOSURE: Dr. Seymour has received institutional research funding from Amgen.

REFERENCE

1. Seymour MT, et al: FOxTROT: An international randomized controlled trial in 1,052 patients evaluating neoadjuvant chemotherapy for colon cancer. 2019 ASCO Annual Meeting. Abstract 3504. Presented June 1, 2019.