The addition of panitumumab (Vectibix) to neoadjuvant FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy significantly improved survival outcomes and reduced recurrence in patients with locally advanced colon cancer (LACC) who have RAS/BRAF wild-type tumors, according to exploratory findings from the FOxTROT trial (ISRCTN838426) published in Annals of Oncology.
The study demonstrated that in the biomarker-selected population, panitumumab plus FOLFOX substantially outperformed FOLFOX alone across multiple clinical endpoints. Disease-free survival (DFS) strongly favored patients receiving the combination therapy versus FOLFOX alone (HR, 0.51; 95% CI, 0.27-0.97; P=0.04). Even more striking improvements were observed in the rate of death from colon cancer (HR, 0.23; 95% CI, 0.06-0.83; P=0.03) and overall survival (OS; HR, 0.36; 95% CI, 0.16-0.85; P=0.02).
Precision Medicine Approach Shows Promise
Lead author Jenny F. Seligmann, MD, professor of gastrointestinal and translational oncology at the University of Leeds, United Kingdom, noted that while the improvement in time to recurrence was nonsignificant, the combination therapy demonstrated "clinically relevant activity limited to a rationally selected and predefined biomarker group."
Interestingly, tumor downstaging at surgery—which typically predicts benefit with FOLFOX alone—did not correlate with long-term outcomes in the panitumumab group. This suggests the anti-EGFR agent may work through a distinct mechanism of action compared to standard chemotherapy.
"The understanding of biological subtypes and response to therapy in metastatic colorectal cancer has greatly improved over the past decades, particularly for anti-EGFR agents," Seligmann and colleagues wrote. This study highlights the importance of revisiting earlier trial conclusions where drugs were tested in suboptimal populations based on the best evidence available at the time of trial conception.
Trial Design and Patient Population
The FOxTROT trial evaluated 24 weeks of perioperative chemotherapy, with all patients receiving 3 cycles of modified FOLFOX before surgery. In the experimental arm, panitumumab (6 mg/kg) was infused prior to the first 3 cycles.
From a total of 4,907 eligible patients, 1,053 were randomly assigned to either postoperative chemotherapy (n=354) or perioperative chemotherapy (n=699). Within the perioperative group, 279 patients entered panitumumab randomization, with 169 ultimately confirmed as RAS/BRAF wild-type after biomarker testing. The study excluded 22 patients with RAS mutations and 41 with BRAF mutations.
The primary objective was time to recurrence (TTR) in the RAS/BRAF wild-type population. Secondary endpoints included DFS, colon cancer-specific survival (CCSS), OS, and short-term efficacy.
Patient Characteristics
The mean age of participants was 60 years. Baseline computed tomography assessment identified T4 disease in 32 of 169 patients (19%). Regarding tumor location, 102 patients (60%) had left primary tumor location (PTL) and 67 (40%) had right PTL. Investigators reported no major imbalances between treatment arms.
Context of Previous Findings
Initial results from the main FOxTROT trial had shown that in patients with KRAS wild-type mutations, there was no significant improvement in pathological tumor down-staging or 2-year recurrence-free survival with panitumumab. While a trend toward benefit was observed across all efficacy endpoints, this was not statistically significant compared with FOLFOX alone.
The current analysis, focusing specifically on the RAS/BRAF wild-type population, reveals the importance of proper biomarker selection for targeted therapies.
Implications for Clinical Practice
Although the study was not powered to definitively change practice, it provides the first evidence that anti-EGFR therapy can improve long-term cancer control in locally advanced colon cancer. "These results validate molecular selection for anti-EGFR agents in nonmetastatic disease," the researchers noted.
The findings suggest that precision medicine approaches already established in metastatic colorectal cancer may also benefit patients with earlier-stage disease when properly selected based on molecular profiles.
Further research is needed to confirm these benefits in larger cohorts and explore potential differences in efficacy between right-sided and left-sided tumors, which have shown varying responses to anti-EGFR therapy in the metastatic setting.
Future Directions
The promising results from this exploratory analysis highlight the potential for expanding the role of targeted therapies in earlier stages of colon cancer treatment. Additional studies with larger sample sizes will be necessary to confirm these findings and potentially establish new standards of care for patients with RAS/BRAF wild-type locally advanced colon cancer.
As molecular testing becomes increasingly routine in colorectal cancer management, the ability to select patients most likely to benefit from specific therapies may significantly improve outcomes across all disease stages.
