PARADIGM trial

Background

Phase 3 RCT. 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer. Compared panitumumab vs bevacizumab added to mFOLFOX6 first-line, with OS in the left-sided population as the primary analysis.

Interventions and follow up

Arm A: mFOLFOX6 + panitumumab
Arm B: mFOLFOX6 + bevacizumab
Primary endpoint: Overall survival (OS), tested first in left-sided then overall population
Median follow-up: 61 mo

Results

OS, left-sided: 37.9 mo (panitumumab) vs 34.3 mo (bevacizumab); HR 0.82, 95% CI 0.68–0.99, P=.03
OS, overall: 36.2 mo vs 31.3 mo; HR 0.84, 95% CI 0.72–0.98, P=.03
PFS: No significant difference reported
Response rate: 80% (panitumumab) vs 68.6% (bevacizumab)

Adverse events

Skin/mucosal: Any-grade acneiform rash 74.8% (panitumumab) vs 3.2% (bevacizumab); stomatitis 61.6% vs 40.5%
Neurologic: Peripheral sensory neuropathy 70.8% vs 73.7%

Conclusions

Adding panitumumab rather than bevacizumab to first-line mFOLFOX6 significantly improved overall survival in RAS wild-type mCRC, with benefit most evident in left-sided primaries.

Key Limitations

PFS was not improved despite the OS gain, raising questions about the mechanism (post-progression therapy, crossover). The hierarchical design tested left-sided tumors first; right-sided patients did not benefit from panitumumab. The trial was conducted entirely in Japan, which may affect generalizability of subsequent-therapy patterns.

Clinical Context

PARADIGM provided the first prospective randomized OS evidence favoring anti-EGFR over anti-VEGF therapy in left-sided RAS wild-type mCRC, validating tumor sidedness as a treatment-selection biomarker. ESMO recommends an anti-EGFR doublet first-line for fit patients with left-sided RAS/BRAF wild-type disease, with bevacizumab favored for right-sided primaries.

References