Colon to Rectum

JAMA. 2023;329(15):1271−82

Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T

Panitumumab versus bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, left-sided metastatic colorectal cancer: A randomized clinical trial

Importance: For patients with RAS wild-type metastatic colorectal cancer (CRC), adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined.
Objective: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) versus bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic CRC.
Design, setting, and participants: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015 to January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic CRC (final follow-up, January 14, 2022). Interventions: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days.
Main outcomes and measures: The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resec-tion rate.
Results: In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median fol-low-up was 61 months. Median overall survival was 37.9 months with panitumumab versus 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death = 0.82; 95.798% confidence interval [CI]: 0.68−0.99; p = 0.03) and 36.2 versus 31.3 months, re-spectively, in the overall population (HR = 0.84; 95% CI: 0.72−0.98; p = 0.03). Median progression-free survival for panitumumab versus bevaci-zumab was 13.1 versus 11.9 months, respectively, for those with left-sided tumors (HR = 1.00; 95% CI: 0.83−1.20) and 12.2 versus 11.4 months overall (HR = 1.05; 95% CI: 0.90−1.24). Response rates with panitumumab versus bevacizumab were 80.2% versus 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI: 4.4−17.9%) and 74.9% versus 67.3% overall (difference, 7.7%; 95% CI: 1.5−13.8%). Median dura-tion of response with panitumumab versus bevacizumab was 13.1 versus 11.2 months for left-sided tumors (HR = 0.86; 95% CI: 0.70−1.10) and 11.9 versus 10.7 months overall (HR = 0.89; 95% CI: 0.74−1.06). Curative resection rates with panitumumab versus bevacizumab were 18.3% versus 11.6% for left-sided tumors (difference, 6.6%; 95% CI: 1.0−12.3%) and 16.5% versus 10.9% overall (difference, 5.6%; 95% CI: 1.0−10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%).

Conclusions and relevance: Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population.

DOI: 10.1001/jama.2023.4428