Panitumumab vs 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

• Published in: JAMA : the journal of the American Medical Association 2023-04, Vol.329 (15), p.1271-1282
• Main Authors: Watanabe, Jun, Muro, Kei, Shitara, Kohei, Yamazaki, Kentaro, Shiozawa, Manabu, Ohori, Hisatsugu, Takashima, Atsuo, Yokota, Mitsuru, Makiyama, Akitaka, Akazawa, Naoya, Ojima, Hitoshi, Yuasa, Yasuhiro, Miwa, Keisuke, Yasui, Hirofumi, Oki, Eiji, Sato, Takeo, Naitoh, Takeshi, Komatsu, Yoshito, Kato, Takeshi, Hihara, Masamitsu, Soeda, Junpei, Misumi, Toshihiro, Yamamoto, Kouji, Akagi, Kiwamu, Ochiai, Atsushi, Uetake, Hiroyuki, Tsuchihara, Katsuya, Yoshino, Takayuki
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Bevacizumab - administration & dosage; Bevacizumab - adverse effects; Bevacizumab - therapeutic use; Cancer; Cancer therapies; Chemotherapy; Clinical trials; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; Female; Fluorouracil - administration & dosage; Growth factors; Humans; Leucovorin - administration & dosage; Male; Metastases; Metastasis; Monoclonal antibodies; Original Investigation; Oxaliplatin; Oxaliplatin - administration & dosage; Panitumumab - administration & dosage; Panitumumab - adverse effects; Panitumumab - therapeutic use; Patients; Peripheral neuropathy; Stomatitis; Survival; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factors - antagonists & inhibitors
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.2023.4428

IMPORTANCE: For patients with RAS wild-type metastatic colorectal cancer, 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) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015–January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (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) resection 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 follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0