Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer

Author(s): Jun Watanabe, MD, PhD¹; Kei Muro, MD, PhD²; Kohei Shitara, MD, PhD^3,4; Kentaro Yamazaki, MD, PhD⁵; Manabu Shiozawa, MD, PhD⁶; Hisatsugu Ohori, MD, PhD⁷; Atsuo Takashima, MD, PhD⁸; Mitsuru Yokota, MD, PhD⁹; Akitaka Makiyama, MD, PhD¹⁰; Naoya Akazawa, MD¹¹; Hitoshi Ojima, MD, PhD¹²; Yasuhiro Yuasa, MD, PhD¹³; Keisuke Miwa, MD, PhD¹⁴; Hirofumi Yasui, MD, PhD⁵; Eiji Oki, MD, PhD¹⁵; Takeo Sato, MD, PhD¹⁶; Takeshi Naitoh, MD, PhD¹⁷; Yoshito Komatsu, MD, PhD¹⁸; Takeshi Kato, MD, PhD¹⁹; Masamitsu Hihara, MS²⁰; Junpei Soeda, MD, PhD²⁰; Toshihiro Misumi, PhD²¹; Kouji Yamamoto, PhD²¹; Kiwamu Akagi, MD, PhD²²; Atsushi Ochiai, MD, PhD^23,24; Hiroyuki Uetake, MD, PhD²⁵; Katsuya Tsuchihara, MD, PhD²⁶; Takayuki Yoshino, MD, PhD³

Source: JAMA. 2023;329(15):1271-1282. doi:10.1001/jama.2023.4428

Dr. Maen Hussein's Thoughts

In this study, Cetuximab beat Bevacizumab in left sided KRAS wild type colon cancer.

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 PARTICIPANT

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%-12.3%) and 16.5% vs 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.

Author Affiliations

¹Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan²Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan³Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan⁴Department of Immunology, Nagoya University Graduate School of Medicine, Aichi, Japan⁵Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan⁶Division of Gastrointestinal Surgery, Kanagawa Cancer Center, Kanagawa, Japan⁷Division of Medical Oncology, Japanese Red Cross Ishinomaki Hospital, Miyagi, Japan⁸Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan⁹Department of General Surgery, Kurashiki Central Hospital, Okayama, Japan¹⁰Department of Hematology/Oncology, Japan Community Healthcare Organization, Fukuoka, Japan¹¹Department of Gastrointestinal Surgery, Sendai City Medical Center, Sendai Open Hospital, Miyagi, Japan¹²Department of Gastroenterological Surgery, Gunma Prefectural Cancer Center, Gunma, Japan¹³Department of Gastroenterological Surgery, Japanese Red Cross Tokushima Hospital, Tokushima, Japan¹⁴Department of Cancer Multimodel Therapy Center, Kurume University Hospital, Fukuoka, Japan¹⁵Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan¹⁶Research and Development Center for Medical Education, Department of Clinical Skills Education, Kitasato University School of Medicine, Sagamihara, Japan¹⁷Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan¹⁸Division of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Japan¹⁹Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan²⁰Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Ltd, Tokyo, Japan²¹Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan²²Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan²³Pathology Division, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan²⁴now with the Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan²⁵National Hospital Organization, Disaster Medical Center, Tokyo, Japan²⁶Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan

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