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

Abstract

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%-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.

Trial registration: ClinicalTrials.gov Identifier: NCT02394795.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Watanabe reported receipt of personal fees and honoraria for lectures (Medtronic, Johnson & Johnson, Eli Lilly) and grants and research funding (Medtronic, AMCO, Terumo). Dr Muro reported receipt of personal fees (Takeda, Eli Lilly, Taiho, Ono Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, AstraZeneca, Amgen, Bayer, Chugai Pharmaceutical, Yakult Honsha, Merck Sharp & Dohme, Sanofi, Pfizer); consultancy (Takeda, Ono Pharmaceutical, AstraZeneca, Amgen); advisory board membership (Takeda, Eli Lilly, Ono Pharmaceutical, Daiichi Sankyo, AstraZeneca, Amgen, Bayer); receipt of grants (Astellas, Amgen, Ono Pharmaceutical, Sanofi, Eisai, Taiho, Merck Sharp & Dohme, Parexel International, Merck KGaA, Pfizer, Daiichi Sankyo, Solasia Pharma, Chugai Pharmaceutical); research funding to institution (Astellas, Amgen, Ono Pharmaceutical, Sanofi, Eisai, Taiho, Merck Sharp & Dohme, Parexel International, Merck KGaA, Pfizer, Daiichi Sankyo, Solasia Pharma, Chugai Pharmaceutical); and receipt of honoraria for lectures (Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, Bayer, Chugai Pharmaceutical, Takeda, Yakult Honsha, Merck Sharp & Dohme, Sanofi, Pfizer). Dr Shitara reported receipt of grants (Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, Merck Pharmaceutical, Medi Science, Amgen, Eisai); advisory role and receipt of personal fees (Astellas, Eli Lilly, Bristol Myers Squibb, Takeda Pharmaceuticals, Pfizer Inc, Ono Pharmaceutical, Novartis, AbbVie Inc, Daiichi Sankyo, Taiho Pharmaceutical, Merck Pharmaceutical, GlaxoSmithKline, Amgen, Boehringer Ingelheim, Janssen, Guardant Health Japan); receipt of research funding (Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, Merck Pharmaceutical, Medi Science, Amgen, Eisai); and receipt of honoraria lecture fees (Bristol Myers Squibb, Takeda, Janssen). Dr Yamazaki reported receipt of personal fees and honoraria (Chugai Pharmaceutical, Daiichi Sankyo, Yakult Honsha, Takeda, Bayer, Merck Serono, Taiho Pharmaceutical, Eli Lilly, Sanofi, Ono Pharmaceutical, Merck Sharp & Dohme, Bristol Myers Squibb). Dr Ohori reported receipt of personal fees (Takeda, Yakult Honsha). Dr Takashima reported receipt of grants (Takeda, Ono Pharmaceutical, Merck Sharp & Dohme, Bristol Myers Squibb, Isofol Medical AB, Hutchison Medipharma, Incyte Corporation, Pfizer Inc, Daiichi Sankyo) and personal fees (Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, Takeda, Merck Serono, Merck Sharp & Dohme). Dr Makiyama reported receipt of personal fees (Eli Lilly Japan KK, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo). Dr Oki reported receipt of personal fees and lecture fees (Takeda, Eli Lilly, Bayer, Chugai Pharmaceutical, Ono Pharmaceutical). Dr Sato reported receipt of grants (Takeda). Dr Naitoh reported receipt of honoraria and personal fees (Chugai Pharmaceutical, Takeda, Johnson & Johnson, Medtronic, Sumitomo Bake, Terumo, Eli Lilly, Taiho Pharmaceutical, Daiichi Sankyo, Kaken Pharma, Yakult Honsha, Bayer) and grants (Chugai Pharmaceutical, Tsumura & Co). Dr Komatsu reported receipt of grants (Takeda, Chugai, Nihonkayaku, Nipro, Taiho Pharmaceutical, Ono Pharmaceutical, Nippon Zoki, Shionogi, EPS, IQVIA, Astellas, Eisai, Merck Sharp & Dohme, Yakult, Daiichi Sankyo, Eli Lilly, Sanofi, Bristol Myers Squibb); receipt of research funding (Takeda, Chugai, Nihonkayaku, Nipro); speakers bureau membership (Chugai, Nihonkayaku); and receipt of personal fees (Chugai, Nihonkayaku, Taiho Pharmaceutical, Ono Pharmaceutical, Yakult, Daiichi Sankyo, Eli Lilly, Bayer, Pfizer, Bristol Myers Squibb, Asahi Kasei). Dr Kato reported receipt of grants (Chugai Pharmaceutical) and personal fees (Ono Pharmaceutical, Takeda, Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical). Dr Soeda reported employment with Takeda. Mr Hihara reported employment with Takeda. Dr Tsuchihara reported receipt of personal fees (Takeda, Chugai Pharmaceutical, Novartis, Boehringer Ingelheim, Illumina). Dr Yoshino reported receipt of grants (Ono Pharmaceutical, Sanofi, Daiichi Sankyo, Parexel International, Pfizer Japan, Taiho Pharmaceutical, Merck Sharp & Dohme, Amgen, Genomedia Inc, Sysmex Corp, Chugai Pharmaceutical, Nippon Boehringer Ingelheim) and honoraria (Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan KK, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, Merck Sharp & Dohme). No other disclosures were reported.

Figures

Figure 1.. Participant Flow in the PARADIGM Trial

mFOLFOX6 indicates modified fluorouracil, l-leucovorin, and oxaliplatin. aThe total number of patients approached for participation in the trial was not recorded. bThe total number of participants overall is not the sum of the participants with left-sided tumors and participants with right-sided tumors because 11 participants had lesions in both the left and right sides (4 in the panitumumab group and 7 in the bevacizumab group).

Figure 2.. Overall Survival and Progression-Free Survival in the Overall Study Population and by Tumor Sidedness

Median follow-up for overall and progression-free survival was 61.3 (IQR, 57.6-65.5) months for panitumumab and 60.6 (IQR, 57.0-66.1) months for bevacizumab in the overall population; 61.3 (IQR, 57.2-65.2) months for panitumumab and 61.0 (IQR, 57.1-66.2) months for bevacizumab for left-sided tumors; and 61.3 (IQR, 60.5-66.6) months for panitumumab and 60.2 (IQR, 55.7-65.5) months for bevacizumab for right-sided tumors. Data are shown ordered as left-sided tumors, right-sided tumors, and overall for clinical interest, but the order of primary statistical analyses was prespecified to evaluate left-sided tumors first, then the overall population. Analyses of right-sided tumors were predefined exploratory outcomes.