90MO - Panitumumab (PAN) vs bevacizumab (BEV) in metastatic colorectal cancer (mCRC) by microsatellite stable (MSS), RAS/BRAF, and HER2 amplification (HER2amp) status: Phase III PARADIGM biomarker study

Background

In PARADIGM (NCT02394795), overall survival (OS) was longer with first-line mFOLFOX6 + PAN vs BEV in RAS wild type (WT) left-sided mCRC (37.9 vs 34.3 mo; hazard ratio [HR] 0.82; P=0.03) and similar in right-sided mCRC (HR 1.09). In left-sided mCRC with RAS/BRAF WT and MSS/microsatellite instability low (MSI-L), OS was 40.6 vs 34.8 mo (HR 0.79). Per treatment guidelines, RAS (KRAS/NRAS), BRAF (V600E), and MSS status should guide treatment selection in mCRC. Current guidelines do not include HER2amp, a clinically relevant biomarker. We compare efficacy in patients (pts) with HER2amp−, MSS or MSI-L, and RAS/BRAF WT (quadruple negative) mCRC vs ≥1 of these gene alterations in PARADIGM.

Methods

Pretreatment plasma circulating tumor DNA (ctDNA; >10 ng/mL; >10 nM DNA) from biomarker study NCT02394834 was assessed by custom PlasmaSELECT-R 91 PGDx panel. OS, progression-free survival (PFS), response rate (RR), and curative resection rate (R0) were compared for mFOLFOX6 + PAN vs BEV by quadruple-negative status and primary location.

Results

Among 733 ctDNA-evaluable pts, 53 (7.2%) were RAS+, 78 (10.6%) BRAF (V600E)+, 20 (2.7%) MSI high (MSI-H), and 32 (4.4%) HER2amp+. In quadruple-negative left-sided mCRC, median OS was longer with PAN vs BEV (HR 0.78; Table). Median PFS was similar with PAN (13.6 mo [95% CI 12.6–15.7]) vs BEV (12.8 mo [11.3–14.1]; HR 0.94 [0.76–1.16]), whereas RR and R0 were higher with PAN (RR: 83.8% [78.5–88.2]; R0: 18.7% [14.0–24.2]) vs BEV (RR: 66.5% [60.0–72.6]; R0: 10.4% [6.8–15.1]) in pts with quadruple-negative left-sided mCRC. OS was similar or inferior with PAN vs BEV in pts with ≥1 gene alteration regardless of tumor sidedness (Table).

Conclusions

Adding HER2amp− to guideline-recommended biomarkers slightly improved OS. These results support first-line PAN + mFOLFOX6 for left-sided HER2amp−, MSS/MSI-L, and RAS/BRAF WT mCRC. Table: 90MO

^a HER2amp−, MSS/MSI-L, and RAS/BRAF WT; ^b HER2amp+, MSI-H, and/or RAS/BRAF mutation

Clinical trial identification

NCT02394834.

Editorial acknowledgement

Professional medical writing assistance was provided by Lela Creutz, PhD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Takeda Pharmaceutical Company Limited.

Legal entity responsible for the study

Takeda Pharmaceutical Company Limited.

Funding

This study was sponsored by Takeda Pharmaceutical Company Limited.

Disclosure

T. Kato: Financial Interests, Personal, Other, Honoraria: Chugai, Ono Pharmaceutical, Takeda, Lilly Japan, Asahi Kasei; Financial Interests, Personal, Research Funding: Chugai. K. Muro: Financial Interests, Personal, Advisory Role: Chugai Pharma, AstraZeneca, Ono Pharmaceutical, Amgen; Financial Interests, Personal, Other, Honoraria: Chugai Pharma, Ono Pharmaceutical, Takeda, Eli Lilly, Bayer, Sanofi, Bristol Myers Squibb, Taiho Pharmaceutical; Financial Interests, Personal, Research Grant: Taiho Pharmaceutical, Astellas Pharma, Amgen Astellas Biopharma; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme, Daiichi Sankyo, Shionogi, Kyowa Kirin, Gilead Sciences, Merck Serono, Pfizer, Sanofi, PAREXEL, Mediscience Planning, Sumitomo Dainippon Pharma, Solasia Pharma. J. Watanabe: Financial Interests, Personal, Speaker’s Bureau: Covidien Japan, Johnson & Johnson/Janssen, Eli Lilly Japan; Financial Interests, Institutional, Research Funding: Medtronic, TERUMO. K. Shitara: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Takeda, Janssen; Financial Interests, Personal, Advisory Role: Eli Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Merck Sharp & Dohme, Taiho, Novartis, AbbVie, GSK, Daiichi Sankyo, Boehringer Ingelheim, Amgen, Astellas Pharma, Guardant Health; Financial Interests, Institutional, Research Funding: Merck Sharp & Dohme, Daiichi Sankyo, Taiho, Chugai Pharma, Ono Pharmaceutical, Astellas Pharma, Eisai, Amgen. K. Yamazaki: Financial Interests, Personal, Other, Honoraria: Chugai Pharma, Daiichi Sankyo, Yakult Honsha, Takeda, Bayer, Merck Serono, Taiho Pharmaceutical, Eli Lilly, Sanofi, Ono Pharmaceutical, Merck Sharp & Dohme, Bristol Myers Squibb; Financial Interests, Institutional, Research Funding: Taiho Pharmaceutical. M. Shiozawa: Financial Interests, Personal, Speaker’s Bureau: Lilly Japan, Merck Serono, Taiho Pharmaceutical, Yakult Honsha, Takeda, Ono Pharmaceutical, Johnson & Johnson, Kaken Pharmaceutical. E. Oki: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma, Eli Lilly Japan, Takeda, Ono Pharmaceutical, Bristol Myers Squibb Japan, Taiho Pharmaceutical; Financial Interests, Personal, Research Funding: Guardant Health. T. Sato: Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma, Eli Lilly Japan, Taiho Oncology, Takeda, Bayer Yakuhin, Ono Yakuhin, Daiichi Sankyo/UCB Japan. T. Naitoh: Financial Interests, Personal, Other, Honoraria: Chugai Pharma, Taiho Pharmaceutical, Kaken, Daiichi Sankyo, Eli Lilly Japan, Takeda, Merck, Bayer, Boehringer Ingelheim; Financial Interests, Institutional, Research Funding: Chugai, Taiho, Kaken, Daiichi Sankyo, Eli Lilly Japan. Y. Komatsu: Financial Interests, Personal, Speaker’s Bureau: Ono, Taiho, Chugai, Eli Lilly, Bayer Yakuhin; Financial Interests, Personal, Research Funding: Ono, Taiho, Daiichi Sankyo, Chugai, IQVIA. J. Soeda: Financial Interests, Personal, Full or part-time Employment: Takeda. K. Yamamoto: Financial Interests, Personal, Other, Honoraria: J-Pharma, CMIC Co., Ltd., Chugai Pharma, Takeda, Sysmex, Johokiko, CM Plus; Financial Interests, Institutional, Research Funding: Ono Pharmaceutical, Chugai Pharma, Bayer, Takeda, Taiho Pharmaceutical, Astellas Pharma, Daiichi Sankyo/UCB Japan, Kyowa Kirin International. R. Yamashita: Financial Interests, Personal, Advisory Role: Takeda. H. Uetake: Financial Interests, Personal, Speaker’s Bureau: Takeda, Chugai, Taiho. K. Tsuchihara: Financial Interests, Personal, Other, Honoraria: Chugai Pharma, Takeda, Illumina, Eisai, Boehringer Ingelheim Seiyaku, Bayer Yakuhin, Gilead Sciences. T. Yoshino: Financial Interests, Personal, Other, Honoraria: Chugai Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical, Merck Sharp & Dohme; Financial Interests, Institutional, Research Funding: MSD, Daiichi Sankyo, Ono Pharmaceutical, Taiho Pharmaceutical, Amgen, Sanofi, Pfizer, Genomedia, Sysmex, Nippon Boehringer Ingelheim, Chugai Pharma. All other authors have declared no conflicts of interest.