Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer

Kohei Shitara; Kei Muro; Jun Watanabe; Kentaro Yamazaki; Hisatsugu Ohori; Manabu Shiozawa; Atsuo Takashima; Mitsuru Yokota; Akitaka Makiyama; Naoya Akazawa; Hitoshi Ojima; Yasuhiro Yuasa; Keisuke Miwa; Hirofumi Yasui; Eiji Oki; Takeo Sato; Takeshi Naitoh; Yoshito Komatsu; Takeshi Kato; Ikuo Mori; Kazunori Yamanaka; Masamitsu Hihara; Junpei Soeda; Toshihiro Misumi; Kouji Yamamoto; Riu Yamashita; Kiwamu Akagi; Atsushi Ochiai; Hiroyuki Uetake; Katsuya Tsuchihara; Takayuki Yoshino

doi:10.1038/s41591-023-02791-w

Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer

Kohei Shitara, Kei Muro, Jun Watanabe, Kentaro Yamazaki, Hisatsugu Ohori, Manabu Shiozawa, Atsuo Takashima, Mitsuru Yokota, Akitaka Makiyama, Naoya Akazawa, Hitoshi Ojima, Yasuhiro Yuasa, Keisuke Miwa, Hirofumi Yasui, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Ikuo MoriKazunori Yamanaka, Masamitsu Hihara, Junpei Soeda, Toshihiro Misumi, Kouji Yamamoto, Riu Yamashita, Kiwamu Akagi, Atsushi Ochiai, Hiroyuki Uetake, Katsuya Tsuchihara, Takayuki Yoshino

Surgery

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Abstract

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS,PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62–0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83–1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795.

Original language	English
Pages (from-to)	730-739
Number of pages	10
Journal	Nature medicine
Volume	30
Issue number	3
DOIs	https://doi.org/10.1038/s41591-023-02791-w
Publication status	Published - Mar 2024

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1038/s41591-023-02791-w

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Shitara, K., Muro, K., Watanabe, J., Yamazaki, K., Ohori, H., Shiozawa, M., 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., ... Yoshino, T. (2024). Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer. Nature medicine, 30(3), 730-739. https://doi.org/10.1038/s41591-023-02791-w

Shitara, K, Muro, K, Watanabe, J, Yamazaki, K, Ohori, H, Shiozawa, M, 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, Mori, I, Yamanaka, K, Hihara, M, Soeda, J, Misumi, T, Yamamoto, K, Yamashita, R, Akagi, K, Ochiai, A, Uetake, H, Tsuchihara, K & Yoshino, T 2024, 'Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer', Nature medicine, vol. 30, no. 3, pp. 730-739. https://doi.org/10.1038/s41591-023-02791-w

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title = "Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer",

abstract = "Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS,PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62–0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83–1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795.",

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AU - Shitara, Kohei

AU - Muro, Kei

AU - Watanabe, Jun

AU - Yamazaki, Kentaro

AU - Ohori, Hisatsugu

AU - Shiozawa, Manabu

AU - Takashima, Atsuo

AU - Yokota, Mitsuru

AU - Makiyama, Akitaka

AU - Akazawa, Naoya

AU - Ojima, Hitoshi

AU - Yuasa, Yasuhiro

AU - Miwa, Keisuke

AU - Yasui, Hirofumi

AU - Oki, Eiji

AU - Sato, Takeo

AU - Naitoh, Takeshi

AU - Komatsu, Yoshito

AU - Kato, Takeshi

AU - Mori, Ikuo

AU - Yamanaka, Kazunori

AU - Hihara, Masamitsu

AU - Soeda, Junpei

AU - Misumi, Toshihiro

AU - Yamamoto, Kouji

AU - Yamashita, Riu

AU - Akagi, Kiwamu

AU - Ochiai, Atsushi

AU - Uetake, Hiroyuki

AU - Tsuchihara, Katsuya

AU - Yoshino, Takayuki

PY - 2024/3

Y1 - 2024/3

N2 - Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS,PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62–0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83–1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795.

AB - Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS,PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62–0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83–1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795.

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Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer

Abstract

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