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Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear i...

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Autores principales: Sartore-Bianchi, Andrea, Pietrantonio, Filippo, Lonardi, Sara, Mussolin, Benedetta, Rua, Francesco, Crisafulli, Giovanni, Bartolini, Alice, Fenocchio, Elisabetta, Amatu, Alessio, Manca, Paolo, Bergamo, Francesca, Tosi, Federica, Mauri, Gianluca, Ambrosini, Margherita, Daniel, Francesca, Torri, Valter, Vanzulli, Angelo, Regge, Daniele, Cappello, Giovanni, Marchiò, Caterina, Berrino, Enrico, Sapino, Anna, Marsoni, Silvia, Siena, Salvatore, Bardelli, Alberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9386661/
https://www.ncbi.nlm.nih.gov/pubmed/35915157
http://dx.doi.org/10.1038/s41591-022-01886-0
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author Sartore-Bianchi, Andrea
Pietrantonio, Filippo
Lonardi, Sara
Mussolin, Benedetta
Rua, Francesco
Crisafulli, Giovanni
Bartolini, Alice
Fenocchio, Elisabetta
Amatu, Alessio
Manca, Paolo
Bergamo, Francesca
Tosi, Federica
Mauri, Gianluca
Ambrosini, Margherita
Daniel, Francesca
Torri, Valter
Vanzulli, Angelo
Regge, Daniele
Cappello, Giovanni
Marchiò, Caterina
Berrino, Enrico
Sapino, Anna
Marsoni, Silvia
Siena, Salvatore
Bardelli, Alberto
author_facet Sartore-Bianchi, Andrea
Pietrantonio, Filippo
Lonardi, Sara
Mussolin, Benedetta
Rua, Francesco
Crisafulli, Giovanni
Bartolini, Alice
Fenocchio, Elisabetta
Amatu, Alessio
Manca, Paolo
Bergamo, Francesca
Tosi, Federica
Mauri, Gianluca
Ambrosini, Margherita
Daniel, Francesca
Torri, Valter
Vanzulli, Angelo
Regge, Daniele
Cappello, Giovanni
Marchiò, Caterina
Berrino, Enrico
Sapino, Anna
Marsoni, Silvia
Siena, Salvatore
Bardelli, Alberto
author_sort Sartore-Bianchi, Andrea
collection PubMed
description Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.
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spelling pubmed-93866612022-08-18 Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial Sartore-Bianchi, Andrea Pietrantonio, Filippo Lonardi, Sara Mussolin, Benedetta Rua, Francesco Crisafulli, Giovanni Bartolini, Alice Fenocchio, Elisabetta Amatu, Alessio Manca, Paolo Bergamo, Francesca Tosi, Federica Mauri, Gianluca Ambrosini, Margherita Daniel, Francesca Torri, Valter Vanzulli, Angelo Regge, Daniele Cappello, Giovanni Marchiò, Caterina Berrino, Enrico Sapino, Anna Marsoni, Silvia Siena, Salvatore Bardelli, Alberto Nat Med Article Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting. Nature Publishing Group US 2022-08-01 2022 /pmc/articles/PMC9386661/ /pubmed/35915157 http://dx.doi.org/10.1038/s41591-022-01886-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sartore-Bianchi, Andrea
Pietrantonio, Filippo
Lonardi, Sara
Mussolin, Benedetta
Rua, Francesco
Crisafulli, Giovanni
Bartolini, Alice
Fenocchio, Elisabetta
Amatu, Alessio
Manca, Paolo
Bergamo, Francesca
Tosi, Federica
Mauri, Gianluca
Ambrosini, Margherita
Daniel, Francesca
Torri, Valter
Vanzulli, Angelo
Regge, Daniele
Cappello, Giovanni
Marchiò, Caterina
Berrino, Enrico
Sapino, Anna
Marsoni, Silvia
Siena, Salvatore
Bardelli, Alberto
Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial
title Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial
title_full Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial
title_fullStr Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial
title_full_unstemmed Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial
title_short Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial
title_sort circulating tumor dna to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 chronos trial
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9386661/
https://www.ncbi.nlm.nih.gov/pubmed/35915157
http://dx.doi.org/10.1038/s41591-022-01886-0
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