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

Abstract

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.

• Authors: Andrea Sartore-Bianchi, Filippo Pietrantonio, Sara Lonardi, Benedetta Mussolin, Francesco Rua, Giovanni Crisafulli, Alice Bartolini, Elisabetta Fenocchio, Alessio Amatu, Paolo Manca, Francesca Bergamo, Federica Tosi, Gianluca Mauri, Margherita Ambrosini, Francesca Daniel, Valter Torri, Angelo Vanzulli, Daniele Regge, Giovanni Cappello, Caterina Marchiò, Enrico Berrino, Anna Sapino, Silvia Marsoni, Salvatore Siena, Alberto Bardelli
• Journal: Nature medicine (Nat Med) Vol. 28 Issue 8 Pg. 1612-1618 (08 2022) ISSN: 1546-170X [Electronic] United States
• PMID: 35915157 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Circulating Tumor DNA
• Panitumumab
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins p21(ras)

Topics

• Antibodies, Monoclonal (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Circulating Tumor DNA (genetics)
• Colonic Neoplasms (drug therapy)
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Humans
• Mutation (genetics)
• Panitumumab (therapeutic use)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Rectal Neoplasms (drug therapy)