CHRONOS Trial: ctDNA-Guided Anti-EGFR Rechallenge Shows 30% Response in Colorectal Cancer
The CHRONOS phase 2 trial used interventional ctDNA screening to guide panitumumab rechallenge in metastatic colorectal cancer patients with acquired anti-EGFR resistance. Of 52 screened patients, 31% were excluded for carrying resistance mutations in blood. Among 27 enrolled RAS/BRAF/EGFR wild-type patients, 30% achieved partial response and 63% disease control. This is the first trial to demonstrate that real-time liquid biopsy screening can safely and effectively select patients for anti-EGFR rechallenge.
The original study
Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial.
- Authors
- Sartore-Bianchi A, Pietrantonio F, Lonardi S, Mussolin B, Rua F, Crisafulli G, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't
- PMID
- 35915157
Original 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.