CHRONOS Trial Supports Metastatic CRC Liquid Biopsy-Guided EGFR Inhibitor Rechallenge

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Circulating tumour (ct)DNA can help direct epidermal growth factor receptor (EGFR) inhibitor therapy rechallenge among patients with metastatic colorectal cancer (CRC) after the development of treatment resistance, Italian researchers believe. 

The phase II study findings were presented at the 2021 ASCO Annual Meeting by Andrea Sartore-Bianchi, from the University of Milan, who described the CHRONOS trial as the “first study of interventional liquid biopsy for guiding anti-EGFR therapy in metastatic colorectal cancer”. 

He explained that EGFR resistance is driven predominantly by mutant RAS and EGFR clones but these resistant alleles decline exponentially after treatment withdrawal, raising the potential for treatment rechallenge after such mutations have cleared. 

Hypothesising that use of ctDNA to identify patients suitable for rechallenge could help improve the reported rechallenge objective response rate of around 20%, the investigators screened 52 patients who initially achieved a response to EGFR-targeted therapy but subsequently experienced progressive disease and were given at least one non-EGFR-targeted therapy. 

Overall, 31% of patients tested positive for a RAS, BRAF, and/or EGFR mutation and were ineligible for rechallenge, thereby avoiding likely “ineffective treatment”, said Andrea Sartore-Bianchi. 

Of the 69% of patients who had ctDNA for wild-type RAS, BRAF and EGFR alleles at molecular screening, 27 were enrolled into the study; nine patients did not progress to treatment following death, clinical issues, alternative treatment or COVID-19. 

Rechallenge patients were aged a median 64 years and predominantly male (59%) with left colon disease (66%) and a good ECOG performance status (0–1, 96%) after a median three prior lines of treatment including an EGFR-targeted agent given in combination with chemotherapy. Over half (55%) had received panitumumab, 51% cetuximab and 4% both agents.  

The trial achieved the primary endpoint of treatment response, with an objective response rate of 30%. All responses were partial and a further 33% of patients had stable disease lasting at least 4 months, giving a disease control rate of 63%.  

Median progression-free survival was 16.4 weeks, the presenter said. 

Among patients eligible for rechallenge, liquid biopsy showed that individuals were free from mutated ctDNA alleles and achieved a partial response to rechallenge from as early as 4 months after finishing their prior anti-EGFR treatment, whereas some patients screened in the trial continued to show mutated alleles more than 30 months after finishing initial EGFR inhibitor therapy. 

This indicates that “molecular data can better guide the optimal timing for rechallenging patients than theoretical estimation from literature or anti-EGFR treatment-free intervals that are required for decay of resistance clones proposed as to have life that is approximately 8 months”, emphasized Andrea Sartore-Bianchi. 

The investigator also noted that further analysis identified HER2 mutations in two patients who did not respond to rechallenge and postulated that adding ctDNA testing for this gene could further improve patient selection. 

The ORR “favourably compares” with standard of care in patients who have received more than two lines of treatment, making ctDNA-driven rechallenge “a valid therapeutic option” that can be incorporated into the management of pretreated metastatic CRC, concluded Andrea Sartore-Bianchi. 

Session discussant Guillem Argiles, from Memorial Sloan Kettering Cancer Center in New York, USA, noted that progression-free survival benefits occurred in patients regardless of number of prior chemotherapy or anti-EGFR treatments or tumour sidedness. 

However, he remarked that the CHRONOS trial lacked randomization and standardisation of ctDNA panels, and issues with both access to testing and turnover of test results may affect implementation of the ctDNA testing strategy. 

Reference  

Sartore-Bianchi A, Pietrantonio F, Lonardi S, et al. Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial. J Clin Oncol 2021;39(suppl 15; abstr 3506). DOI: 10.1200/JCO.2021.39.15_suppl.3506