Longitudinal ctDNA profiling to guide anti-EGFR rechallenge in metastatic colorectal cancer: a prospective single-arm phase II trial

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Anti-epidermal growth factor receptor (EGFR) rechallenge is a late-line treatment option for molecularly selected metastatic colorectal cancer. Although guidelines support molecular assessment before rechallenge, it remains unclear whether longitudinal circulating tumour DNA (ctDNA) profiling across the anti-EGFR-free interval provides additional relevant information. We aimed to investigate whether testing immediately after the progression on prior anti-EGFR therapy, followed by retesting before rechallenge, improves patient selection. We conducted a prospective study linking the REMARRY monitoring cohort with the PURSUIT multicentre single-arm phase II treatment trial. Eligible patients had tumour tissue RAS/BRAF V600E wild-type metastatic colorectal cancer, prior response to anti-EGFR therapy, plasma RAS negativity before rechallenge, and an anti-EGFR-free interval of at least 4 months. Patients received panitumumab plus irinotecan every 2 weeks until disease progression or unacceptable toxicity. The study started in May 2019. Trial Registration: PURSUIT (jRCTs031190096), REMARRY (UMIN000036424), GOZILA (UMIN000029315). Clinical trial information: jRCTs031190096. Here we show results from 185 patients enrolled in REMARRY, 51 subsequently enrolled in PURSUIT, and 50 received study treatment. The confirmed objective response and disease control rates were 14.0% and 80.0%, respectively. The median progression-free survival and overall survival were 3.6 and 12.0 months, respectively. No response occurred in patients with detectable plasma RAS mutations immediately after progression on anti-EGFR therapy (0/7). Plasma RAS positivity in cycle three was associated with shorter progression-free and overall survival. Panitumumab plus irinotecan rechallenge demonstrated meaningful antitumor activity in a molecularly selected chemorefractory population. Longitudinal ctDNA assessment, immediately after progression to prior anti-EGFR therapy and before rechallenge, provides clinically relevant information on resistant clone dynamics and may help refine patient selection. PURSUIT: Japan Registry of Clinical Trials (jRCT) (registration number: jRCTs031190096; date of registration: 1 October 2019). REMARRY: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (registration number: UMIN000036424; date of registration: 5 April 2019). GOZILA: UMIN-CTR (registration number: UMIN000029315; registration date: 27 September 2017). This study examined whether blood-based tumour DNA testing could identify patients with metastatic colorectal cancer who may benefit from anti-EGFR rechallenge treatment. Some patients initially respond to anti-EGFR therapy later develop resistance; however, this resistance may temporarily become less detectable after other treatments. We prospectively followed patients and tested circulating tumour DNA at key stages, including after progression to prior anti-EGFR therapy and before rechallenge. Eligible patients were treated with panitumumab and irinotecan. We showed that patients with detectable plasma RAS alterations after anti-EGFR progression are less likely to benefit from rechallenge, even if later pre-rechallenge blood test results are negative. These results suggest that repeated ctDNA testing may enhance patient selection and warrant future investigations.

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