Piotr Wysocki: Rechallenge with anti-EGFR antibodies is a feasible and safe strategy in refractory metastatic colorectal cancer patients with RAS/BRAFwt ctDNA

Piotr Wysocki, Professor of Medicine and Head of the Department of Oncology at Jagiellonian University Hospital, shared on LinkedIn:

“Results of a non-randomized controlled trial have been published in JAMA Open by Ciardiello D. et al.

This study used a pooled analysis of individual patients’ data from patients with RAS/BRAF wt ctDNA mCRC enrolled in 4 Italian trials (CAVE, VELO, CRICKET, and CHRONOS) and treated with anti-EGFR rechallenge between 2015 and 2022. Overall, 114 patients received anti-EGFR rechallenge as experimental therapy (48 received cetuximab plus avelumab, 26-trifluridine-tipiracil plus panitumumab, 13 received irinotecan plus cetuximab, and 27 received panitumumab monotherapy). Eighty-three patients (72.8%) had received 2 previous lines of therapy, and 31 patients (27.2%) had received 3 or more previous lines of therapy.

The pooled analysis revealed that anti-EGFR rechallenge resulted in:

• Overall response rate in 17.5% of patients
• Disease stabilization in 57% of patients
• Progressive disease in 28% of patients

The median PFS was 4.0 months, and the median OS was 13.1 months in the study population.
The authors have not elaborated on whether the benefit of anti-EGFR rechallenge was associated with using other agents in combination or was unrelated to any particular type of treatment.

The absence of liver metastases was the only predictive factor for improved PFS and OS:

• No liver metastases – median PFS – 5.7 months, median OS – 17.7 months
• Liver metastases – median PFS – 3.6 months, median OS – 11.5 months

The study demonstrates that rechallenge with anti-EGFR antibodies is feasible and safe in advanced colorectal cancer patients without RAS/BRAF mutations detected in ctDNA. However, the relative benefit of this treatment seems small, with less than 20% of patients experiencing ORR and short PFS (4.0 months).

The development of resistance to anti-EGFR antibodies is a complicated phenomenon that involves not only mutation in the MAPK signaling pathway but also other molecular events like activation of collateral signaling pathways (e.g., PI3K-AKT-mTOR), downregulation of EGFR, or upregulation of immunosuppressive mechanisms responsible for inhibition of ADCC.

Nevertheless, in patients with treatment-refractory CRC, after exhausting all standard regimens and the unavailability of suitable clinical trials, the rechallenge with anti-EGFR may represent the last and only option for systemic treatment.”

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Source: Piotr Wysocki/LinkedIn

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