Journal
NATURE MEDICINE
Volume 28, Issue 8, Pages 1612-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-022-01886-0
Keywords
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Funding
- FONDAZIONE AIRC under 5 per Mille 2018 [21091]
- AIRC under IG 2018 [21923]
- European Research Council under the European Union 2020 research and innovation programme [101020342]
- IMI [101007937]
- International Accelerator Award, ACRCelerate
- Cancer Research UK [A26825, A28223]
- FC AECC [GEACC18004TAB]
- AIRC [22795]
- BiLiGeCT, Progetto PON [ARS01_00492]
- Ministero della Salute Ricerca Corrente 2021-2022
- European Research Council (ERC) [101020342] Funding Source: European Research Council (ERC)
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This study aimed to use blood-based testing of RAS/BRAF/EGFR mutation levels to guide anti-EGFR therapy in patients with colorectal cancer. The results showed that rechallenge therapy with panitumumab, guided by liquid biopsies, had favorable outcomes compared to standard treatments. This suggests that liquid biopsies can effectively and safely guide treatment decisions in patients with mCRC.
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: ; 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.
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