Early [18F]FDG PET/CT response evaluation after a single dose of anti-EGFR therapy as a predictive biomarker for treatment benefit in patients with advanced colorectal cancer.
Authors: Menke Catharina Wilhelmina , Gerritse Sophie , Van Helden Erik Jacobus , Arens Anne I.J. , Boellaard Ronald , Buffart Tineke E. , Labots Mariette , Angus Lindsay , De Vries Elisabeth , Pruijt Hans , Koornstra Rutger H.T. , Hoekstra Otto S. , Gootjes Elske C. , Verheul Henk M.W. 
Published: June 2024

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Background: The use of anti-Epidermal Growth Factor Receptor monoclonal antibody therapy (anti-EGFR mAb) for patients with metastatic colorectal cancer (mCRC) is ongoing subject of research. Initially, absence of mutations in KRASand NRAS oncogenes was identified as biomarker for response, however, not all patients benefitted. Molecular imaging to assess metabolic response could serve as an early biomarker for treatment response. We evaluated the predictive performance of early evaluation of metabolic rate with [18F]FDG PET/CT and baseline and after 1 intravenous anti-EGFR mAb administration to distinguish patients with and without clinical benefit. Methods: The multicenter IMPACT-CRC study (NCT02117466) prospectively included patients with RASwild-type mCRC starting treatment with biweekly monotherapy anti-EGFR mAb (cetuximab or panitumumab) as second or third line treatment. Clinical benefit was defined as partial, response (PR)complete response (CR) and stable disease (SD) according to RECIST (version 1.1) with CT-imaging at 8 weeks. Patients underwent an [18F]FDG PET/CT at baseline and 2 weeks after start therapy prior to the second treatment cycle. Change in sum Total Lesion Glycolysis (TLG, defined as metabolic active tumor volume (MATV) times mean standard uptake value corrected for lean body mass (SULmean)) of 5 lesions according to van Helden et al (PLoS One 2016 May 19;11(5):e0155178) was evaluated as a predictive biomarker for clinical benefit using a predetermined data-driven threshold. Tumor sidedness and BRAF mutations were determined. Results: Seventy-five out of 80 participating patients were evaluable for metabolic response: The mean change in sum TLG was -58% (SD 19%) for patient with clinical benefit (n=57) versus -1·9% (SD 36%) without clinical benefit (n=18); P =0·003. A threshold of < -15% change in sum TLG had a 100% negative predictive value for clinical benefit. Metabolic responders had a longer progression-free survival (PFS) compared to metabolic non-responders (6.5 versus 1·7 months ( P<0·001)). Sixty-five (out of 80) patients had RAS/BRAF wild-type (wt) left-sided mCRC, with a 91% clinical benefit rate (30% PR and 61% SD) and a median PFS of 5·7 months (95% CI 5·2 – 10). Conclusions: Early [18F]FDG PET/CT after a single dose of anti-EGFR mAb therapy demonstrates a 100% negative predictive value for clinical benefit. Selection of patients with left-sided RASwt/ BRAFwt mCRC successfully identifies the majority (91%) of patients with clinical benefit from anti-EGFR monotherapy. For mCRC patients with inconclusive mutational screens early [18F]FDG PET/CT evaluation may have clinical value to predict treatment benefit. Clinical trial information: NCT02117466 .