Tumour-tissue biopsy testing is the standard of care (SOC) to assess RAS mutation in mCRC pts. However, the analysis of circulating cell-free DNA (cfDNA) has the added advantage of being able to evidence genetic tumour heterogeneity. We explored the correlation of the RAS mutational status assessed in plasma samples with first-line (1L) treatment outcomes in SOC RAS wild type (wt) mCRC pts.
Prospective, observational, multi-centre study in mCRC pts with RASwt according to tumour-tissue biopsy and treated following standard clinical practice. Plasma samples were collected before starting 1L treatment and sent to Sysmex Inostics GmbH for BEAMing analysis. The lower threshold limit was a mutant allele fraction (MAF) ≥ 0.02%. Tumour response (TR) was evaluated approximately every 3 months based on RECIST criteria.
119 pts were included (61% male; median age: 65 y). 113 received chemotherapy (CT) + anti-EGFR, 4 CT + anti-VEGF and 2 CT alone. Overall response rate (ORR) was 68.1% (95%CI: 58.9-76.3) for all pts and 75% (95%CI: 65.8-82.8) in the108 pts with TR data. In pts treated with panitumumab (n = 92), the most homogeneous group, 76.1% (n = 70) presented left-sided tumours and 19.6% (n = 18) right-sided; overall ORR was 78.3% (95%CI: 68.4-86.2); 81.4% (95%CI: 70.3-89.7) for left and 72.2% (95%CI: 46.5-90.3) for right-sided pts. ORR in the panitumumab subgroup according to RAS mutational status analysed in cfDNA for the three MAF (cut-offs) considered is presented in the table.Table: 546P
|ORR (not confirmed) % (95% CI)||ORR (not confirmed) % (95% CI)||Odds Ratio (95% CI); P-value*|
|Mutant allele fraction, cut-off (n)||RASwt||RASmt|
|≥1% (90 wt/2 mt)||78.9 (69.0 – 86.8)||50.0 (1.3 - 98.7)||3.7 (0.2 – 62.6) 0.389|
|≥0.1% (87 wt/5 mt)||79.3 (69.3 – 87.3)||60.0 (14.7 - 94.7)||2.6 (0.4 – 16.5) 0.297|
|≥0.02% (80 wt/12 mt)||80.0 (69.6- 88.1)||66.7 (34.9-90.1)||2.0 (0.5 – 7.5) 0.285|
Fisher Test; CI=confidence interval; ORR: Overall Response Rate.
A high ORR was observed in pts treated with panitumumab independently of the localization. ORR in panitumumab treated patients tends to be higher in plasma RASwt. ORR in pts with plasma RASmt increases when a lower MAF cut-off is used. Further investigation is needed to find the optimal clinical cut-off. Study supported by Amgen.
Clinical trial identification
Legal entity responsible for the study
P. García Alfonso: Consulting fees: Amgen, Bristol, Merck, Sanofi, Roche, Bayer, Servier. M. Valladares-Ayerbes: Research grants: Roche; Consulting fees: Amgen, Roche, Merck, Sanofi, Servier. J.M. Viéitez: Research grants: Amgen, Roche; Consulting fees: Amgen, Roche, Servier, Shire, Bayer. J.J. Cruz Hernandez: Consulting fees: Amgen, Merck, Roche, BMS. A. Lloansí Vila: Full time employee, stocks: Amgen. All other authors have declared no conflicts of interest.