593P - Role of circulating tumor DNA (ctDNA) in assessing primary anti–epidermal growth factor receptor (EGFR) resistance in untreated RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC) patients (pts)

Background

Current guidelines recommend anti-EGFR–based first-line therapy after evaluation of RAS, BRAF mutational status and primary tumor sidedness in mCRC pts. However, knowledge gaps about primary resistance to EGFR inhibition exist and more negative predictive biomarkers are required to identify pts who can be spared toxicities from anti-EGFR therapy and benefit from alternative biologic agents. With limited prospective data available, this study was conducted to explore the clinical utility of ctDNA NGS (Guardant360) in assessing alterations of primary EGFR resistance.

Methods

This is a prospective study looking to identify 40 newly-diagnosed, untreated mCRC pts who are RAS/BRAF WT by routine tumor profiling and planned for chemotherapy in combination with anti-EGFR therapy. Prior to treatment initiation, all pts underwent ctDNA testing to assess presence of at least one of the following alterations associated with resistance to anti-EGFR: mutations (mt) (RAS, BRAF, PTEN, AKT, PI3KCA, SMAD4, EGFR), amplifications (amp) (ERBB2, MET), and fusions (NTRK/ROS1/ALK/RET). Pt characteristics, treatment information and outcomes were analyzed.

Results

With 21 pts consented thus far, sequencing success rate was 95.2% (20/21). Median age was 62 years, 100% left-sided tumors, 53% male and 90% (18/20) had at least 1 cycle of anti-EGFR therapy. Average turnaround time for ctDNA was 7.2 days. 6 pts (30%) had alterations of primary EGFR resistance including mt in ERBB2 (N=1) and SMAD4 (N=3); ERBB2 amp (N=1) and RAF amp (N=1). Treatment response to anti-EGFR was observed in 10 of 13 pts (76.9%) without resistant alterations vs. 2 of 5 pts (40%) with alterations (odds ratio=1.92; p=0.27). With a median follow-up of 4.7 months(m), there was a trend towards improved median progression-free survival of pts without vs. with alterations (7.0 vs. 2.8m; HR=0.88; p=0.88).

Conclusions

ctDNA testing detects primary resistance to EGFR inhibition in a subgroup of untreated, RAS/BRAF WT mCRC pts, thus serving as a prognostic classifier and providing additional value above routine tumour profiling. Updated results will be presented.

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R. Sundar: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, DKSH, GSK, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Eli Lilly, Bristol Myers Squibb, Roche, Taiho, AstraZeneca, DKSH, Ipsen; Financial Interests, Personal and Institutional, Local PI: MSD, Taiho, Bristol Myers Squibb, Novartis; Financial Interests, Personal, Stocks/Shares: Teladoc; Financial Interests, Institutional, Advisory Board: Paxman Coolers; Non-Financial Interests, Advisory Role: Paxman Coolers; Non-Financial Interests, Principal Investigator: MSD, Natera. S. Hsing, S. Jain: Financial Interests, Personal, Full or part-time Employment: Guardant Health. C.E. Chee: Financial Interests, Institutional, Advisory Board: AstraZeneca, Roche, Merck; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Other, Educational meeting chair: Pierre Fabre. All other authors have declared no conflicts of interest.