562P - Acquired genomic alterations on first-line chemotherapy (CT) + cetuximab in advanced colorectal cancer (mCRC): Circulating tumor (ct)DNA analysis of the randomized phase II trial TIME-PRODIGE-28

Background

We aimed to describe tissue and ctDNA profiling in RASwt mCRC as prognostic/predictive biomarkers for the efficacy of cetuximab (cetux) maintenance in the TIME trial. In this trial, mCRC patients (pts) without disease progression (PD) after 1st-line induction CT with 8 cycles of FOLFIRI+cetux were randomized to bi-weekly maintenance with cetux alone (arm A) or observation (arm B). At PD, the same full CT regimen was reintroduced for 16 weeks followed by maintenance with cetux/observation until PD under full induction CT regimen.

Methods

Tissue and ctDNA were analysed using targeted next generation sequencing (NGS ; Colon-Lung Panel v2) using the base position error rate method. ctDNA samples were collected at T1=baseline, T2=after 4 month-induction FOLFIRI + cetux, T3= 4 weeks after start of 1st maintenance/observation interval, T4=at PD after full 1st-line regimen reintroduction. Study objectives were: to describe baseline and acquired ctDNA NGS alterations associated with resistance to anti–EGFR, to compare the occurrence of acquired alterations in the 2 arms, to study the impact of ctDNA kinetics/alterations with clinical outcomes.

Results

A total of 103 (74%; n=49/54 in arm A/B) of the 139 randomized pts had at least one available ctDNA NGS data. ctDNA could be detected in 81/95 pts (85%) at T1, 26/92 (28%) at T2, 33/75 (44%) at T3, and 51/64 (79%) at T4. In baseline ctDNA, additional alterations as compared to tumor tissue were found in 22 (27%) pts including BRAFV600 (n=1), KRAS (n=3), NRAS (n=1) mutations, HER2 (n=1) and EGFR (n=1) amplifications. At T4, acquired anti-EGFR resistance alterations were detected in 14/64 (22%) pts including KRAS (n=10), NRAS (n=1), HER2 (n=1), FGFR1 (n=2) mutations/amplifications, and were more frequently observed in cetux arm: n=10/26 vs 6/37 pts in arm A vs B (p=0.046). Correlation between ctDNA kinetics/alterations and clinical outcomes will be presented at the meeting.

Conclusions

ctDNA monitoring and extended molecular profiling beyond RAS may have the potential to improve patient selection for anti-EGFR containing maintenance regimens, including treatment adaptation over time.

Clinical trial identification

NCT02404935.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Merck Serono.

Disclosure

All authors have declared no conflicts of interest.