Abstract 124P
Background
Anti-epidermal growth factor receptor antibodies (EGFRabs) such as cetuximab/panitumumab are effective treatments for RAS/RAF wild-type (wt) metastatic colorectal cancer (mCRC). Acquired resistance (AR) to single-agent EGFRabs frequently occurs through genetic aberrations (GAs) that reactivate the RAS/RAF pathway. Surprisingly, only 6.6% of patients (pts) in the SWOG-80405 trial had mutations (MTs) that activate the RAS/RAF pathway in their ctDNA after first line chemo- and EGFRab combination-therapy. This may suggest that AR differs when EGFRabs are given with chemo- compared to monotherapy. Here, we report the analysis of genetic AR in biopsies from mCRCs that progressed on EGFRab and chemotherapy.
Methods
Biopsies from left-sided and initially RAS/RAF wt mCRCs were collected after progression on first-line EGFRab and chemotherapy in the iSCORE trial (NCT03867799). Whole exome sequencing (WES) of 17 biopsies was performed with a median depth of 465x.
Results
GAs that activate the RAS/RAF pathway were detected in 7/17 biopsies (41%). Of these, 3 (18%, 2x KRAS Q61H, 1x BRAF V600E) were clearly acquired as the affected genes had been sequenced and were wt at diagnosis. Of the other 4 GAs, 1 (KRAS G13H) had been present at diagnosis but had remained undetected due to assay limitations, and 3 (MEK1 K57T, ERBB2 S310F, ERBB2 amplification) were in genes that had not been sequenced at diagnosis. Sequencing of these in pre-treatment biopsies is ongoing to ascertain if they were acquired. No subclonal hotspot MTs were identified in other RTKs or RAS/RAF pathway genes despite our ability to detect down to 1% variant allele frequency.
Conclusions
Deep WES identified AR MTs in 18% of biopsies which is higher than ctDNA results from SWOG-80405. 10/17 (59%) biopsies harboured no GAs in the RAS/RAF pathway or upstream RTKs. This is similar to published data on biopsies from pts with AR to single-agent cetuximab (Woolston, 2019) and supports the existence of alternative resistance mechanisms. Our study indicates that ctDNA alone may underestimate the frequency of AR MTs in the RAS/RAF pathway and that there is additional value in biopsy-based analyses beyond genetic alterations which are critical to define the landscape of EGFRab resistance.
Clinical trial identification
NCT03867799.
Legal entity responsible for the study
Royal Marsden NHS Foundation Trust.
Funding
Bristol Myers Squibb supported this trial through provision of research funding and the investigational agents.
Disclosure
I. Chau: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eli Lilly, MSD, Roche, Merck Serono, AstraZeneca, OncXerna, Boehringer Ingelheim, Astella, Incyte, GSK, Sotio, Daiichi Sankyo, Eisai, Taiho, Seagen, Turning Point Therapeutics, Novartis; Financial Interests, Personal, Invited Speaker: Eisai, Eli Lilly, Servier, Servier; Financial Interests, Institutional, Invited Speaker: Cilag-Janssen, Eli Lilly. N. Starling: Financial Interests, Personal, Advisory Board: GSK, Novartis, MSD Oncology, Servier, AstraZeneca, Pfizer, Gilead Sciences; Financial Interests, Personal, Invited Speaker: Clinical Options, Eli Lilly, Pierre Fabre, Amgen, Merck Serono, Novartis, MSD Oncology, GSK, Servier, Seagen; Financial Interests, Institutional, Research Grant, Sept 2017 (24m)- Paid to institution research: Merck; Financial Interests, Institutional, Research Grant, Nov 2017 (48m) - Paid to institution research fund: AstraZeneca; Financial Interests, Institutional, Research Grant, Jan 2018 - Paid to institution research fund: Pfizer; Financial Interests, Institutional, Research Grant, July 2018 (36m) - Paid to institution research fund: BMS; Financial Interests, Institutional, Research Grant, June 2022: Guardant; Non-Financial Interests, Advisory Role, Ad Board uncompensated: Guardant. M. Gerlinger: Financial Interests, Institutional, Funding: BMS, Roche, Merck KG; Other, Personal, Advisory Role: Roche, MSD, BMS, GSK. All other authors have declared no conflicts of interest.