Abstract 1688P
Background
In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective. However, data from the AVETUX trial suggests PD-L1 epitope escape upon avelumab treatment in MSS-mCRC patients expressing the high affinity SNP of FcγR3a (rs396991).
Methods
Biomarker substudy of a patient on the FIRE-6 (AIO KRK-0118) trial with histologically confirmed, treatment-naïve, RAS/RAF wild-type metastatic colorectal cancer (MSS). The patient received 4 cycles of FOLFIRI/cetuximab, followed by 4 cycles FOLFIRI/cetuximab + avelumab, followed by avelumab maintenance treatment for 10 weeks until end of treatment (EOT) due to progression in week 19. Mutational profiling of cell-free DNA (cfDNA) was performed with custom gene panels and liquid biopsy monitoring by digital droplet PCR (ddPCR). Identified PD-L1 variants were functionally validated in cell culture models using standard molecular genetics tools.
Results
We confirmed the principle of PD-L1 immune escape in MSS-mCRC patients expressing the high affinity SNP of FcγR3a under avelumab treatment. In the monitored patient PD-L1 L88E and L88fs mutations emerged under selective pressure with avelumab. Functional validation of PD-L1 in cell models suggests that L88E represents a phosphomimetic variant of L88S identified in the AVETUX trial. Both variants exhibit loss of protein stability and proteasomal degradation.
Conclusions
PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a. Leucine 88 of PD-L1 is a hotspot residue critically regulating PD-L1 cell surface expression with clinical significance in the context of immune checkpoint blockade. Together with the emergence of truncated PD-L1 variants, regulation of PD-L1 availabilty but not epitope disruption appears to be the key mechanistic principle towards PD-L1 escape. Future trials confirming this principle in other entities are warranted especially in patient subpopulations with rs396991.
Clinical trial identification
NCT05217069.
Editorial acknowledgement
Legal entity responsible for the study
AIO-Studien-gGmbH.
Funding
Has not received any funding.
Disclosure
V. Heinemann: Non-Financial Interests, Institutional, Invited Speaker: Merck, Amgen, Roche, Sanofi, Sirtex, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS, MSD, Novartis, Boehringer Ingelheim, Celgene, Terumo, Oncosil, Seagen; Non-Financial Interests, Institutional, Funding: Merck, Amgen, Roche, Sanofi, Pfizer, Boehringer Ingelheim, Sirtex, Servier. S. Stintzing: Non-Financial Interests, Institutional, Invited Speaker: Amgen, AstraZeneca, Bayer, BMS, Esiai, LEO Pharma, Lilly, Merck, MSD, Pierre Fabre, Roche, Sanofi, Servier, Taiho, Takeda; Non-Financial Interests, Institutional, Funding: Merck, Pierre Fabre, Roche, Servier. All other authors have declared no conflicts of interest.