Efficacy of PD-L1 targeting and novel mechanisms of resistance in metastatic colorectal cancer

In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade (ICB) is ineffective but combinatorial approaches enhancing immunogenicity have been insufficiently explored. We treated RAS/BRAF wild-type mCRC patients on a phase II trial combining chemotherapy with the EGFR antibody cetuximab and the PD-L1 antibody avelumab. Circulating tumor DNA showed rapid clearance mirroring impressive early tumor responses while increasing levels over time predicted imminent clinical progression. While resistance mediating RAS or EGFR ectodomain mutations were largely suppressed, B2M and JAK1 ICB resistance mutations were selected in some patients. In three patients expressing the high-affinity Fc?R3a, novel PD-L1 variants were discovered leading to loss of tumor PD-L1, avelumab binding and activity. These variants represent a novel mechanism of immune escape on PD-L1 directed ICB and are the first proof-of-activity of ICB and direct anti-tumor effects of avelumab in the setting of MSS mCRC.