Beyond CPS for PD-L1 scoring: Genetic alterations that impact efficacy of immunotherapy in hepatocellular carcinoma (HCC)


Emil Lou, Yasmine Baca, Phillip Walker, Anthony Frank Shields, Ajay Prakash, Benjamin Adam Weinberg, Anwaar Saeed, Sanjay Goel, Chadi Nabhan, Wolfgang Michael Korn, Joanne Xiu

Background: Tumor-agnostic approvals of immune checkpoint inhibitors (ICI) include deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) and high tumor mutational burden (TMB) while in cancer like metastatic gastroesophageal cancers, ICI use has been predicated on PD-L1 expression. ICI are increasingly used for metastatic HCC, but without required markers. We aimed to examine the genomic landscape of HCC in context of PD-L1 expression, and to determine clinical responses to ICI in this setting.

Methods: Next-generation sequencing of DNA (592 or WES) and RNA (WTS) was tested at Caris Life Sciences (Phoenix, AZ). PD-L1 expression was tested by IHC (SP142) and compared as high (2+,5%), low (1-2,1%) and negative (0). dMMR/MSI-H was tested by IHC/NGS and TMB-High was defined as ³10 mutations/MB. QuantiSEQ was used to estimate the tumor microenvironment. X2/Fisher-Exact were used and significance was determined as P-value adjusted for multiple comparison (Q < 0.05). Real-world overall survival (rwOS) was obtained from insurance claims and calculated from tissue collection to last contact; time-on-treatment (TOT) was calculated from start to finish of ICI treatments.

Results: Overall, 17.7% of HCC expressed PD-L1 by IHC; 79/1306 (6.1%) had high expression. The overall prevalence of dMMR/MSI-H was 0.2%; TMB was high in 5.1%. PD-L1 expression was not associated with MSI-H or high TMB. When comparing tumors that are PD-L1 high vs. negative vs. low, expression of several immuno-oncologic (IO) markers LAG3 (median TPM: 2.4, 0.8, 0.5), CTLA-4 (2.9, 1.2, 0.5), IDO1 (4.2, 1.3, 0.6) and others, as well as T-cell inflamed and IFNg scores all decreased significantly with PD-L1 (all q<0.05), similar trends were seen with B cells, M1 macrophages, CD8+ T cells and T regs while opposite differences seen in NK cells (q<0.05). Additionally, when PDL1-high tumors were compared to PDL1-negative, mutations in CTNNB1 trended lower (21% vs 35%) while amplifications of KRAS (4% vs 0%), PDCD1LG2 (4% vs 0%) and mutations in HNF1A (3% vs 0%), HOXB13 (6% vs 0%), STK11 (5% vs 0%) trended higher; when PDL1-low were compared to PDL1-negative, mutations in TP53 (45% vs 32%), ELF3 (3% vs 0%), TSC2 (6% vs 2%) and PIK3CA (5% vs 1%) and amplifications in BCL9 (2% vs 0%) and CCNE1 (2% vs 0%) trended higher. When investigating clinical outcome of a cohort of 908 HCC tumors, PD-L1 expression had no effect on prognosis, and was not associated with differences in TOT of ICI in HCC.

Conclusions: Prevalence of dMMR/MSI-H and TMB-H is very low in HCC. PD-L1 is only expressed in <20%. Even with a finding of strong association of expression of several established IO biomarkers with PD-L1 expression, it’s still not predictive of response to ICI. New biomarkers or molecular signatures need to be identified and validated to objectively identify HCC patients most likely to benefit from ICI treatment.

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