182MO - Immune co-regulator (co-reg) expression in mismatch repair-deficient (MMRd) endometrial cancer (EC) patients (pts): Anti-PD-(L)1-responders (R) versus (vs) non-responders (NR)

Background

MMRd status predicts benefit from anti-PD-(L)1 agents in EC, however half of them do not respond. We aimed to describe the co-regs expression in R versus NR MMRd EC to uncover escape mechanisms to anti-PD-(L)1 agents.

Methods

Clinical data and outcomes of metastatic MMRd EC pts, treated with anti-PD-(L)1 agents at Gustave Roussy Institute (2016-2021), were retrospectively collected. Pts were classified as R (CR, PR, or SD ≥12 months) or NR (PD or SD <12 months). IDO-1, PD-L1, LAG3 and TIM-3 expression were scored as the % of immune cells (IC) and tumor cells (TC) in the tumor area. Positivity cut-off for co-reg expression was ≥ 5% (IC and/or TC). % of HLA-I expression was classified as retained (≥10%) or diffuse loss (<10%). T cell infiltration was described as High or Low (intraepithelial CD3+: 2+/3+ vs 0/1+ CD3+, respectively). Non-parametric statistical tests and Pearson’s r were used.

Results

Twenty-four pts were identified: 15 R and 9 NR. Most had endometrioid histology (79%), MLH1/PMS2 loss (83%) with MLH1 hypermethylation (hm-MLH1) (75%), and had received prior platinum therapy (88%). Non-hm-MLH1 MMRd showed a trend for higher ORR compared to hm-MLH1 (71% vs 60%). Most of R (93%) had High T-cell tumors versus 56% in NR (p=0.047). R showed higher co-regs positivity compared to NR: IDO-1 (93% vs 53%), PD-L1 (73% vs 44%), LAG-3 (87% vs 22%), TIM-3 (87% vs 44%). R showed higher PD-L1 expression on intraepithelial IC compared to NR (p=0.0065), with strong correlation with other co-regs: LAG-3 (r=0.90; p<0.001), TIM-3 (r=0.76; p=0.001) and IDO-1 (r=0.58; p=0.024). Only 2/9 NR showed positive co-regs expression on intraepithelial IC (TIM3 and LAG3). NR was significantly associated with diffuse HLA loss when compared to R (55% vs 7%; p=0.01).

Conclusions

Our results suggest that resistance to anti-PD-(L)1 agents in MMRd EC may be attributable to several factors including lower intratumoral T cell infiltration, lack of PDL1 expression and loss of antigen presenting capacity. Resistance may not be mediated via upregulation of other co-regs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Alexandra Leary.

Funding

Comprehensive Program of Cancer Immunotherapy & Immunology I (CAIMI-I) funded by BBVA Foundation. Program Parrainage pour la Recherché contre les Cancers Gynécologiques- IGR.

Disclosure

M. Kfoury: Financial Interests, Personal, Invited Speaker: AZ. P. Morice: Financial Interests, Personal, Advisory Board: AZ, GSK. P. Pautier: Financial Interests, Personal, Advisory Board, 2015, 2022: PharmaMar; Financial Interests, Institutional, Advisory Board, 2020: Roche, Clovis; Financial Interests, Institutional, Advisory Board, 2021: AstraZeneca; Financial Interests, Personal, Advisory Board, 2019-2020: AstraZeneca; Financial Interests, Institutional, Advisory Board: GSK; Financial Interests, Personal, Advisory Board, 2018-2019: Roche; Financial Interests, Institutional, Expert Testimony, 2022: MSD. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape, Onko+; Financial Interests, Institutional, Other, Steering committee: MSD; Financial Interests, Institutional, Advisory Board: GSK, AZ, Clovis, Ability Pharma, MSD, Tesaro, Merck Serono, Apmonia, Blueprint; Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing; Financial Interests, Institutional, Other, Consultancy: Orion; Financial Interests, Institutional, Invited Speaker: Tesaro, AZ, Clovis; Financial Interests, Personal, Other, Consultancy: GLG; Financial Interests, Institutional, Research Grant, PI translational research: ARCAGY-GINECO, Sanofi, AZ; Financial Interests, Institutional, Funding, CI clinical trial: AZ; Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE immuno; Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK; Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche; Financial Interests, Institutional, Funding, PI 2 clinical trials: AZ; Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD; Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair; Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis; Non-Financial Interests, Personal, Proprietary Information, IDMC chair: Pfizer. All other authors have declared no conflicts of interest.