23P - Circulating immune cells and activity of immune checkpoint inhibitors in metastatic renal cell carcinoma

Background

Immune checkpoint inhibitors (IO) combinations are standard in metastatic renal cell carcinoma (mRCC) but validated biomarkers are lacking to guide strategies towards either dual IO or IO plus tyrosine kinase inhibitors (TKI). Circulating immune cells (CIC) may inform antitumor immune response but have been mostly studied with IO monotherapy. We aimed at exploring the association between CIC and outcomes in mRCC patients treated with IO including combinations.

Methods

Phenotyping of peripheral blood mononuclear cells was performed by flow cytometry before systemic treatment in PREMIS (NCT03984318) and NIVOREN trials (NCT03013335). CIC included T cells (total CD8+, senescent CD8+, total CD4+, senescent CD4+) and B cells (naive, naive transitional, switched and unswitched memory, double negative, plasmablasts) subpopulations. We assessed associations between CIC and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) across treatment subgroups. An exploratory analysis of CIC and tissue immune infiltrate was conducted.

Results

Among 112 patients, median age was 61 y.o; 75% had clear cell histology, 64% intermediate/poor risk disease. Regimens included IO-TKI in 28%, dual IO in 15%, IO monotherapy in 54%. A lower proportion of CD8+ T cells was associated with improved ORR in the overall population (p=0.008), and improved ORR (p=0.002) and PFS (HR 0.6, p=0.030) in patients treated with IO monotherapy or dual IO. No association between T cells and outcomes in patients treated with IO-TKI was observed. Senescent CD8+ T cells were highly associated with CD8+ T cell levels (r=0.51, p<0.001), and inversely associated with the presence of tertiary lymphoid structures or lymphoid aggregates within the tumor. Among B cells, plasmablasts were inversely associated with ORR (p=0.019) in the overall population with no impact on survival. Across treatment regimens, B cell subtypes were only predictive in IO monotherapy, with switched memory B cells associated with improved ORR (p=0.014) and PFS (HR 0.54, p=0.020).

Conclusions

Circulating CD8+ T cells and CD8+ senescence may inform resistance to dual IO but not IO-TKI. The role of B cells warrants further investigation. Longitudinal analyses are ongoing.

Clinical trial identification

NCT03013335, NCT03984318.

Legal entity responsible for the study

The authors.

Funding

French National Cancer Institute, ARC Foundation, Artur Foundation.

Disclosure

R. Flippot: Financial Interests, Institutional, Funding: Bayer; Financial Interests, Personal, Invited Speaker: Astellas, Janssen, MSD; Financial Interests, Personal, Non-financial benefits: BMS; Financial Interests, Personal, Speaker, Consultant, Advisor: Ipsen, Pfizer. B. Escudier: Financial Interests, Personal, Financially compensated role: Ipsen, Pfizer, Oncorena, Aveo, BMS, Ipsen; Financial Interests, Personal and Institutional, Research Funding: BMS. L. Albiges: Financial Interests, Institutional, Other, Consulting: Astellas, BMS, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Merck; Financial Interests, Personal, Other, Honoraria: Novartis; Non-Financial Interests, Personal, Principal Investigator, Clinical trial steering committee: Pfizer, BMS, AVEO, AstraZeneca, MSD; Non-Financial Interests, Personal, Principal Investigator: Ipsen; Non-Financial Interests, Personal, Other, Clinical trial steering committee: Roche, Exelixis; Non-Financial Interests, Personal, Member: ASCO; Non-Financial Interests, Personal, Other, Medical Steering Committee: Kidney Cancer Association; Non-Financial Interests, Personal, Other, Member of the Renal Cell Carcinoma Guidelines Panel: European Association of Urology (EAU). All other authors have declared no conflicts of interest.