689P - Human leukocyte antigen (HLA) class I/II expression as a predictive biomarker for response to immune oncology (IO) therapy in metastatic clear-cell renal cell carcinoma (m-ccRCC)

Background

Predictive biomarkers for IO in m-ccRCC are lacking. As antigen presentation by HLA class I/II is essential for T cell activation, impact of tumoral HLA expression on IO efficacy was studied in one French (NIVOREN GETUG-AFU 26) and two Belgian patient (pt) cohorts.

Methods

RNA sequencing of tumoral FFPE tissue was performed in m-ccRCC pts treated with nivolumab (NIVO) in any line, ipilimumab-NIVO (IPI-NIVO) in first line and pts never treated with IO. HLA score was defined as the sum of expression of classical HLA class I/II genes (omitting poorly detected genes, selecting HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRA and -DRB1) divided into high (^hi) and low (^lo) groups by highest tercile.

Results

Belgian NIVO treated pts (n=37) with HLA^hi score had higher ORR (42 vs. 8%, p=0.03), longer median (m-) PFS (7 vs. 3 months (mo), HR 0.36, 95% CI 0.15-0.85, p=0.02) and a non-significant trend towards longer mOS (not reached (NR) vs. 18 mo, HR 0.39, 95% CI 0.13-1.16, p= 0.08). Belgian IPI-NIVO treated pts (n=18) with HLA^hi score had higher ORR (100 vs. 31%, p=0.01), longer mPFS (47 vs. 9 mo, p=0.002) and mOS (NR vs. 45 mo, p=0.04). On multivariable analysis in Belgian pts, the effect was independent of IMDC risk groups and the molecular ccrcc1-4 subtypes. In the French NIVO treated pts (n=116), HLA^hi score was associated with longer mPFS (5 vs. 3 mo, HR 0.64, 95% CI 0.42-0.99, p= 0.04). Non-significant trends towards longer mOS (25 vs. 18 mo, HR 0.59, 95% CI 0.33-1.06, p=0.08) and higher ORR (29 vs. 16%, p=0.14) were seen. In Belgian pts never treated with IO (n=82), no effect was observed. Kidney Immune Classification Immune^hi Stromal^lo subtypes, responding well on IO, were enriched in HLA^hi tumors (NIVOREN cohort, 41 vs. 13%, p=0.002). HLA^hi tumors had upregulated immune-related gene sets (allograft rejection, interferon alpha and gamma response) in all cohorts.

Conclusions

High tumoral HLA class I/II expression in m-ccRCC appears predictive of IO efficacy, an effect not seen with other therapies, highlighting its potential as a predictive biomarker. Further study of underlying tumoral features driving increased HLA class I/II expression, and type of cells expressing HLA, is warranted.

Clinical trial identification

S53479/S63833 (Belgian cohorts), NCT03013335 (NIVOREN GETUG-AFU 26 phase II trial).

Editorial acknowledgement

Legal entity responsible for the study

Unicancer (NIVOREN GETUG-AFU 26 study), University Hospitals Leuven (Belgian cohort).

Funding

Institut National du Cancer, Bristol-Myers-Squibb and “Kom op tegen Kanker” (Stand up to Cancer), Flemish Cancer Society.

Disclosure

Y. Vano: Financial Interests, Personal, Royalties, honoraria for advisory board, travel expenses/accomodations: Bristol Myers Squibb; Financial Interests, Personal, Royalties, honoraria for advisory board, travel expenses/accomodations: Pfizer; Financial Interests, Personal, Royalties, honoraria for advisory board: Novartis; Financial Interests, Personal, Royalties, honoraria for advisory board: Ipsen; Financial Interests, Personal, Royalties, honoraria for advisory board: Merck; Financial Interests, Personal, Royalties, honoraria for advisory board, travel expenses/accomodations: MSD; Financial Interests, Personal, Royalties, honoraria for advisory board: Janssen; Financial Interests, Personal, Royalties, honoraria for advisory board: Sanofi; Financial Interests, Personal, Royalties, honoraria for advisory board: Astellas; Financial Interests, Personal, Royalties, honoraria for advisory board, travel expenses/accomodations: Roche. N. Chaput: Financial Interests, Institutional, Sponsor/Funding, Sponsored research at Gustave Roussy Cancer Center: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding, Sponsored research at Gustave Roussy Cancer Center: Bristol-Myers-Squibb; Financial Interests, Institutional, Sponsor/Funding, Sponsored research at Gustave Roussy Cancer Center: GlaxoSmithKline; Financial Interests, Institutional, Sponsor/Funding, Sponsored research at Gustave Roussy Cancer Center: Roche; Financial Interests, Institutional, Sponsor/Funding, Sponsored research at Gustave Roussy Cancer Center: Sanofi; Financial Interests, Institutional, Sponsor/Funding, Sponsored research at Gustave Roussy Cancer Center: Cytune Pharma. B. Beuselinck: Financial Interests, Royalties: Bristol Myers Squibb; Financial Interests, Royalties: Merck; Financial Interests, Royalties: Pfizer; Financial Interests, Royalties: Ipsen; Financial Interests, Royalties: AstraZeneca. All other authors have declared no conflicts of interest.