171P - Combined expression of MKI67, FOXC1 and PDL1 is a pan-tumor tissue-agnostic predictor of PD1/PDL1 inhibitor efficacy in metastatic renal cell cancer: Validation in checkmate 009, 010 and 025 clinical trial cohorts

Background

Accurate prediction of PD1/PDL1 inhibitor therapeutic efficacy (TE) as well as any resultant durable clinical benefit (improved progression-free survival (PFS), overall survival (OS)) is not consistently achieved with existing biomarkers like PDL1 or tumor mutational burden(TMB). We hypothesized that a multi-marker (MM) predictive biomarker strategy that tracks plasticity using FOXC1 expression, in parallel to tumor proliferation and immune evasion, using expression of MKI67 and PDL1, respectively, may demonstrate superior TR prediction, and also enable accurate prediction of risk for hyperprogressive disease (HPD).

Methods

Metastatic renal cell carcinoma (mRCC) patients enrolled in Checkmate (CM) 009, 010 and 025 clinical trials (n=35, 168, 803) with available pre-treatment tumor RNA-Seq data (n=16, 45, 250 respectively) were analysed for FOXC1, MKI67 and PDL1 expression, and correlated with overall response rate (ORR), PFS, OS and HPD, the latter defined as time-to-treatment-failure <=2 months post-treatment initiation. Optimized biomarker cut-off values based on model area-under-curve were leave-one-out cross validated and prediction algorithms derived to predict Predicted Responders (PR) and Non-Responders (NR). The unmodified strategy was then validated in independent datasets.

Results

In CM025 ORR prediction by MM was specific to the Nivolumab arm [ITT CR%=22.5%, PR CR%=41.8%, NR CR%-3.6% OR=19.4 (4.3- 87.8)95%CI, p<0.0001, n=111] and not the Everolimus arm [ITT CR%=4.6%, PR CR%=3.3%, NR CR%= 5.4%, n=109]. This was confirmed further in combined CM009+CM010 cohorts (OR=9.63 (0.98-94.54) 95%CI, p=0.03). MM-predicted PR consistently displayed superior PFS (p<0.0001) and OS (p=0.03) compared to predicted NR who displayed either Progressive Disease or Hyperprogressive Disease, and were superior to results with PDL1.

Conclusions

Tracking multiple dimensions of cancer biology using our MM approach again proved its superiority in predicting PD1/PDL1 inhibitor efficacy in advanced/metastatic tumors, this time in mRCC patients. This approach merits further testing in prospective clinical trials.

Clinical trial identification

NCT01358721 - October 28, 2021 NCT01354431 - May 12, 2022 NCT01668784 - August 9, 2022.

Editorial acknowledgement

Legal entity responsible for the study

Partha S. Ray, MD.

Funding

Has not received any funding.

Disclosure

P.S. Ray: Non-Financial Interests, Institutional, Advisory Board: Onconostic Technologies Inc.; Financial Interests, Institutional, Stocks/Shares: Onconostic. T. Ray, R. Hussa: Financial Interests, Institutional, Stocks/Shares: Onconostic Technologies Inc. C. Taylor: Non-Financial Interests, Institutional, Advisory Board: Onconostic Technologies Inc.; Financial Interests, Institutional, Stocks/Shares: Onconostic Technologies Inc.